Extracorporeal liver support therapies (ELS) are technical options (for bridge-to-recovery as well as bridge-to-transplant) in patients with acute liver dysfunction (e.g. acute liver failure (ALF), acute-on chronic liver failure (AoCLF) or decompensated chronic liver disease (decomp. CLD)) to reduce effects of failing hepatic detoxification functions. The present study investigates the real-life utilization of ELS , mortality rates as well as data regarding specific populations of liver transplantation in Germany.Data on patient cases receiving extracorporeal liver support therapy were identified in a nationwide data set from the Federal statistical Office of Germany from 1 January 2007 through 31 December 2015 and analyzed regarding in-hospital mortality, age- and sex-specific distribution and use of ELS in the context of liver transplantation. Mortality rates in patients with primary acute liver dysfunction and secondary acute liver dysfunction (in the context of cardiothoracic surgery) were evaluated.Annual incidences of ELS use remained stable between 0.39/100.000 in 2007 and 0.47/100.000 ELS in 2015. In-hospital mortality rate was 51.49% in the 2886 evaluated patient cases. Mortality was higher in men (56.04%) than in women (43.70) in the observed time period between 2007 and 2015. ELS utilization and case-related liver transplantation rates were low (12.47%). Since 2012, the annual numbers for ELS therapy in cardiosurgical patients exceeded the frequency of ELS utilization in cases of primary liver dysfunction .ELS utilization remained stable between 2007 and 2015. Mortality rates are high in this patient population of acute liver dysfunction, especially in combination with case-related cardiothoracic surgery. ELS is rarely used in the setting of liver transplantation. In 2015, more than 50% of all ELS cases in Germany were performed in the context of cardiothoracic surgery. Acute liver dysfunction might occur in patients with preexisting  or non-preexisting  liver disease , 2. SimiAim of this study was to investigate the epidemiologic development of ELS utilization and evaluate real-life mortality in a high-income country from 2007 to 2015. In detail, age distribution, sex specific mortality rates, causes of underlying liver dysfunction (primary or secondary) as well as mortality rates of patients with ELS and primary or secondary liver failure were points this study intended to address. Furthermore, we investigated clinical utilization of ELS as a bridge-to-transplant or graft-failure option through examination of the performed evaluation steps for liver transplantation as well as successful transplantation numbers in ELS patients.We performed a database analysis using data provided by the Federal Statistical office in Germany . We received permission by this institution to publish this data within our manuscript. Thus, no further institutional review board approval was required. The German health care system records and documents all patient cases of hospital treatments according to the German accounting method (German DRG) as main diagnosis according to ICD  as well as further diagnoses and performed case-related operations and procedures (OPS).As ELS treatments are only performed in a hospital setting, we were able to provide information on the total annual German case numbers. Procedures performed during the hospital stay were documented according to the current OPS coding (operation & procedure key codes). Case related data of the respective diagnosis and OPS were transferred from hospitals or insurance companies to the federal statistical office according to national laws.A database query was performed for the given years regarding patient cases with the respective OPS code for “extracorporeal liver assist device”  was performed to estimate the real-life use of ELS in combination with bridge-to-transplant therapy or for graft dysfunction . Thus, OPS codes of ELS and performed liver transplantation (OPS 5–504) or evaluation for liver transplantation (OPS 5–504 within the same case of ELS) were analyzed Table .Another subgroup analysis was performed to evaluate subpopulations of patients with primary  and secondary acute liver failure. Regarding the secondary acute liver dysfunction, we decided to explore the utilization of ELS technology in patients with acute liver failure in the context of major cardiac surgical procedures as several studies suggested an increase of ELS usage within this population during the last decade , 13, 14.Using typical ICD coding of acute primary liver failure with typical indications for liver transplantation according to Eurotransplant criteria , a “primPatients were not involved in the research questions, outcome measures or other study-related issues.We followed the STROBE recommendations for adequate reporting of observational routine data.Data were analyzed descriptively. Absolute numbers and mortality rates were stratified for different age groups and by sex and year. Annual incidences were calculated as described above. Excel for Mac  and SPSS  were used for analysis.A total of 2886 patient cases with extracorporeal liver support (ELS) was documented in the German nationwide database in the observed time-frame from 2007 until 2015.The annual numbers of ELS ranged from 205 in 2013) to 390 cases (in 2009). This represents an incidence of 0.39/100.000 inhabitants in 2007 and 0.47/100.000 inhabitants in 2015. Overall mortality was 51.49% for the 2886 investigated patients . Additionally, sex-specific mortality rates were higher for males (56.04%) compared to female patients (43.70%) receiving extracorporeal liver support therapy  received ELS as a peri-transplantation therapy option (before (“bridge-to-transplant”) or after liver transplantation (due to graft dysfunction) within the same case) between 2007 and 2015. Forty-nine