Multi-sensor imaging systems have a very important role and wide applications in surveillance and security systems. In many applications, it is necessary to use an optical protective window as an optical interface connecting the imaging sensor and object of interest’s space; meanwhile an imaging sensor is mounted in a protective enclosure, providing separation from environmental conditions. Optical windows are often used in various optical and electro-optical systems, fulfilling different sometimes very unusual tasks. There are lots of examples in the literature that define optical window design for targeted applications. Through analysis of the various effects that follow optical window application in connection with imaging systems, we have suggested a simplified methodology and practical recommendation for how to define optical protective window specifications in multi-sensor imaging systems, using a system engineering approach. In addition, we have provided initial set of data and simplified calculation tools that can be used in initial analysis to provide proper window material selection and definition of the specifications of optical protective windows in multi-sensor systems. It is shown that although the optical window design seems as a simple task, it requires serious multidisciplinary approach. Multi-sensor imaging systems have a very important role and wide application areas in long-range surveillance and security systems ,2,3,4,5.An optical protective window is used as optical interface connecting the imaging sensor and object of interest space; thus, proper selection of a window’s optical performance is fundamental to guarantee that imaging channel data will not be degraded due to the window of the multi-sensor surveillance system.Optical protective windows are usually built as plane parallel plates of transparent optical material that allow undisturbed application of the imaging sensor while protecting the given system from dust and debris and providing environmental protection and vacuum seals. In addition, optical protective windows are used to protect sensitive and expensive imaging sensors from any harmful actions that could happen during system usage. The protective window design should also allow for easy window replacement. Because of this, optical protective windows are often called “sacrificing glass”.Optical windows can be designed in other more complicated shapes such as domes, segmented windows and conical sections. In addition to the fact that windows provide mechanical protection for optical systems, they are also important optical elements of these systems. Even though the windows can be simple plane parallel plates, extreme environmental conditions such as pressure and temperature variations can cause the windows to distort incoming optical signal, thereby diminishing the performance of the optical sensor.One of the most demanding applications of the protective window is the infrared (IR) dome in the missile homing head, wherein the dome is a part of the aerodynamic envelope and exposed to extreme mechanical and thermal loads; therefore, all effects must be treated seriously . The desIt seems that in multi-sensor surveillance systems, environmentally caused image degradations are not critical, but in long-range systems, the high resolution of the imaging sensors adds new requirements for window material and design quality.New challenges in defining optical protective windows’ requirements are bound to come with the application of the multi-sensor systems in autonomous driving vehicles and with the application of machine vision systems in agriculture, wherein window cleaning can be very important to provide constant readiness.One of the goals of this article is to present a condensed review of the effects that can cause image degradation. We use scientific results generated in the more complicated application cases, and define simplified guidelines for optical protective window design for application in stationary surveillance systems.For optical protective windows in the multi-sensor surveillance system containing more electro-optical (EO) and infrared (IR) imaging channels, the process of defining their requirements is treated as a system design challenge. The potential impact of the window’s properties and assembly methods on EO/IR imaging systems’ performance and sensitivity will be discussed following selected practical experience and laboratory-based simulations.First, we explore the multi-sensor systems’ generalized design and describe the role of the optical protective windows in such systems. After that, we describe the most important effects that could appear in various applications, and their influence on defining the requirements of window design. Additionally, we show some results obtained previously to illustrate how window design specifications influence the final system quality, and what can go wrong in the exploitation period.The design of optical protective windows seems as a simple task, but there are several factors a designer must be aware of when designing a window for an optical system . Optical protective window materials and coating choices are limited, so they should be carefully selected during multi-sensor system design requirements’ development. The design requirements also lead to the optimization of numerous mechanical, optical, material, and electrical parameters.The key objective of this paper is to provide a review of the most important effects of optical protective windows’ implementation in multisensory surveillance systems, and refer to the other papers with more detailed treatment. Following the surveillance systems’ specificities, we present a simplified methodology and procedures which may assist in defining initial design requirements, and which proves to be sufficient in most cases.The work presented in this paper provides a simplified methodology and practical recommendations for an easier systems engineering approach to defining optical protective windows’ specifications for multi-sensor imaging systems. This work has resulted from a system engineering approach, through the analysis of various effects that are common to optical window application in relation to imaging systems.Multi-sensor surveillance systems are adaptable modular systems composed of several imaging sensors mounted at the sensor head and controlled remotely . The desA typical multi-sensor surveillance system is shown in The Imaging Group, which contains several imaging channels providing images of the space of interest. The simplified structure of one imaging channel is shown in Daylight (low light) video imaging sensorIR imagers— imaging sensorsLIDAR sensorUV imaging sensorThe Position Sensing and Control group, which provides the sensor head’s position and orientation in the space, and collects position and orientation related data.Imaging sensors’ video signals and position sensors’ data are processed and integrated using an EO system built in computer command and control software packages. Advanced solutions for image enhancement, image stabilization and sensor data fusion may be optionally added.The basic purpose of an optical protective window in a complex electro-optical system is to provide a clear optical aperture and to keep the optical sensor enclosed and separated from outside environmental influences. The window should be designed to provide minimal degradation of the optical sensor performance and to protect sensitive parts from harsh environmental impact. This means that the window will be exposed to all environmental influences, and because of that, window design and sealing methods applied should be rigid enough to minimize mechanical and thermal distortions.The desirable characteristics of an optical window are listed below.○Low absorption of transmitted light○Low reflection of light incident on the surfaces of the window○Low refraction (or bending) of the transmitted light rays○Low scattering to minimize stray light influence and contrast degradation○Minimum distortion of the transmitted beam due to imperfections in the optical material or the surface finish, keeping wave front undisturbed and image sharpness unchanged○Durable and not susceptible to damage, having an ability to withstand degradation from environmental causes. This may include strength, resistance to water or temperature, etc.With the use of a protective window in the system, we introduce a new optical element which will influence the imaging sensor’s overall optical performance. The insertion of an optical protective window on the image optical path may introduce several potential problems, including(a)reduced transmission resulting from the reflection, absorption, and scattering of the window material, causing reduction of the operational range of the sensors ,(b)contrast reduction caused by lack of control of the reflected and scattered energy in the window material,(c)a further increase in scatter or reduction of transmission by environmental effects such as erosion, or accumulated dust and dirt on the window surface,(d)an increase in the wave front aberrations due to the window shape, the window clear optical opening, and the positioning of the associated imaging system,(e)further aberrations induced in the window, caused by the mechanical and thermal effects during exploitation.The typical protective window application and key parameters’ definitions are illustrated in W—window thickness [mm]TW—window diameter [mm]DSA—lens input aperture [mm]DOW—window optically clear area [mm]DM—window mounting area width [mm]WW—window–lens distance [mm]ZFOV—imaging sensor maximal field of view [degrees]Θtilt—window tilt angle [degrees]Θ(a)Window material and coatings;(b)Window thickness;(c)Window position and tilt to sensor optical axes; and(d)Window shape and sealing technique.In the case of the plane parallel plate, there are several key design parameters that should be defined during the design process:In critical applications, the window impact will require more precise study, which then should be included as an integral part of the lens design analyses. All influences and processes, as illustrated in Accelerations, pressure differentials, other mechanical forces and thermal perturbations will affect both surface flatness and optical homogeneity.Thermal effects can generate the following simultaneous effects on the protective window optical properties: (a) temperature dependence of the optical window material optical properties, (b) non-uniform temperature distribution over window opening, and (c) thermally induced shape changes.Excellent thermal optical performances of the optical window are fundamental to guarantee that the imaging system will operate normally. In order to decrease the potential influence of the deformation of the window surface caused by thermal stress, an athermal design to decrease the thermal stress of optical window is an additional requirement of the selected window mounting and sealing method.Derivation