liver transplantations were performed in 2007 and 18 in 2015 within the observed ELS patient cases  with cardiac surgery OPS coding versus 131 cases  with a typical ICD diagnosis for primary liver failure Table . MortaliThis is the first epidemiological study investigating real-life utilization of extracorporeal liver support therapy in a high-income country (Germany) from 2007 through 2015. The main findings are:Use of extracorporeal liver support therapy in Germany remained stable during the observed period. A high mortality in the population was shown, potentially due to the underlying diseases. Mortality was higher in male than in female patients with ELS. Since 2012, the annual numbers of ELS therapies in patients with case-concomitant cardiothoracic surgery exceeded the numbers of ELS utilization in cases of typical acute primary liver dysfunction.Extracorporeal liver support therapy before and after liver transplantation was only a marginal aspect in clinical practice according to our real-life data. Mortality in patients treated with ELS due to primary causes of acute liver dysfunction was lower than in patients with case-concomitant cardiothoracic surgery.Our real-life data study shows a higher in-hospital mortality in patients who received extracorporeal liver support therapy compared with the mortality rates of patients who received ELS treatment in randomized controlled clinical trials, e.g. a 28-day mortality of 58% in the RELIEF trial (ACLF population) , 30-day Thus, we agree with individual authors  as well Our epidemiological study using a nation-wide data set has some relevant limitations.First, the incidences of ELS usage might not be transferable to other high-income countries due to limited access to extracorporeal therapy or limited reimbursement by the responsible health system providers. In Germany, ELS therapies are not restricted to specific tertiary care or transplant centers but may be performed by any ICU. Additionally, due to data protection restrictions, no further detailed analysis was allowed regarding care-provider-specific mortality. As with many other epidemiological studies, correlations of mortality rates between subpopulations are no causations.We are unable to provide mortality rates for the subpopulations of patients with ALF, AoCLF or decompensated liver cirrhosis without ELS therapy. This is related to the fact, that these definitions are disease states of specific underlying entities which can be recorded within the DRG-System with a larger number of codes. This is comparable to the limitation of a recently published study by Karagiannidis et al. who explored the mortality of ECMO  patients but were unable to provide mortality rates for ARDS due to different codings of the respective underlying disease . SubgrouThus, as mentioned above, real incidences of acute liver dysfunction cannot be estimated from this data set. Additionally, our federal statistics office data set does not allow to explore the specific pathologies of liver dysfunction that resulted in a case-related ELS therapy in the primary nor secondary liver dysfunction subpopulations. Thus, the indications for ELS in the cardiothoracic subpopulation are speculative . Further studies in the future should explore these issues.Underreporting bias might be another relevant limitation. Extracorporeal organ support therapies as well as surgical procedures  are expensive. Therefore, a relevant underreporting bias by the care provider might only be theoretical as correct documentation of these expensive procedures are in the interest of the institution to receive financial reimbursement. On the other hand, evaluation for liver transplantation can be documented using specific coding as shown above. However, as these case-specific evaluations do not result in relevant reimbursement, a relevant underreporting bias might have occurred. We were unable to separate data sets of patient cases with ELS use before (“bridge-to transplant”) and after liver transplantation (graft dysfunction) as the data source does not provide exact time points for performed procedures within a single case. As above, future observational trials should investigate this relevant liver transplantation topic.The numbers of ELS sessions per case cannot be extrapolated from the data set as there are no specific DRG-codes for this question. Additionally, we are only able to provide data for case-related in-hospital mortality but not for other time spans . Last, we are unable to provide data of hospital-specific ELS utilization as the data source provider did not allow us to evaluate this question due to data protection laws and the low annual number of ELS cases per hospital.In conclusion, there was a continuous utilization of extracorporeal liver support therapy in Germany between 2007 and 2015. Since 2012, more than 50% of all annual ELS cases were performed in the context of cardiac surgery. ELS was rarely used in a liver transplantation setting (bridge-to-transplant / graft dysfunction), as the majority of patients was not even evaluated for or received a liver transplantation. Mortality rates were higher in the German “real-world” patient population compared with international RCT study settings. Male patients as well as patients with secondary causes of acute liver dysfunction in the context of cardiothoracic surgery had a higher mortality rate compared to female patients or patients with primary liver failure . Future studies should focus on the identification of specific patient populations in which an extracorporeal liver support therapy might be beneficial. Contrary, patient populations with a high level of mortality should be identified to avoid futile extracorporeal organ support therapy. We suggest, that extracorporeal liver support therapies should only be performed in the context of clinical trials.


Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small “fragment” molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds. Diversity-oriented synthesis (DOS) is a synthetic strategy that aims to efficiently produce compound collections with high levels of structural diversity and three-dimensionality and is therefore well-suited for the construction of novel fragment collections. This Mini-Review highlights recent studies at the intersection of DOS and FBDD aiming to produce novel libraries of diverse, polycyclic, fragment-like compounds, and their application in fragment-based screening projects. Within the biomedical community there remains a pressing need for new molecules to seed early stage drug discovery programs. Diversity-oriented synthesis (DOS) emerged in the early 2000s in response to this challenge, a strategy which involves the efficient and deliberate construction of multiple scaffolds in a divergent manner . FBDD is now a widely adopted technique across both industry and academia, with two marketed drugs having emerged from this methodology decane and bicyclo[3.3.1]nonane scaffolds in moderate yield. The generality of this methodology was exemplified through the synthesis of six further compounds through modification of the N-substituent the bicyclic ring systems.Hassan et al. recently disclosed an interesting example via the exploitation of twisted bicyclic amide compounds for the generation of a 3D fragment screening library  and generally 17 or fewer heavy atoms and a clogP < 2.5. Furthermore, PMI analysis of the shape distribution suggested the library possessed significant 3D character to complement existing fragment collections for screening purposes.In turn, these three key scaffolds were ultimately then divergently modified through manipulation of either the ketone or amide functionalities to generate a further nine compounds. The ketone moiety within the bicyclo[3.3.1]nonane was first modified by the use of either gold- or palladium-mediated reactions to afford tetra- or tricyclic heteroaromoatic fused motifs. Alternatively, this moiety could also be reduced and a variety of heteroaromatics or alkyl moiety installed N-substituted quaternary carbon, an important and underrepresented motif within screening collections .Subsequent computational assessment of the resulting library via X-ray crystallographic screening methods. The researchers took inspiration from natural product frameworks, utilizing intramolecular [5+2] cyclizations to forge bridged structures incorporating natural product-related heteroaromatic frameworks -enantiomer of the chiral center to be more potent, and further studies identified the substituent at this site as an important potential growth vector. Fragment growth by incorporating large aryl groups into the scaffold via the same B/C/P pathway yielded the lead compound, with a large indolyl unit connected to the core heterocycle. This fragment exhibited a Kd = 9 μM, a 60-fold improvement over the initial fragment hit. Ultimately an X-ray crystal structure of the lead compound with GSK3β was obtained, revealing it binds in the ATP pocket of this kinase.Using this fragment collection, screening against GSK3β was performed using differential scanning fluorimetry (DSF) to detect fragment binding. Initial results identified a benzopiperizinone-library member to exhibit good thermal stabilization and subsequent assays showed 46% inhibition of GSK3β at 1 mM concentration. A library of derivatives based on this initial hit were then synthezised using the modular and rapid DOS chemistry initially developed. Thus, the single enantiomer variants and other derivatives could easily be constructed to generate structure-activity relationships (SAR). Preliminary fragment-level SAR indicated the This study demonstrated the successful implementation of a DOS-based FBDD workflow to evolve fragments against an important kinase target. Key to the success of this project was the utility of the DOS concept as a tool to generate skeletally and stereochemically diverse initial libraries, and later as an efficient, modular route to analogs for SAR and fragment growth.The studies discussed herein have demonstrated the utility of DOS as an effective approach for populating new areas of fragment space, in areas largely complementary to existing fragment collections. In each case, the resulting libraries featured high structural and shape diversity, increased 3D character and exemplified synthetic vectors for fragment growth. The latter two examples discussed detail applications of these libraries for the identification of novel fragment binders and inhibitors against challenging protein targets, ultimately demonstrating the utility of DOS within drug discovery efforts.in silico-based screening techniques to guide library design and prioritization of synthesis. Moreover, a focus on applications of newly developed methodologies to DOS, for example C-H activation, and site selective late-stage modifications of complex scaffolds would enable population of underexplored areas of chemical space and further derivatization of the resulting scaffolds. Finally, an outstanding requirement within this field is the establishment of new translational collaborations between academic and industrial groups to enable the routine screening of the novel libraries.It is worth noting the increasing application of computational virtual library enumeration, an element of which has featured in several of the publications discussed. It is envisioned that these methodologies will only increase in their utility when coupled to SLK and TJO conceived and wrote the manuscript. All other authors  provided comments and discussion on the manuscript to aid its preparation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Crosslinked liquid crystalline polymers (CLCPs) containing azobenzene (AZO-CLCPs) are a type of promising material due to their significance in the design of light-driven smart actuators. Developing AZO-CLCP composites by incorporating AZO-CLCPs with other materials is an effective way of enhancing their practicability. Herein, we report an AZO-CLCP/CNT nanocomposite prepared by the in situ polymerization of diacrylates containing azobenzene chromophores on carbon nanotube (CNT) sheets. The liquid crystal phase structure of CLCP matrix was evidenced by the two-dimensional X-ray scattering. The prepared pure AZO-CLCP films and AZO-CLCP/CNT nanocomposite films demonstrated strong reversible photo-triggered deformation under the irradiation of UV light at 366 nm of wavelength, as a result of photo-induced isomerization of azobenzene moieties in the polymer network. But compared to pure AZO-CLCP films, the AZO-CLCP/CNT nanocomposite films could much more rapidly return to their initial shapes after the UV light irradiation was removed due to the elasticity effect of CNT sheets. The deformation behavior of AZO-CLCP/CNT nanocomposite films under the light irradiation was also different from that of the pure AZO-CLCP films due to the interfacial interaction between a polymer network and CNT sheet. Furthermore, incorporation of a CNT sheet remarkably increased the mechanical strength and robustness of the material. We also used this AZO-CLCP/CNT nanocomposite as a microvalve membrane actuator, which can be controlled by light, for a conceptual device of a microfluidic system. The results showed that this AZO-CLCP/CNT nanocomposite may have great potential in smart actuator applications for biological engineering, medical treatment, environment detection and microelectromechanical systems (MEMS), etc. The ini−2) with a high-pressure mercury lamp  through a glass filter for 3 h. As the polymerization completed, the cell was opened, and the AZO-CLCP film of about 20 µm thickness was removed from the cell with a cutter. The AZO-CLCP/CNT nanocomposite films were prepared via the same procedure, but the photopolymerization was carried out in the glass cell with a CNT sheet sandwiched between the two inner surfaces  using tetramethylsilane (TMS) as the internal reference. Mass spectra (MS) were taken with a Bruker Daltonics Ultraflex III MALDI TOF/TOF Mass Spectrometer . The morphology and structure of the CNT sheet and AZO-CLCP/CNT nanocomposite were examined by scanning electron microscopy . The mesomorphic properties of AZO-CLCP films were observed by using polarizing optical microscopy . The mesomorphic properties of AZO-CLCP/CNT nanocomposite films were examined by the two-dimensional X-ray scattering (2D-WAXS) experiments which were performed by a Bruker/Siemens Hi-Star 2D X-ray Diffractometer  with a monochromatic CuKalpha point source (0.8 mm). A 366 nm UV-LED  was used as the light source for photo-actuated deformation experiments. A universal material mechanical analyzer  with a pair of tension clamps was employed to measure the mechanical properties or photomechanical properties of the AZO-CLCP/CNT films and AZO-CLCP/CNT nanocomposite films, the two ends of the tested material were gripped by the two clamps. The environment temperature of experiments was 20 °C.The chemical structures of the synthesized DA11AB and C9A were measured by the way of nuclear magnetic resonance (NMR) spectra cooperated with mass spectra (MS). 1H NMR spectra of DA11AB and C9A are shown in 1H NMR and MS measurements of DA11AB and C9A are in the Support Information. From the measurements of 1H NMR and MS, the chemical structures of the synthesized monomers are consistent with the standard chemical structures of DA11AB and C9A.The chemical structures and The free radical photopolymerization reaction process of AZO-CLCP formation is shown in The polymerization was carried out in a cell that was precoated with rubbed polyimide alignment layers. The alignment layer assisted to align the LC mesogens when the precursors were melted under heating so that they could be polymerized in an aligned state. The POM was used to evaluate the alignment effect of the LC mesogens in AZO-CLCP film by measuring the transmittance of a probe light through two crossed polarizers with an AZO-CLCP film between them. As shown in 2 was performed.The prepared AZO-CLCP films and AZO-CLCP/CNT nanocomposite films demonstrated photoinduced