of the optical protective window requirements and definition of the protective window key design requirements should be carried out after an integrated multidisciplinary analysis ,19,20 whOptical phenomena in the window material  are extrAdditionally, we should be concerned with additional optical effects induced by external thermal and mechanical stress influencing the optical beam; thermally induced aberrations due to index of refraction temperature dependence and non-uniform heating; thermally induced birefringence in windows; and elasto-optic effects and material surface shape change due to mechanical stress, etc. In addition, we should be concerned with material mechanical properties’ ability to provide rigidity of design.Protective optical window material properties are carefully reviewed ,24,25,26The surface quality of an optical window is determined by evaluation of surface imperfections that may be caused during manufacturing or handling. These defects typically cause small reductions in throughput and small increases in scattered light, which have little to no adverse effect on the overall system performance in most imaging or light gathering applications. However, some surfaces are more sensitive to these defects, such as surfaces at image planes, because surface defects are in focus. Windows used with high power level lasers are also sensitive to surface defects because they can cause increased absorption of energy and damage the window.Surface quality is often described by the scratch-dig specification in the U.S. Standard MIL-PRF-13830B . The scrImaging sensor spectral sensitivity defines basic window optical material selection. Electro-optical and infrared imagers are designed for limited spectral sensitivity related to particular spectral regions, as illustrated in The imager’s spectral sensitivity band is a starting point for optical protective window spectral transmission band definition and window optical material initial selection.The interaction of optical radiation with the optical protective window, as illustrated in Radiation scattering and absorption in the window material contributes to a reduction in the imager’s sensitivity (transmission losses) and image contrast reduction. These effects can be minimized using high-quality  base material.Window surface reflection could contribute to the stray light spreading through the imager’s lens system, causing ghost images formation and/or image contrast reduction. The reflection, r, from the window boundary surface (Fresnel reflection losses), depends on optical material index of refraction, n:Surface reflection is very high for materials with a high index of refraction. In order to reduce surface reflection, various techniques are applied to modify component surface  using diAnti-reflective coatings (ARCs) have evolved into highly effective reflectance and glare reducing components for various optical materials with wide application in industry. The ARCs for infrared (IR) optical substrates  are moreVeiling glare is unwanted light in an image arising from reflections and scattering within the system. Such reflections occur from component surfaces, component edges and mounts, sides of barrels, stops and diaphragms, and scattering occurs from component surface defects and contaminants, bulk defects and diffusely reflecting surfaces . Light tIn visible light systems, double-reflection ghosts are caused by double-reflection ghost of the sunlight or other dominant illumination source. In an infrared system, a cryogenically cooled detector, having low radiance, acts somewhat like sunlight but generates a dark (low temperature) area in the image. This effect is called the narcissus phenomenon ,38 and hOptical protection windows are directly exposed to all environmentally generated influences. Because of this, it is important to examine how the physically generated effects affect overall window performance. Temperature-related effects and mechanical effects could cause optical protective window performance degradation. Aero-optical effects are the best example of how severe physical influences combined with optical window properties may be. Although aero-optical effects could not be found in the common surveillance systems applications, we review them in the Ambient temperature can have influence on window heating, leading to window thermal expansion and change of index of refraction. Window thermal expansion can be easily compensated through proper window mounting design  and hardness ,24,25 haThe strength of an optical material is governed by the random distribution of the size, orientation, and location of the surface flaws or inner material flaws in relation to the regions under stress . SurfaceIn addition, stress propagation inside a material depends on the window mounting condition , so a prIn optical protective windows in surveillance systems, stress causing fractures is rare, but optical distortion caused by external stress is the most common case. There are different definitions of the distortion influences and different methods for their evaluation . The mosOptical protective windows intended for application in surveillance systems are sensitive to surface damage caused by mechanical effects (scratches) related to the optical material, or coating hardness or durability.Long-range observation systems are designed to operate under harsh environmental conditions while demanding outstanding detection, recognition and identification (DRI) range capabilities, superb image quality, and accurate line-of-sight (LOS). EO/IR windows design is a significant challenge for the long range surveillance system designer who must specify it for high EO performance, durability, producibility and affordable initial and life cycle costs. This is particularly true in the LWIR band, at which window materials and coating choices are limited by the system’s design requirements. The requirements also drive the optimization of numerous mechanical, optical, materials, and electrical parameters. EO/IR imaging system window design is a challenge, as illustrated in Optical specifications and requirements cover a wide range of needs . FunctioThere are two types of specifications that must be applied to an optical protective window: mechanical tolerances of the shape that indirectly affect the optical quality, and specialized descriptions related to materials that directly affect the image quality.The specification of a material requires identification of the material type, and data on the homogeneity class, birefringence, and so on. The method of specifying optical material varies with the material type and manufacturer ,51. It iThe optical material index of refraction and Abbe number, together with the spectral transmission band, define the material basic optical properties.Requirements for refractive index and dispersion coefficientRequirements for optical uniformityRequirements regarding birefringenceRequirements regarding light absorptionRequirements regarding stripes, bubbles and striae.The general requirements for optical materials are as follows:birefringence, the refractive index depends on the direction from which the light enters the crystal, and on the light’s polarization. This phenomenon characterizes some crystalline and plastic optical materials.In Striae are frozen regions of refractive index non-uniformity which cause lines of refractive index inhomogeneity within the bulk material. Their effect on precision optics is similar to the aberrations. When present in a transmissive optical element, striae can cause a phase shift of the light that passes through it.Cracks and inclusions are breaks in the uniformity and continuity of the glass. They cause scattering sites and also interrupt the phase of the light that passes through the glass. Additionally, they may serve as a seed for material crack under stress. All of these flaws should be minimized during the fabrication of precise optical elements, and they should be evaluated during quality assurance testing.The optical material selected for optical protective windows can be described as optical grade material, meaning that material properties should be suitable for high-precision components, having low tolerance margins for all selected material parameters.In the design of optical protective windows, one must take care of the following basic material optical properties listed below, although material mechanical and temperature properties are equally important considerations.Transmittance ;Surface reflection; andIndex of refraction.The most important properties of optical windows are as follows:w is:1 and t2 are surface transmission, μ is the material absorption coefficient, and tW is window thickness.Window total transmission TA lower index of refraction means lower surface reflection and higher window overall transmittance.For normal application of a protective optical window, a key requirement is a suitable spectral transmission range. The applicable spectral range of selected materials suitable for optical protective windows is illustrated in The surface specifications of optical windows affect their optical performance and must be considered when selecting or specifying a window. It is important to make sure your optical window has the appropriate specifications with respect to tightness to meet your application requirements, but over-tolerancing the window will unnecessarily increase the cost.Surface quality is usually described using surface flatness and irregularity definition, parallelism (wedge) tolerance and cosmetic scratch and dig properties. Surface roughness can be measured absolutely and defined using mean roughness amplitude and maximal peak-to-valley amplitude. Surface flatness is commonly tested by comparing the interference pattern generated when the tested surface is compared with perfectly flat test surface interference. In this case, the analysis of the interference fringe shape and curvature provides enough data to measure the surface accurately. The surface flatness description and definition criteria are presented in Due to the different roles of optical protective windows in surveillance systems, requirements for optical material quality could vary widely, but design requirements derived from image quality requirements are similar. Selected tolerances that can be applied for optical protective windows are presented in Scratches and digs are optical protective window surface or coating flaws that can greatly affect the optical performance of a coating. Scratches are lines that are cut along the outer surface of a precision optical element, and digs are tiny pits in the surface. Both can cause scattering sites that limit the transmission through and optical quality of a surface.The thin film coatings (protective and antireflective) that are applied to the optical protective window surfaces require careful consideration. In general, the spectral characteristics, such as passband and maximum reflectivity, need to be specified for an antireflection (AR) coating. Examples of typical AR coating spectral reflection curves for several spectral bands are presented in Requirements for environmental stability also need to be described, with reference to tests for film adhesion and durability. Generally, the optical coatings’ durability specification is the most important and the most difficult task. The coating supplier will have a set of “in-house” specifications that will guarantee a specific result that can be used as the basis for the coatings’ specification. In accordance with the importance of the optical coatings, nowadays, there are standards ,55,56,57During the optical coating manufacturing process, it is common practice to produce a so-called test (witness) piece or sample.Witness samples are typically flat, 1”-diameter windows that are made of the same material, undergo similar processing, and have identical coatings to the optical protective window. They are created to represent the optical properties of the optical protective window, thereby ensuring optical window quality control  and durability of the applied coating.Based on the fracture mechanics analysis, the thickness of the optical window should be determined to ensure the window design is reasonable and reliable.Considering the complex environment, steady-state temperature fields should be determined and temperature load included in overall force load. The expected deformation of the optical window under the structure–thermal coupling condition should be calculated. In the case that expected deformations are higher than selected critical values, detailed optical analysis should be conducted to predict the impact of the deformation of the optical window on the optical performance of the multi-spectral camera. In most cases of optical protective windows’ application in surveillance, the impact of the optical protective window’s deformation on the imaging quality of the optical system is negligible.The mechanical strength of the optical protective window depends on the window’s thickness, optical material strength and optical window mounting options. The most common mounting options are presented in Modulus of Rupture, frequently abbreviated to MOR (and sometimes referred to as bending strength), is a measure of a specimen’s strength before rupture. It can be used to determine a material sample’s overall strength .Wt-window thickness [mm]WA-unsupported window area diameter [mm]W, WWL-window length and widthR-W/WWratio LWK-support-related empirical coefficient (from 0.75 for a clamped window to 1.25 for an unclamped window)Sf-safety factor FS-modulus of rupture, expressed in [psi]WΔP-pressure difference, expressed in [psi]In the case that the optical window is used for separation between two media with different pressures, the minimal window thickness can be calculated , using ENOTE: psi—pound per square inch = 7 kPa = 0.007 MPa; 1 atm = 14.7 psi = 101.324 kPa,Wt-window thickness [mm]WA-unsupported window area diameter [mm]1K-empirical coefficient (from 1.71 for a clamped window to 0.696 for an unclamped window)E-Young’s modulus of elasticity (mpa)WΔP-pressure difference (mpa)Deflection through a circular window due to pressure difference could have some influence on the window’s optical power, introducing degradation to optical sensor performances. The maximal deflection for a circular window can be calculated  using EqOnce the window thickness is determined according to the selected clamping and sealing design, it is useful to check window deflection for design conditions. Usually, the deflection value is negligible so the calculated minimal thickness can be used as design thickness; otherwise, we need to increase the thickness until the deflection achieves a satisfactory value. In the worst-case scenario, we need to carry out a detailed optical analysis to optimize the window shape.Optical protective windows in the stationary surveillance systems are not exposed to aerodynamic heating; usually only solar thermal radiation and ambient temperature contribute to window temperature. Elevated window temperature contributes to additional background noise in infrared thermal imaging channels.The temperature of optical protective windows should be considered during mounting design selection to avoid additional stress due to different material temperature expansion coefficients. In the case that thermal expansion could cause issues, the un-clamped mounting design is more suitable.In the case of a circular optical protective window, one can calculate window size. Using the notations of Once the optical protective window is defined  proper mechanical drawing should be produced according to standards applicable to optical components ,60.In the case that plastics materials are used, one needs to take care of their specific properties .The design process for optical protective window for application in surveillance systems is illustrated in Optical protective window design is iterative process that should determine the following factors.Window material and coatings: The imager spectral sensitivity range should be used for initial optical material selection. Final optical material selection should follow window mechanical strength limitations.Window thickness: Optical protective window thickness should be determined using Equation (4) or (5), and refined after window deflection is checked (Equation (6)).Window position and tilt to sensor optical axes should follow the available space in the mechanical envelope and stray light influence analysis.Window shape and sealing technique should be determined according to application requirements, mechanical envelope and cost.The design process of an optical protective window should provide proper functioning for application within a surveillance system and allow for easy replacement in case of damage.Practical issues that appeared in our surveillance system application triggered our interest about protective window design and related AR coating application. An example of these issues is the appearance of ghost images when protective window glass without AR coating was applied shown in . Our lonIn The second group of experimental results is related to experimental evaluation of the optical protective window’s influence on the imaging system’s performance.In In The third group of experimental results is related to simulated experiments in laboratory environment to demonstrate how protective window can influence image. In these experiments, we used a protective window with an AR layer only in the central part of the window, as illustrated in Experiment 1 is designed per the setup shown in Experiment 2 is designed per the setup shown in Experimental results showed that optical protective windows can cause issues and degrade images; images may also be damaged because of their unsuitable design, emphasizing the importance of their proper design.The selected results of the evaluation of the multi-sensor imaging systems using an optical protective window show that optical protective windows can be designed and applied without noticeable degradation of images; however, they can cause degradation, even when well designed, when they are not properly selected in accordance with the imager’s properties.The results of these specially designed experiments show some of the effects that optical protective windows can have on the imaging chain, influencing image quality and content.The wide application of multi-sensor electro-optical surveillance systems is supported by the successful development and mass production of the focal plane array, or FPA, image sensors. In the majority of applications, key attention was paid to multi-sensor system integration and advanced image processing issues. During this time, more applications were in a harsh environment, requiring application of an optical protective window to isolate imagers from environmental influences. Nowadays, the application of optical protective windows is common in the most deployed systems.The design and application of optical protective windows in surveillance systems seems to be a relatively easy task, but in real applications it can cause failures that require a great effort to be corrected. These failures show that real solutions need a more rigorous approach that uses multidisciplinary analysis and application of rigid evaluation techniques in the design phase. At the same time, experience and development results from the area of protective aerodynamic domes in missile systems, in which more harsh effects exist, have generated a knowledge base which will aid in better understanding of the effectiveness that an optical protective window can have in delivering proper solutions.We analyzed the most important processes and influences that could be caused by applying optical protective windows to imaging systems. Using the results of this analysis, we derived a simplified methodology for optical protective window design that can deliver initial window designs. At the same time, we have shown that a rigorous multidisciplinary approach is necessary for full evaluation of optical windows’ performance.The application of the multidisciplinary knowledge and scientific methodologies in engineering is always necessary for delivering proper design solutions. Good understanding of the processes involved leads to proper selection of technical requirements and easier troubleshooting in the case of failure.