reversible deformation behaviors. As shown in trans–cis isomerization of azobenzene moieties, which resulted in a reduction in the size of azobenzene moieties and the alignment order of LC mesogens, and subsequently in a contraction of the polymer network along the alignment direction [cis–trans isomerization of azobenzene moieties [irection ,5. The mirection . Thus, tmoieties ,5, and htrans–cis isomerization of azobenzene moieties induced by the UV irradiation. However, the AZO-CLCP/CNT nanocomposite films behaved in an opposite photodeformable way compared to the AZO-CLCP films, which should be caused by the interfacial interaction between the CLCP network and CNT sheet [cis–trans isomerization of azobenzene moieties, and hence the CLCP network reverted to its initial structure, resulting in the reversion to the initial flat state of the AZO-CLCP/CNT nanocomposite films. Comparing cis–trans isomerization process of azobenzene moieties.NT sheet . The mesIt is interesting to note that the maximum bending extents of films varied with different molar ratios of DA11AB to C9A. F20 demonstrated the highest maximum bending extent among the AZO-CLCP films while CF20 demonstrated the highest maximum bending extent among the AZO-CLCP/CNT nanocomposite films. The reason for this should be that the films with different molar ratio of DA11AB to C9A had different amounts of azobenzene moieties. A low content of azobenzene moieties would create weak contraction actuation under UV irradiation, resulting in a low bending extent of the film. Higher content of azobenzene moieties would mean a greater percentage of UV energy being absorbed in the near-surface region of the film. For an AZO-CLCP film, a too high content of azobenzene moieties could also weaken the contraction actuation under UV irradiation due to the depth of the region in which contraction occurred being too low, resulting in a lower bending extent of the film. For an AZO-CLCP/CNT nanocomposite film, a too high content of azobenzene moieties would result in the contraction extent of interphase region being seriously decreased since a very low percentage of UV energy could be absorbed by this region, thus the bending extent of the film under UV irradiation would also be lowered. Therefore, a suitable content of azobenzene moieties is needed to create the highest deformation effect of the film under UV irradiation. It revealed from The photoinduced force is one of the important factors for photo-actuated materials. The photomechanical properties of the prepared AZO-CLCP films and AZO-CLCP/CNT nanocomposite films were quantitatively studied by using a universal material mechanical analyzer, as shown in The AZO-CLCP films and AZO-CLCP/CNT nanocomposite films showed anisotropic mechanical properties due to the anisotropic network structure of AZO-CLCP matrices. The tensile strengths were measured both parallel and perpendicular to the alignment direction by using the universal material mechanical analyzer , and theThe superior photo actuation performances, well mechanical properties and robustness feature demonstrated by the AZO-CLCP/CNT nanocomposite films, are promising for application in light-driven smart actuators. Considering the optimum photo actuation performance of CF20, we demonstrated it as a light-controlled microvalve membrane actuator for a conceptual device of microfluidic system, the experimental setup is shown in The microvalve membrane actuator demonstrated a sensitive function of opening or closing the valve under light regulation. As shown in We report an effective approach to fabricate photo-actuated AZO-CLCP/CNT nanocomposite films by incorporating CNT sheets into AZO-CLCP matrices through a facile melting process and in situ photo polymerization. Compared with the pure AZO-CLCP films, the AZO-CLCP/CNT nanocomposite films demonstrated much improved mechanical properties, robustness feature and photo actuation performances.The AZO-CLCP/CNT nanocomposite films could not only deform with similar rapid speeds as the pure AZO-CLCP films could under the irradiation of UV light, but also could much more rapidly return to their initial shapes after the UV light was removed. The AZO-CLCP/CNT nanocomposite films also indicated a different photodeformable direction relative to the pure AZO-CLCP films due to the interfacial interaction between the polymer network and CNT sheet. The optimum photo actuation performance could be achieved when the AZO-CLCP matrix contained a suitable content of azobenzene moieties.Utilizing the AZO-CLCP/CNT nanocomposite film which possessed the optimum photo actuation performance, we demonstrated a light-controlled microvalve membrane actuator for a conceptual device of a microfluidic system. It effectively realized the function of a microvalve. The valve could be sensitively opened or closed by light regulation, and the opening and closing processes could be repeated for many times without obvious decay. Our work sheds significant insight for the development of high-performance actuation materials and their applications in driving smart actuators and microrobots, etc.