Hypertensive disorders of pregnancy and maternal diabetes profoundly affect fetal and newborn growth, yet disturbances in intermediate metabolism and relevant mediators of fetal growth alterations remain poorly defined. We sought to determine whether there are distinct newborn screen metabolic patterns among newborns affected by maternal hypertensive disorders or diabetes in utero.A retrospective observational study investigating distinct newborn screen metabolites in conjunction with data linked to birth and hospitalization records in the state of California between 2005 and 2010.A total of 41,333 maternal–infant dyads were included. Infants of diabetic mothers demonstrated associations with short-chain acylcarnitines and free carnitine. Infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia had alterations in acetylcarnitine, free carnitine, and ornithine levels. These results were further accentuated by size for gestational age designations.Infants of diabetic mothers demonstrate metabolic signs of incomplete beta oxidation and altered lipid metabolism. Infants of mothers with hypertensive disorders of pregnancy carry analyte signals that may reflect oxidative stress via altered nitric oxide signaling. The newborn screen analyte composition is influenced by the presence of these maternal conditions and is further associated with the newborn size designation at birth. The NBS has also been used as a means of identifying altered metabolic states of the newborn associated with clinical disease unrelated to primary genetic or metabolic diagnoses.10 These studies demonstrate that the NBS can yield important insights on metabolic disturbances associated with conditions other than genetic inborn errors of metabolism, including gestational dating, and the risks of acquired diseases of the newborn, including sepsis, respiratory distress syndrome, hyper-bilirubinemia, persistent pulmonary hypertension, necrotizing enterocolitis (NEC), hypoxic–ischemic encephalopathy, and mortality. However, the impact of common maternal conditions such as diabetes and preeclampsia that may affect newborn metabolic function as reflected in the NBS has not been widely explored.11 This knowledge gap is important as the NBS metabolic composition is influenced by the intrauterine environment and immediate postnatal transition to extrauterine life.13 Although there are studies that have evaluated the metabolic composition of newborns vis-à-vis the newborn growth status,15 we are not aware of prior investigations that assess the metabolite composition of the newborn via the NBS for normal and growth-altered states secondary to maternal conditions.The newborn screen (NBS), obtained via heel stick dried blood spot collection, is a population metabolic screening test for inborn errors of metabolism conducted by individual states on all newborns shortly after birth.16 Growth as measured by anthropometric indices is largely defined by epidemiologic standards and reference curves20 that help clinicians weigh clinical risk of disease.21 For the fetus and newborn, the maternal diabetic and hypertensive disorder phenotypes are most profoundly expressed via metabolic-dependent processes that manifest in extremes of newborn size and include large for gestational age (LGA) and small for gestational age (SGA) designations.23 The birth weight for age designation of the newborn is critical, as significant short- and long-term morbidity and mortality risk occurs secondary to in utero growth disturbances. In addition, extremes of birth weight place the infant at heightened risk for adult metabolic disease.24 Despite these sequelae, little is understood about the relationship between maternal disorders of pregnancy, infant size, and effects on the newborn metabolome.The effects of maternal diabetes and hypertensive disorders on the fetus are often reflected in growth parameters that are measured throughout gestation and at birth.The objective of this study was to determine whether there are distinct NBS metabolic patterns among newborns affected by maternal hypertensive disorders and diabetes in utero. We hypothesized that the effects of maternal diabetes and hypertension on newborn metabolism and clinical growth phenotypes, manifested as birth weight, can be quantified using universally applied NBS analytes. Additionally, we posited that the NBS analyte composition will enable us to develop a metabolic model of fetal growth outliers. These findings are potentially significant as greater mechanistic understanding of the means by which the intrauterine environment contributes to newborn biologic vulnerability for acquired diseases associated with the growth altered fetus is needed.We analyzed 41,333 singleton live births from a total of 3,175,992 singleton live births in California between 2005 and 2010 by merging California Perinatal Quality Care Collaborative (CPQCC) and California Office of Statewide Health Planning and Development (OSHPD) birth and hospitalization records with California Biobank NBS analyte data . NBS col25Records obtained from the California GDSP included live born infants at 20–29 weeks gestation, a proportion of whom carried diagnoses of NEC, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and intraventricular hemorrhage (IVH). Records also included a random sampling of liveborn infants born at 30–44 weeks gestation, none of whom carried diagnoses of NEC, ROP, BPD, and IVH. From this case–control collection of infants, we obtained NBS metabolite measurement values from the California State Biobank and linked this with demographic information and clinical data for both the newborn and the mother obtained from OSHPD and CPQCC. These pooled records favored inclusion of premature infants, as 33% of the study population included infants born at <37 weeks gestation. This enabled us to more robustly examine for the presence or absence of maternal conditions that may lead to early preterm birth such as preeclampsia and more easily compare preterm and term populations. Certain demographic and clinical data elements were converted to categorical form. Additionally, gestational age records were converted to 2-week intervals and birth weights were converted to 50-g intervals. All forms of diabetes and hypertensive disorders were defined using International Classification of Diseases (ICD)-9 code definitions that were part of the hospital record . Size foK-fold cross-validation loop on the training set to select an optimal strength of regularization for metabolite feature selection using area under the receiver-operator curve (AUROC) as the selection criteria for hyperparameter values. The optimal hyperparameters were then used in a new model that was evaluated on the test set. Performance was evaluated on the basis of AUROC for model predictions made on test set samples. Model coefficients were collected at the end of each tenfold cross-validation iteration to identify metabolites that were the most predictive in identifying infants from mothers with various conditions. For analysis of SGA and LGA outcomes of infants from mothers with hypertensive or diabetic disorders of pregnancy, additional regression correction was performed for the potentially confounding covariates of cigarette smoking, body mass index, gestational age, and maternal age. Models were then trained using residual metabolite values after covariate correction.To determine NBS analyte associations with maternal outcomes of interest including maternal diabetes and hypertensive disorders of pregnancy, we used elastic net logistic regression modeling with repeated tenfold cross-validation. The elastic net modeling assumed statistical independence between all metabolite variables enabling us to observe metabolites reflective of a given maternal condition. NBS metabolite values were used as input features for elastic net logistic regression. Binary indicators were used for the presence or absence of a given maternal outcome and were subsequently used as labels for model training. Controls were defined as mothers who did not have ICD-9 code definitions of any form of diabetes or hypertensive disorder of pregnancy. Hyperparameter tuning was performed on an inner The maternal and neonatal characteristics from the dataset are depicted in Individual NBS metabolic analytes were also used to develop a model via elastic net regression to identify mothers with analytes reflective of all forms of diabetes, including gestational diabetes, type 1 diabetes, or type 2 diabetes. Similarly, NBS analytes were used to develop a model of maternal hypertensive disorders . For thex-axis) and LGA infants with any form of diabetes (y-axis). Elastic net regression was used to identify predictive analytes implicated, with Spearman correlation coefficients used for validation. Notable analytes associated and predictive of LGA infants born to diabetic mothers include glycine, C5-OH, C3, and long-chain acylcarnitines C14, C16, C18, and C18:1. Further, the variable of infant size for gestational age was introduced to the model and overlaid with our prior modeling for diabetes and hypertensive disorders to determine whether there were analytes specific to the LGA designation with and without diabetes. 29 Second, for infants born to mothers with a hypertensive disorder of pregnancy, there are significant changes in analytes that may promote oxidative stress via altered nitric oxide signaling and abnormal lipid metabolism. Metabolites implicated in these pathways include C2, ornithine, citrulline, and free carnitine.33 Lastly, the analyte composition in the newborn is associated with a growth phenotype , and this association is further influenced by the presence or absence of maternal diabetes or hypertension. We posit that with further investigation the analyte composition may act as a biological taxonomy for the growth altered fetus, extending the definitions of the SGA and LGA newborn and associated clinical risk by reflecting underlying biological processes, rather than relying on anthropometric indices alone.To our knowledge, this study is the largest to demonstrate that there are characteristic metabolic signatures observed in newborns who have been delivered by mothers who had common conditions of pregnancy, including hypertensive and diabetic disorders. This study provides at least three novel findings. First, the metabolic signs of insulin resistance are already present in infants born to diabetic mothers, as evidenced by positive associations with short-chain acylcarnitines and free carnitine, both of which have been found to be elevated in various metabolomic studies in animal models and patients with diabetes.11 Jelliffe-Pawlowski et al. found that the NBS metabolites could predict gestational age and that size for gestational age was a variable that changed the predictive ability of their model.10 A range of studies have utilized NBS metabolites to predict newborn and pediatric conditions, with varying degrees of success.36 Our results extend the extant literature in several ways. NBS metabolites demonstrate a good ability to reflect infant metabolic alterations associated with diabetic and hypertensive disorders of pregnancy. As demonstrated in Few prior studies have examined NBS metabolites to identify metabolic signatures associated with pregnancy disorders that also affect the newborn. Ryckman et al. observed that mothers with preeclampsia had newborns with higher concentrations of acylcarnitines and free carnitine on their NBS compared to non-preeclamptic mothers.37 For instance, it has been postulated that in obese individuals various metabolic signaling pathways lead to elevations in branched chain amino acids and mechanistic target of rapamycin signaling, which result in elevations in C3 and C5 acylcarnitines.38 C2 is also notable, as it associated with insulin resistance and directly correlates with hemoglobin A1C levels in adults, perhaps via its role in substrate switching at the level of the mitochondrial membrane.29 In sum, associations with short-chain acylcarnitines, C5-OH, and free carnitine in neonates born to diabetic mothers suggests that the metabolic signs of insulin resistance may already be present at birth. In fact, changes in nutrition status over long periods of time can create an imprint or “memory” of a metabolic disturbance that is passed down to offspring via germ-line epigenetic changes.42 Our investigation suggests that this effect may have been present for newborns exposed to maternal diabetes and is reflected in the NBS metabolites shortly after birth. Future studies that selectively examine infants from pregnancies with well and poorly controlled diabetes may help clinicians to understand, target, and design mitigating strategies to prevent short- and long-term sequelae of in utero hyperglycemia exposure.Since NBS analytes have been chosen by design to reflect metabolic disturbances associated with specific genetic and/or metabolic diseases, the analytes themselves robustly reflect alterations in specific lipid and protein metabolic pathways. Accordingly, through a detailed examination of the rank order of coefficients for those analytes associated with a specific maternal morbidity  and 3, i43 While ornithine was positively predictive for infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia, citrulline was negatively predictive for infants born to any cohort of hypertensive disorders of pregnancy  are mediated via changes in these pro-inflammatory mediators, it is possible that elevations in long-chain acylcarnitines in LGA infants of diabetic mothers deleteriously impact an already sensitized inflammatory milieu. When examining SGA infants born to preeclamptic mothers  change the analyte composition longitudinally. Moreover, our findings were derived from a case–control study, and thus there was an oversampling relative to the population base of preterm infants. To the extent that our prediction models are unique to preterm infants, we are not indicating specific metabolite screening cutoffs be inferred from this work. Future investigations on a population cohort are necessary to determine whether recommendations of metabolite cutoffs might be warranted. Lastly, given that the NBS is a clinical application of targeted metabolomics limited to a few dozen analytes designed to alert to the possibility of specific heritable diseases, we speculate that future non-targeted metabolomic studies capable of examining hundreds to thousands of additional analytes will reveal ever greater biologic insight and clinical precision for applications in maternal and neonatal disease.This is one of the largest studies to date using standardized NBS laboratory methods to assess the metabolic profile at birth of >40,000 newborns, with linked results to the presence or absence of maternal disease and corresponding newborn size designation at birth. However, there are a few limitations of this study. The sample population was not random as this was a population study that selected infants for specific diseases of prematurity. Because many mothers who had preeclampsia delivered prematurely, it is possible that the metabolites in these infants reflect metabolism at younger gestational ages. There are also some variables such as birth weight, exposure to total parenteral nutrition, blood transfusions, enteral intake, and timing of NBS collection that were not entirely controlled for. Further, maternal conditions such as diabetes and hypertensive disorders of pregnancy may contribute to both maternal and fetal oxidative or catabolic stress.Supplementary Material


By 2030, approximately 75 million adults will be living with Alzheimer disease and related dementias (ADRDs). ADRDs produce cognitive, emotional, and behavioral changes for persons living with dementia that undermine independence and produce considerable stressors for persons living with dementia and their spousal care-partners—together called a “dyad.” Clinically elevated emotional distress  is common for both dyad members after ADRD diagnosis, which can become chronic and negatively impact relationship functioning, health, quality of life, and collaborative management of progressive symptoms.This study is part of a larger study that aims to develop, adapt, and establish the feasibility of Resilient Together for Alzheimer Disease and Related Dementias (RT-ADRD), a novel dyadic skills-based intervention aimed at preventing chronic emotional distress. This study aims to gather comprehensive information to develop the first iteration of RT-ADRD and inform a subsequent open pilot. Here, we describe the proposed study design and procedures.All procedures will be conducted virtually (via phone and Zoom) to minimize participant burden and gather information regarding feasibility and best practices surrounding virtual procedures for older adults. We will recruit dyads (up to n=20) from Mount Sinai Hospital (MSH) clinics within 1 month of ADRD diagnosis. Dyads will be self-referred or referred by their treating neurologists and complete screening to assess emotional distress and capacity to consent to participate in the study. Consenting dyads will then participate in a 60-minute qualitative interview using an interview guide designed to assess common challenges, unmet needs, and support preferences and to gather feedback on the proposed RT-ADRD intervention content and design. Each dyad member will then have the opportunity to participate in an optional individual interview to gather additional feedback. Finally, each dyad member will complete a brief quantitative survey remotely  via a secure platform to assess feasibility of assessment and gather preliminary data to explore associations between proposed mechanisms of change and secondary outcomes. We will conduct preliminary explorations of feasibility markers, including recruitment, screening, live video interviews, quantitative data collection, and mixed methods analyses.This study has been approved by the MSH Institutional Review Board. We anticipate that the study will be completed by late 2023.We will use results from this study to develop the first live video telehealth dyadic resiliency intervention focused on the prevention of chronic emotional distress in couples shortly after ADRD diagnoses. Our study will allow us to gather comprehensive information from dyads on important factors to address in an early prevention-focused intervention and to explore feasibility of study procedures to inform future open pilot and pilot feasibility randomized control trial investigations of RT-ADRD.PRR1-10.2196/45532 Alzheimer disease and related dementias (ADRDs) are already experienced by 55 million individuals worldwide, and this number is projected to increase to roughly 75 million by 2030 . ADRDs pFrom symptom onset to receiving a formal or suspected diagnosis, both persons living with dementia and their spousal care-partners experience substantial changes in roles, plans, and expectations ,10,11. WBoth individuals living with ADRDs and their spousal care-partners describe having insufficient support and a lack of resources to assist them in managing early symptoms, expressing personal needs, and learning to address shared challenges together ,27. DyadDyadic interventions delivered early after ADRD diagnoses may be an optimal avenue for promoting adjustment to the challenges experienced by persons living with dementia and their spousal care-partners while they are still able to engage collaboratively in treatment and care planning. Such approaches are capable of simultaneously providing both partners with individual and interpersonal skills training to (1) effectively cope with adversity, thereby reducing emotional distress, and (2) preserve the quality of life by maintaining identity and normalcy, preserving social connections, and communicating to better navigate shared challenges and long-term care plans . Dyadic Early dyadic interventions have the potential to promote positive adjustment to ADRD by improving dyads’ individual and interpersonal resiliency   and provMembers of our team developed Recovering Together, a brief dyadic resiliency intervention that prevents chronic emotional distress in patients and informal care-partners shortly after intensive care unit admission for acute neurological conditions  ,50. ThisThis study was approved by the Mount Sinai Hospital (MSH) Independent Review Board (22-01623).We are currently conducting a mixed methods investigation involving persons living with ADRD and their romantic or spousal care-partners . This study is designed to (1) gather impressions of dyads’ challenges and needs early after ADRD diagnosis, and (2) obtain feedback on proposed RT-ADRD program procedures  and intervention content. Quantitative assessment measures will be used to explore the feasibility of assessment procedures and gather data to explore preliminary associations among hypothesized intervention mechanisms and target outcomes see .We will recruit dyads with English fluency and literacy who are willing to participate and comply with the requirements of the study (including surveys and an interview). Eligible persons living with ADRD will be individuals aged 65 years or older who have a chart-documented ADRD diagnosis within the past month, ADRD symptom onset after the age of 65 years, and cognitive assessment scores and symptoms consistent with early-stage dementia  and appreciation (recognition of factors that apply to that person) of the presence and severity of cognitive impairment. Results of these assessments are included in patient’s medical records, and can be used as a metric for facilitating appropriate referrals. Treating providers will confirm diagnoses of ADRDs and clear patients for participation in the study before facilitating referrals. Potential participants will first hear about the study from their treating providers, who will introduce the study around the time of diagnostic disclosure and provide interested dyads with a study flyer. Providers will also obtain permission for the dyad to be contacted by the research team for recruitment purposes.With dyads’ permission, providers will refer potentially eligible patients by sharing relevant dyad information with the study team, including (1) patient and spouse names and contact information, (2) medical record numbers, (3) diagnosis, and (4) date of diagnosis. Dyads can also contact the study team directly via a screening survey accessed through the study flyer on the Research Electronic Data Capture (REDCap) program. The research team will contact dyads via email to complete screening procedures using the REDCap survey and a screening call (Zoom video or telephone). The screening call will be used to provide dyads with more information about the study, answer questions, and assess eligibility. A member of the research team will speak with persons living with ADRD and spousal care-partners individually while administering initial screening measures to ensure privacy. Once determined eligible on these initial measures, dyads will have the option to complete the remaining screening and consent procedures individually or together according to preference. If either dyad member is deemed unable to meaningfully participate in the study based on screening procedures  but is eligible based on the remaining criteria, the study staff will provide the dyad with a resource sheet containing local and national resources for ADRDs. If eligible, a member of the research team will document