Kenyan paediatric treatment protocols recommend the use of zinc supplement for all children with diarrhoea. However, there is limited evidence of benefit for young children aged 1-5 months and those who are well-nourished. We examine effectiveness of zinc supplementation for children admitted with diarrhoea to Kenya’s public hospitals with different nutritional and age categories. This is to determine whether the current policy where zinc is prescribed for all children with diarrhoea is appropriate.We explore the effect of zinc treatment on time to discharge for children aged 1-5 and 6-59 months and amongst those classified as either severely – moderately under-nourished or well-nourished. To overcome the challenges associated with non-random allocation of treatments and missing data in these observational data, we use propensity score methods and multiple imputation to minimize bias.The analysis included 1645 (1-5 months) and 11 546 (6-59 months) children respectively. The estimated sub-distribution hazard ratios for being discharged in the zinc group vs the non-zinc group were 1.25  = 1.07, 1.46) and 1.17  in these respective age categories. Zinc treatment was associated with shorter time to discharge in both well and under-nourished children.Zinc treatment, in general, was associated with shorter time to discharge. In the absence of significant adverse effects, these data support the continued use of zinc for admissions with diarrhoea including those aged 1-5 months and in those who are well-nourished. Diarrhoea is a major cause of morbidity and mortality in lower and middle income countries with the primary treatment being rehydration regimens matched to the severity of the dehydration ,2. Co-trDespite these recommendations, there remains some debate on the benefits of zinc since:The prevalence of zinc deficiency varies by settings  and thisTrials supporting the use of zinc have included fewer participants from Africa than other low and middle income settings  and it iThere are few data supporting the benefits of zinc in children younger than six months and few data on the effects of zinc in children of all ages who are relatively well-nourished .Conducting trials to address all these questions would likely be expensive and time-consuming. Appropriate analyses of observational data sets may help address such questions while also providing data on the effectiveness of zinc treatment in non-trial populations.The primary focus of this analysis is to examine the effectiveness of zinc supplementation, assuming those prescribed zinc actually received it, in reducing time to discharge for children admitted with diarrhoea in Kenyan hospitals. In secondary analyses, we aim to examine the effectiveness of zinc amongst those classified as either severely-moderately under-nourished or well-nourished.We use observational data from the Kenyan Clinical Information Network (CIN) that was initiated in September 2013 to improve inpatient paediatric data availability from 14 hospitals. These hospitals typically have one paediatrician leading services predominantly provided by junior clinical teams. Data in these hospitals are collected post discharge by trained data clerks guided by well-defined standard operating procedures, under supervision by the hospital medical records department and the research team. Clinicians admitting patients fill standardized Paediatric Admission Record (PAR) forms  that havWe include in the analysis all children who had diarrhoea as one of the illnesses on admission. We exclude children aged <1 month and ≥60 months, had shock or who had impaired consciousness (response only to pain or unresponsive), and those who had a clinical diagnosis of severe acute malnutrition. We primarily examine the effect on time to discharge of whether children were prescribed zinc in two age groups: all children aged 1-5 months (group 1) and all children aged 6-59 months (group 2). The analysis is stratified into two age groups as these are the age groups considered in the guidelines, with different zinc prescription recommendations. Within each of these groups, we examine the effects of zinc treatment in severely-moderately under-nourished and well-nourished children. To define nutritional status in this population not clinically identified as having severe acute malnutrition, we derive weight for age z scores using WHO reference population data . ChildreAs there were missing data in the variables  assumption . Under Ma priori to influence the clinical outcomes of interest such as fluid regimen prescribed and comorbidities (see Table S1 in sub section (d) of As CIN comprises data from routine care settings, not being prescribed zinc cannot be considered random. In fact, this would be as a result of failure to adhere to national guidelines. Analyses must try and account for any potential bias in treatment allocation. To help create balance in population characteristics amongst those with and without zinc prescription, we compare propensity score full-matching and weighting ,18. A prWe consider time to being discharged alive as the primary outcome. Mortality is treated as a competing risk as it would preclude the chance of a patient being discharged alive. To allow for covariates with varying effects across the discharge time points, we use a flexible modelling approach suggested by Scheike (2011) . Both KoFor each of the imputed and then propensity score adjusted data sets, Scheike’s flexible regression models are fitted while adjusting for all the variables  and 2 (aged 6-59 months) respectively. About 72% (1-5 months) and 77% (6-59 months) were prescribed zinc