informed consent for dyads using an e-consent feature on REDCap.Individuals’ ability to understand the study and research protocol will be determined by a standardized teach-back method. Research staff will receive extensive training and supervision to administer the assessment, which will consist of the 10-item UBACC scale . Scores After both dyad members consent to participate in the study, a member of the research team will schedule a 60-minute joint interview with a PhD-level clinical psychologist with expertise in conducting dyadic interviews. In advance of the interview, we will send dyads an interview guide with potential discussion topics and tips for using the secure live video software. A member of the research team will also be available to provide technology support and orientation to Zoom before and during the scheduled interview session. During the 60-minute interview, the clinical psychologist will follow a semistructured interview guide see . AnotherFollowing the completion of the qualitative interviews, we will send each dyad member a quantitative survey to complete individually via the web-based REDCap platform which will take approximately 30-50 minutes to complete. Dyad members will have the option to complete the survey independently or over Zoom with assistance from a member of the research team. If completing the survey over Zoom, the research team member will use the “Share Screen” feature to gather responses to survey items and progress through the questionnaires. Questionnaires were selected to gather additional information surrounding the hypothesized intervention targets , and outcomes, as well as selection criteria for individuals to target in the context of an early dyadic intervention. We selected questionnaires for the survey that each have strong psychometric properties and were feasible and acceptable in prior dyadic studies. Survey responses will be stored on the REDCap platform and accessed via password-protected laboratory computers. Paper data files (with coded subject identification) will be stored in a locked filing cabinet accessible only to the research team.We selected demographic variables to assess factors that may impact dyad experiences and adjustment to ADRD diagnoses. We will collect information on participants’ gender, age, race, ethnicity, marital status, education level (number of years in school), employment , and mental health history.We selected clinical characteristics to assess dyads’ experiences in the context of their ADRD symptoms and medical care. For the person living with dementia, we will collect information on their ADRD diagnosis and symptoms via electronic medical records, including clinical characteristics, type of diagnosis, age at diagnosis, and date of diagnosis.We selected proposed outcomes based on prior research documenting the prevalence and correlates of emotional distress and low quality of life among dyads experiencing dementia and recent calls for interventions to promote positive adjustment early after diagnosis. We will use the 14-item Hospital Anxiety and Depression Scale (HADS)  total scWe selected treatment targets assessing individual and dyadic coping and relationship functioning based on our hypothesized mechanisms underlying changes in proposed outcomes . We will use the 12-item Cognitive and Affective Mindfulness Scale, Revised (CAMS-R)  to assesAudio data from dyadic and individual interviews will be transcribed verbatim using a transcription service and then deidentified. We will upload and analyze deidentified transcripts using the Dedoose qualitative analysis software . Our appWe will use descriptive statistics to characterize the number and proportion of individuals approached, screened for eligibility, screened eligible, consented, and retained through interviews and surveys. For proposed outcome measures and treatment targets, we will calculate means and standard deviations of scores for each dyad member, and average scores of each dyad member to assess average responses across dyads. We will examine preliminary associations between treatment primary targets and emotional distress and quality of life outcomes using bivariate correlations. In addition, we will conduct a preliminary assessment of dyadic interdependence (similarity in patterns of responses) by calculating bivariate correlations of dyad members’ scores on survey composites.We will use a convergent parallel mixed methods approach to evaluate and interpret qualitative and quantitative findings simultaneously ,69. ThisThis study is funded by the National Institute on Aging grant 1K23AG075188 to SMB, who recently moved to MSH. This study was approved by the institutional review board of MSH. Recruitment started in April 2023. Data collection is anticipated to be completed by September 2023, and data analysis is anticipated to be completed by November 2023.Receiving a diagnosis of ADRDs can have a devastating impact on individuals and their care-partners given the lack of available ameliorative interventions or cures and insufficient support early postdiagnosis ,34. PrioThis paper describes a mixed methods study design that is part of the development phase of a larger study that aims to develop a novel postdiagnosis dyadic resiliency intervention for couples facing ADRDs. We describe the study aims and details of the procedures for recruitment, screening, data collection, and data analysis. This description is valuable for future studies focused on the adaptation and tailoring of dyadic interventions for ADRDs as well as other chronic and progressive conditions. Results of this trial will critically support the development of the first version of the proposed RT-ADRD intervention content and procedures. In addition, findings can be used in conjunction with our prior study of ADRD medical stakeholders to elucidate ways of integrating the RT-ADRD intervention and other supports within existing clinical infrastructures, and to navigate barriers and facilitators to dyads’ recruitment and participation in the RT-ADRD intervention. Our approach is consistent with National Institutes of Health stage model recommendations  to leverThis mixed methods study aims to gather comprehensive information from persons living with dementia and their spousal care-partners surrounding their experiences, unmet support needs, and feedback on proposed intervention content and procedures for a postdiagnosis dyadic intervention. The overarching goal is to inform the design, procedures, and content of the novel RT-ADRD program prior to subsequent pilot testing, clinical trials, and implementation efforts. Findings from this study also have the potential to increase available information surrounding dyads’ experiences following ADRD diagnosis and perceptions of helpful supports, which has implications for ADRD clinical care and can extend to other chronic and progressive neurological conditions.


Nonalcoholic fatty liver disease (NAFLD) has been increasingly diagnosed worldwide and is now recognized as a source of public health concern. It comprises a wide spectrum of histological features that range from simple steatosis to severe forms of fibrosis, steatohepatitis and even cirrhosis. The impact of bariatric surgery on the course of NAFLD in individuals with obesity has been extensively studied. Narrative review; public university hospital. A comprehensive review was conducted based on an online search on the electronic databases MEDLINE and LILACS using the MeSH terms “fatty liver” and “bariatric surgery”. The exact mechanisms that lead to improvement in NAFLD following bariatric surgery are not completely understood. Since Roux-en-Y gastric bypass (RYGB) is the bariatric surgical procedure most performed worldwide, it is also the one from which the effects on NAFLD have been most studied, although there is also consistent evidence regarding the effects from gastric banding, sleeve gastrectomy and biliopancreatic diversions. According to the currently available evidence, bariatric surgery leads to significant improvement in NAFLD. Further research, especially by means of randomized controlled trials enrolling larger cohorts of individuals, is needed to determine the optimal procedure for this group of subjects. The histological stage is nevertheless crucial for the longer-term prognosis. Among patients with NASH, compared with patients with simple steatosis, the prevalence of cirrhosis development within the first 15 years of follow-up is significantly higher  and liver-related mortality is also significantly higher (7.3% versus 0.9%). The overall and liver-related mortality among patients with NASH is correspondingly higher than would be expected among individuals of the same age and gender with simple NAFLD.,,,,Among obese populations with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM), the prevalence of NAFLD is much higher, ranging from about 50% to 90%. NAFLD has become a challenging public health concern, given that the prevalences of obesity and overweight have increased to epidemic levels over the last few decades. It constitutes an additional risk factor for this group of patients, especially because of the possibility of evolution to severe forms of liver fibrosis (including end-stage liver disease and cirrhosis) and even liver cancer.Among cases labelled as “cryptogenic cirrhosis”, the prevalence of NAFLD appears to be very high. Nayak et al.,,,,,The risk factors for development of NAFLD have been established. Increasing age presents a direct correlation with the prevalence of NAFLD. This is possibly related to the increasing insulin resistance and incidence of metabolic syndrome that occurs with age.,,,,,Several studies have revealed high rates of NAFLD among obese populations who undergo bariatric surgery.,,,,,The underlying mechanisms that are present in the development of NAFLD are not completely understood, although much progress has been made over recent years. The classical pathogenetic pathway that leads to NAFLD was described as the “two-hit hypothesis”. This theory stated that damage to the liver tissue begins through triglyceride accumulation (the first hit), which functions as a sensitizing factor for secondary damage caused by inflammatory mediators (mainly cytokines or adipokines), mitochondrial dysfunction and oxidative stress (the second hits). These secondary aggressions would lead to steatohepatitis and fibrosis.,,,,,In NAFLD, lipid accumulation within the liver (steatosis) may result from several mechanisms: increased fat synthesis, increased fat delivery, decreased fat export and/or decreased fat oxidation.,,,,IR plays an important role in NAFLD development and evolution, and NAFLD also contributes towards worsening of IR. In individuals with IR who present excess visceral fat, the influx of FFAs to the liver is increased, thus leading to both triglyceride accumulation and direct lipotoxicity. On the other hand, several abnormalities intrinsic to NAFLD impair insulin receptor signaling, especially FFAs, tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), ceramide, Jun N-terminal kinase 1 (JNK1), suppressors of cytokine signaling (SOCS) and cytochrome CYP2E1. The cumulative effect generates a vicious cycle of IR and NAFLD worsening each other.,,,,,,Steatosis is strongly associated with chronic hepatic inflammation, an effect that is partly mediated by activation of the Iκκ-β/NF-κB signaling pathway. This is associated with elevated hepatic expression of inflammatory cytokines such as TNF-α, interleukin-6 (IL-6) and interleukin 1-beta (IL-1β), and activation of Kupffer cells. Both serum and hepatic levels of TNF-α are elevated in patients with NASH, and these levels are correlated with histological severity.,,,Increased leptin levels are observed in cases of obesity and NAFLD. These are usually regarded as states of leptin resistance. It is possible that leptin may have an important role in the pathogenesis of NAFLD. Conversely, the circulating levels of adiponectin are inversely proportional to body fat content and become reduced in patients with NAFLD.,,,,,Oxidative stress and mitochondrial dysfunction play a well-reported role in NASH, with a direct correlation between the degrees of oxidative stress and the severity of liver disease. Structural mitochondrial abnormalities and impairment of mitochondrial respiratory chain activity have been reported in human studies.Endoplasmic reticulum (ER) stress and endotoxemia derived from the gut microbiota are other mechanisms that appear to be implicated in NASH pathogenesis. ER stress is associated with various types of biological stress, such as hyperinsulinemia and hyperlipidemia, and it usually causes IR, inflammation, apoptosis and mitochondrial dysfunction, through several mechanisms. In cases of alcohol-related steatohepatitis, ER stress is a well-established pathophysiological factor, but further study on the possible role that it plays in the development of NASH is needed.,,,,,,,,,The role of gut bacterial overgrowth in the pathogenesis of NASH is now emerging through recent evidence. Bacterial overgrowth leads to production of ethanol and release of bacterial lipopolysaccharides, both of which can activate TNF-α production in Kupffer cells, thereby inducing inflammation in liver tissue. Individuals with NASH more frequently present bacterial overgrowth in the small intestine and increased gut permeability than do controls. These findings also suggest that this is a possible explanation for the rapid onset of NASH and liver fibrosis following jejunoileal bypass surgery. Furthermore, there is evidence that hepatic inflammation can be reduced by means of changes to the gut microbiota induced by antibiotics and probiotics.,,,Under high levels of oxidative stress, which is a feature usually observed in the presence of injurious factors such as NASH and viral infection, mature hepatocytes may present impairment of their replication process, thus leading to reduction of their proliferative ability. Subsequently, hepatic progenitor cells (HPCs) are recruited; these cells have the capacity to differentiate into either hepatocytes or cholangiocytes and may be involved in carcinogenesis relating both to hepatocellular carcinoma and to cholangiocarcinoma. Initial research has observed that there is a strong association between expansion of HPCs and a ductular reaction in liver biopsy specimens in NASH cases. The extent of ductular reactions in turn strongly correlates with the degree of fibrosis, thus suggesting that HPC expansion/ductular reaction may play an important role in stimulating progressive periportal fibrosis.,NAFLD encompasses a wide spectrum of liver histopathological abnormalities that may also have highly variable natural courses. It is grossly divided into two main categories: simple steatosis, in which only hepatocellular steatosis is observed; and NASH, in which necroinflammatory reactions are associated with hepato-cellular steatosis. Simple steatosis usually presents a benign course. NASH, on the other hand, is a progressive disease that can evolve into liver cirrhosis and HCC. Steatohepatitis-associated hepatocellular carcinoma (SH-HCC) is a variant of classical HCC in which the onset appears to be strongly linked to NASH.,It is important to emphasize that NAFLD/NASH presents a different pattern in pediatric individuals, with lesions that may or may not resemble those observed in adults. It constitutes an area of ongoing investigation within pathology.,,,,Hepatocellular steatosis is the hallmark of NAFLD; steatosis in more than 5% of the hepatocytes is required for the diagnosis of NAFLD.,,Mild intralobular inflammation is present in NASH and consists of an infiltrate of mixed inflammatory cell types . Satellitosis may be sporadically observed in NASH and consists of ballooned hepatocytes surrounded by polymorphs; this feature is more commonly associated with alcoholic hepatitis. Lipogranulomas and lobular microgranulomas are frequently seen in NASH. Portal inflammation in NASH is usually absent or mild; when there is disproportionately severe portal inflammation, the possibility of other concurrent hepatic diseases needs to be considered.Hepatocellular ballooning is another feature associated with NAFLD and is characterized by the presence of swollen hepatocytes with rarefied cytoplasm, which may contain fat droplets and Mallory-Denk bodies. It usually reflects hepatocellular injury.,Fibrosis in NASH characteristically follows a perisinusoidal/pericellular pattern and usually begins in zone 3. Typically, an active necroinflammatory reaction is observed, along with fibrosis. Progression of perisinusoidal/pericellular fibrosis may lead to occurrences of portal/periportal fibrosis, bridging fibrosis and liver cirrhosis.,,Other important features of NAFLD/NASH include glycogenated nuclei, acidophil bodies, Mallory-Denk bodies (MDBs), iron deposition and megamitochondria.According to the current guidelines of the American Association for the Study of Liver Diseases (AASLD), there are four requirements for diagnosing NAFLD:presence of hepatic steatosis detected using imaging methods or biopsy;absence of significant alcohol consumption;absence of possible competing etiologies for hepatic steatosis;absence of concurrent chronic liver disease.,,There are several noninvasive methods for assessing and diagnosing NAFLD, although none of them are able to provide the same amount of information that is brought through liver biopsy.,,,Ultrasonography-based transient elastography (FibroScan) is a promising method that can bring reliable results by means of safe examination. However, its cost and low availability compromise its potential impact.,,Development of noninvasive scores for assessing liver disease, including NAFLD, is an important field of study nowadays. The ultimate goal in using these scores is to obtain reliable information from noninvasive laboratory and clinical variables that are available in general practice. The NAFLD fibrosis score is the one most used today and can easily be calculated based on six readily available variables: age, body mass index (BMI), hyperglycemia, platelet count, albumin and aspartate transaminase/alanine transaminase (AST/ALT) ratio. A meta-analysis on 13 studies that enrolled 3,064 patients showed that the NAFLD fibrosis score yielded an area under the receiver operating characteristic curve (AUROC) of 0.85 for predicting advanced fibrosis (bridging fibrosis or cirrhosis). Scores ≤ -1.455 had 90% sensitivity and 60% specificity for ruling out advanced fibrosis, whereas scores > 0.676 had 67% sensitivity and 97% specificity for identifying the presence of advanced fibrosis.,Despite recent developments in noninvasive methods for assessing NAFLD, liver biopsy remains the gold-standard method for diagnosing and characterizing it, since it may provide a nuanced evaluation that no other method is capable of today. On the other hand, it is expensive and highly invasive, and carries significant risk of morbidity and even mortality.with NAFLD, who are at increased risk of development of fibrosis and steatohepatitis;with suspected NAFLD, in whom concurrent etiologies for hepatic steatosis and/or coexisting chronic liver diseases cannot otherwise be ruled out.The current treatment strategies for NAFLD are based on the various aspects of its pathophysiology, especially its relationship with obesity and insulin resistance. The current nonsurgical strategies can be divided in non-pharmacological and pharmacological.,,,,,,,,,The primary goals of the main nonpharmacological strategies are weight loss and lifestyle changes. Interventions based on low-fat and low-calorie diets have been evaluated in several studies in which it was observed that these diets were associated with reductions in liver enzyme levels and liver fat content and improvement in liver histology.,The primary goal of pharmacological interventions aimed towards NAFLD may either be weight loss or consist of a direct effect on liver disease and its pathophysiological features, especially insulin resistance and inflammation. Evidence regarding the effect of weight loss medications on NAFLD is scarce. The results relating to orlistat were inconclusive in several trials.,,Regarding insulin resistance, the potential therapeutic effect of insulin sensitizers on NAFLD/NASH has gathered much attention. Rosiglitazone was shown to improve steatosis and aminotransferase levels in patients with NASH in a randomized controlled trial,,,,,Use of vitamin E, because of its antioxidant effects, has shown benefits regarding liver histology among non-diabetic individuals with NASH. Nonetheless, it is important to emphasize that the safety of long-term usage of vitamin E is questionable, since high-dosage vitamin E supplements are associated with increased incidence of prostate cancer in healthy men, and with all-cause mortality.,,,,The current usage of lipid-lowering drugs targeted towards NAFLD (mainly statins) is so far unsupported by any substantial results from well-conducted studies. Thus, this practice is not recommended by American guidelines.,There is a lack of conclusive evidence supporting the use of ursodeoxycholic acid, N-3 polyunsaturated fatty acids, angiotensin receptor blockers, probiotics and synbiotics as validated treatment options for NAFLD.The aim of this study was to conduct a critical analysis on the evidence available regarding the effect of bariatric surgery on NAFLD.in vitro or animal studies, articles in which the participants’ characteristics did not match those mentioned above, poster session abstracts, review articles and other types of publications . Other papers were used for contextualization and discussion.A review of the literature was conducted through an online search for the MeSH terms “fatty liver” and “bariatric surgery” in MEDLINE (via PubMed) and LILACS (via BVS) . We incl,,,,,,,,,,,,,,,,,,There was significant overlap between the databases. After