supplements . The additive interaction resulted in four sub-groups of children including those who were: (a) well-nourished with zinc prescribed; (b) well-nourished without zinc prescribed; (c) under-nourished with zinc prescribed and; (d) under-nourished without zinc prescribed. Patient characteristics were approximately similar across the four sub-groups in both age groups (see Tables S2 and S3 in The estimated SHRs (comparing zinc vs no zinc) using the instrumental variable for children aged 1-5 and 6-59 months were 1.24  and 1.31  respectively – and these were consistent with those obtained in Both Kolmogorov-Smirnov and Cramer Von Mises tests showed that the use of zinc had varying effects on mortality (across the discharge time points) both for children aged 1-5 and 6-59 months  with children under 6 months [There are limitations whenever one uses routine, observational data sets. The WHO recommends two measures of malnutrition – m id-upper arm circumference and weight for height – but we were not able to use these as they are poorly documented in hospitals. Instead we used weight for age z score, associated with undernourishment, as a proxy. Data on specific covariables were also sometimes missing. We used multiple imputation to overcome this challenge assuming data were MAR. Methodologically, this assumption seemed plausible as estimates of the effects associated with zinc under assumptions of MAR and MNAR were approximately similar.observed signs, symptoms, co-treatments and comorbidities. Analyses of these samples provided biologically plausible results showing the benefits of zinc in reducing time to discharge for all children below five years. However, as analytic methods used in observational studies may not completely eliminate unobservable bias [Comparative effectiveness analyses using observational data sets offer the potential advantage of evaluating “real world” effectiveness of treatments. In part, this is because children who may not qualify to be part of RCTs may be included in these observational studies. The use of propensity scores and multiple imputation provided a means to analytically handle the challenges of non-random allocation and missing data by creating samples of patients that are comparable in terms of ble bias ,32, we cble bias . These fble bias ,34, whicble bias . The posOur finding that zinc is associated with shorter time to discharge is consistent with meta-analyses of RCTs but extends this observation to less studied populations. RCTs have, however, not shown an advantageous effect of zinc on mortality in acute diarrhoea. The protective association of zinc against mortality we see does raise the possibility that there is residual (unobservable) bias in our observational analyses possibly due to clinicians allocating this treatment to less sick children. Despite this caveat, and as zinc is well tolerated and cheap, our results support the continued use of routine zinc supplementation in all children aged 1-59 months hospitalised with diarrhoea in Kenya and probably elsewhere in Africa.


Our objective was to identify social and physical environmental factors associated with current cigarette smoking among adults by metropolitan county in the United States.We linked cigarette smoking data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) Selected Metropolitan Area Risk Trends (SMART) data set to 7 social and physical environmental characteristics: county type (metropolitan designation), primary care physician density, income inequality, percentage of the population that was a racial/ethnic minority, violent crime rate, education, and percentage of county residents with low income and no health insurance, all obtained from several county data sets. Spatial regression and hierarchical logistic regression modeling were performed.P < .001), lower education levels (high school graduate or less) (P < .001), and high violent crime rates (P < .001) had a higher adult cigarette smoking prevalence than other metropolitan counties. Spatial models showed 63.3% of the variability in county cigarette smoking prevalence was explained by these 3 factors as well as county type (based on population size of the of metropolitan area), primary care physician density, and percentage of county residents with low income and no health insurance. At an individual level, results showed that as the density (population) of primary care physicians increased in a county, the odds of being a current smoker decreased .Results showed that metropolitan counties with a high proportion of non-Hispanic white adults (We found a significant association between adult cigarette smoking and county social and physical environmental factors. These place-based factors, especially social environmental characteristics, may reveal tobacco-related disparities to be considered when developing strategies to reduce tobacco use. International studies show that place-based characteristics  are associated with cigarette smoking. However, limited data are available about whether place-based characteristics are associated with cigarette smoking among US adults.Of 7 metropolitan county characteristics studied, 3  had a higher smoking prevalence than their counterpart metropolitan counties.Findings from this study highlight the need for more novel approaches, such as collaborations between tobacco use prevention and control organizations and crime prevention entities, when addressing tobacco-related disparities.Although progress has been made in reducing cigarette smoking among the general population, cigarette smoking is still the leading cause of preventable disease and