careful analysis, we selected three systematic reviews, seven prospective cohort studies and twelve retrospective cohort studies. A schematic representation of the search in the online databases and the identification, exclusion and selection of the articles is presented in The impact of bariatric surgery on the course of NAFLD in obese individuals has been extensively reported. Surgery plays a significant role in the expected natural history of NAFLD and usually leads to rapid changes in its evolution. Different surgical methods act within this context through a variety of mechanisms, which over the long term may be directly associated with the weight loss achieved, but over the short to medium term appear to be more related to acute structural and endocrine changes that are attributable to the procedures. A pioneering study conducted by Silverman et al.,In a study that evaluated 70 individuals who underwent a variety of bariatric procedures by means of intraoperative and postoperative liver biopsies, Mattar et al.In a case series that enrolled 16 individuals, Clark et al.In a historical cohort that enrolled 90 individuals who underwent liver biopsies during RYGB and one year afterwards, Mottin et al.In a study on 19 individuals who underwent liver biopsy during RYGB that confirmed the presence of NASH and were then contacted to undergo a repeat biopsy, Barker et al.In a study that enrolled 16 individuals who underwent liver biopsy during primary RYGB and a new biopsy during repairs on incisional hernias, Csendes et al.de Almeida et al.An exploratory study carried out by Klein et al.In a retrospective analysis on paired needle liver biopsies taken during and following RYGB in 39 patients, Liu et al.A controlled study conducted by Furuya et al.,Kakizaki et al.Tai et al.A retrospective study by Moretto et al.In a study on 26 paired biopsies collected during RYGB and at an average of 16 months afterwards, Vargas et al.In a large prospective study that enrolled 1236 participants, Caiazzo et al.Abdennour et al.Cazzo et al.In an exploratory study that compared 14 RYGB and 9 sleeve gastrectomy (SG) patients, Froylich et al.Luyckx et al.Busetto et al.Stratopoulos et al.Dixon et al.Jaskiewicz et al.In a prospective study conducted by Phillips et al.,Gastaldelli et al.A prospective study by Moschen et al.,In a retrospective study that enrolled 16 individuals, Swierczynski et al.A prospective study was conducted by Frige et al.In an analysis on prospective data gathered from 236 individuals, Karcz et al.A retrospective study was conducted by Algooneh et al.A prospective study conducted by Coupaye et al.,Billeter et al.In a retrospective analysis on 99 consecutive individuals who underwent surgery, Papadia et al.Ferrer Márquez et al.In an analysis on 104 individuals who underwent the duodenal switch procedure and required further reoperation, Kral et al.Keshishian et al.In a study on different procedures, WeinerJohansson et al.In a retrospective cohort study evaluating the influence of duodenal switch surgery on liver enzyme levels over a four-year period, among morbidly obese patients with normal aminotransferase and high baseline aminotransferase levels, Aller et al.A meta-analysis conducted by Mummadi et al.,There are some major concerns regarding research on the effects of bariatric surgery for treating NAFLD that need to be emphasized. Firstly, as is common among surgical studies, there is a lack of randomized controlled studies; in fact, the majority of studies are retrospective and non-controlled, and these aspects may produce data of poor quality. Secondly, and specifically regarding studies on NAFLD, there is no standardized measurement for the outcomes evaluated: some studies have evaluated liver biopsy specimens, while others have compared data from imaging studies or noninvasive methods for assessing liver disease. Thirdly, optimal evaluation of NAFLD is only possible by means of liver biopsies. These can easily and safely be carried out at the time of the primary surgery, but this procedure is not widely available later on, given that it is not risk-free and therefore performing it in individuals who do not require surgical interventions constitutes an ethical concern. This leads to great heterogeneity of outcomes that also cannot be ignored.Despite the lack of controlled and randomized studies, there is a clear trend towards better results with regard to NAFLD outcomes among obese individuals who undergo surgery. It is also clear that the staging of NAFLD at the time of surgery is an important predictor of success, since it is noticeable that the rates of resolution for simple steatosis are much higher than those observed for steatohepatitis and especially for fibrosis.,,The exact mechanisms that lead to improvement in NAFLD following bariatric surgery are probably strongly related to the metabolic changes that are involved in amelioration of metabolic syndrome (MetS). These changes occur early after the procedures, during a phase when no significant weight loss has yet been achieved. It is clear that while weight loss plays an important role in controlling metabolic abnormalities, this effect appears to be more significant over the long term.,,,,,,The causes of early improvement of MetS after bariatric surgery are complex and relate to changes on the entero-insular axis mediated by gastrointestinal hormones called incretins.,Furthermore, there is a decrease in portal influx of free fatty acids following surgery, which may be related both to feeding restrictions and to metabolic changes in visceral insulin sensitivity.,,In the most recent IFSO consensus statement,Despite the increasing prevalence of obesity among the population with liver cirrhosis, along with the general epidemic of obesity, the number of studies on this topic is still limited. The main factors that need to be taken into account whenever a candidate for bariatric surgery is cirrhotic are the presence of portal hypertension and abnormalities of hepatocytic function. Regarding obese individuals who are also candidates for liver transplantation, the choice of technique and optimal timing for performing bariatric surgery are also significant issues that are not fully addressed in the current literature.Among individuals with severe cirrhosis, surgical morbidity and mortality are significantly higher than what is observed in the general obese population. A retrospective study by Mosko et al.Among candidates for liver transplantation, the choice of technique is of major importance, because of two factors: potential impairment of the absorption of immunosuppressive drugs and the possibility of endoscopic access to the biliary tract. Currently, there are no studies analyzing the pharmacokinetics of immunosuppressive drugs in liver-transplanted individuals who underwent bariatric surgery, but among kidney transplantation recipients who underwent RYGB, there are reports of the need for higher dosages of tacrolimus, sirolimus, mycophenolate sodium and cyclosporine.,,The optimal timing for performing bariatric surgery in individuals with cirrhosis who are also candidates for liver transplantation is yet to be determined. This surgery may be performed before, after or even during the transplantation.NAFLD is becoming a public health concern worldwide today, and its prevalence is expected to grow even further in the near future. There is enough evidence to suggest that bariatric surgery should be considered to be the optimal treatment option for NAFLD by choice, and no longer only by chance.,,Although bariatric surgery is currently recognized as the standard treatment option for morbid obesity and its related comorbidities, the number of operations performed is far from sufficient to meet the need for intervention. In fact, less than 500,000 bariatric surgery procedures are performed worldwide every year today. This number represents less than 0.1% of the entire supposedly obese population.,,Hence, the most practical and effective action that can be implemented in relation to this entire disease chain is prevention. Encouragement towards practicing physical activity and following healthy low-fat/low-calorie diets needs to be extensively included in educational and community programs as early in life as possible, since obesity has become a pediatric issue too.,Regarding the role of bariatric surgery in relation to the clinical course of NAFLD, many questions remain to be answered. Since there is a lack of randomized controlled trials, no ultimate conclusions can yet be provided. It is clear that the overall impact of bariatric surgery on NAFLD is positive, but the optimal surgical technique remains to be determined, as do the longer-term effects and the ways of maintaining the benefits achieved. Since there is also concern regarding the onset of persistent IR or even re-emergence of IR and T2DMAll procedures performed in the studies evaluated involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.The currently available evidence shows that bariatric surgery may become the treatment of choice for individuals with NAFLD. It is important to emphasize that further research, especially by means of randomized controlled trials enrolling larger cohorts of individuals, is necessary in order to determine the optimal procedure for this group of subjects, as well as whether only individuals with morbid obesity might benefit from the effects of metabolic surgery, since there are vast numbers of lean and overweight individuals who also present NAFLD.


JCI, Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD.Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the  Diabetic kidney disease (DKD), defined broadly as kidney damage due to diabetes, is the leading global cause of progressive chronic kidney disease and end-stage kidney disease (ESKD) ,2. DKD dJCI, Sharma and colleagues used this groundbreaking approach to demonstrate that endogenous adenine drives kidney disease progression in DKD  and clinical endpoints — namely ESKD and all-cause mortality . They deSharma and colleagues have demonstrated how an integrated multiomics approach can bridge the gap between identifying mechanistic biomarkers and developing therapeutics based on those targetable pathways. This approach also provides a framework to elucidate mechanisms of kidney protection for known therapeutics and to promote drug discovery. SGLT2 inhibitor treatment results in dose-dependent improvements in measures of kidney function and inflammatory and oxidative stress in animal models of adenine-induced chronic kidney disease , 17 and With this breakthrough study by Sharma and colleagues, we can more clearly envision a future where multiomics approaches enable discovery of predictive biomarkers — such as the UAdCR — that can be assayed routinely and noninvasively early in the disease course. This example should serve as a call to accelerate drug discovery, which will be needed to truly revolutionize our ability to prevent DKD.