death in the United States . In addiCurrent cigarette smoking is associated with individual characteristics, such as age, sex, race/ethnicity, income, education, and mental health status –4; howevMany international studies show that place-based characteristics are associated with cigarette smoking, including neighborhood deprivation, disadvantage, or crime –15; tobaThe objectives of this study were to 1) assess the association between selected place-based characteristics and the prevalence of current cigarette smoking among US adults by county; and 2) determine the potential influence of selected place-based characteristics on cigarette smoking after controlling for known individual-level characteristics associated with cigarette smoking .We conducted spatial analyses to examine the association between selected place-based metropolitan county characteristics and county-level cigarette smoking. Spatial analyses were used to examine aggregate-level patterns and associations in the data; however, aggregate associations can falsely attribute aggregate patterns to individual characteristics (objective 1). To diminish the potential for such bias, we further conducted hierarchical logistic regression to explore the variation in individual cigarette smoking status among counties by examining the individual characteristics at one level of analysis and the characteristics of the counties (objective 2). Both statistical methods were used to further explain the relationships that may occur at the aggregate level and to determine if the pattern of these relationships existed at both an individual and aggregate level.Current cigarette smoking status was obtained from 182,172 survey respondents residing in 179 US metropolitan counties by using the 2012 Behavioral Risk Factor Surveillance System (BRFSS) Selected Metropolitan Area Risk Trends (SMART) data . BRFSS iAggregate county-level current smoking prevalence was calculated by using small area estimation methods. Data on county social and physical environmental influencers were obtained from several data sets . For somWe assessed prevalence of sociodemographic indicators of the individuals and of county-level characteristics. Correlation analysis was conducted with all selected county-level variables to determine if a high correlation between these variables existed. After finding that no pair of variables were strongly correlated (no correlations ≥0.8), a bivariate analysis was conducted to determine which of the variables were associated with current cigarette smoking . We then conducted spatial analyses to examine the relationship between county cigarette smoking and metropolitan county type, PCP density, percentage of minority population, violent crime rate, low-income uninsured, and education, variables that were found to have a bivariate association with smoking.Spatial statistics were used to test for spatial autocorrelation. The Moran I statistic was used to measure the global spatial autocorrelation of the data to determine whether county observations were clustered. We then created local indicators of spatial association maps to visualize where local clustering existed and determine whether those locations were significant. The type of spatial autocorrelation was further examined by testing for spatial lag and spatial error. We conducted ordinary least squares regression to diagnose the presence of lag or error. The spatial lag model assumes that the prevalence of current cigarette smoking at one location (county) is affected by variables predicting cigarette smoking at nearby locations (counties). In contrast, the spatial error model assumes that cigarette smoking in one location (county) is not affected by predictor variables at nearby locations, but might be attributed to unmeasured predictor variables or the use of spatial data, regardless of the model being theoretically spatial or not. The robust Lagrange multiplier test indicates the presence of error and confirms that a spatial error regression model is needed to correct for autocorrelation. All aggregate-level analysis was conducted by using Stata version 14 (StataCorp LLC) and GeoDa version 1.10  software.The final analysis conducted was a hierarchical logistic regression model to help explain what was observed in the spatial analyses and to identify the influence of both county-level and individual-level characteristics on the likelihood of being a current smoker. We created a 2-level model with the individual’s characteristics at the first level (level-1) and the social and physical environmental characteristics at the second level (level-2). Because current smoking in a county might vary on the basis of individual characteristics, we included respondents’ age, sex, race/ethnicity, education, health insurance coverage status, and self-reported health status. At level-2, we included variables reflecting the county type, PCP density, percentage of minority county population, low-income uninsured population, and violent crime rate.P less than .05.We conducted 4 separate hierarchical models. Model 1 was an intercept only (null) model and did not contain any variables, but only incorporated county random effects to give us a sense of how much variability in current cigarette smoking existed within and between counties. Model 2 (random coefficients model) tested the relationship between each level-1 characteristic  and the odds of being a current smoker. Model 3 (means as outcomes model) tested the significance and direction of the relationship between the county-level (level-2) variables and the odds of being a current smoker. Model 3 included only level-2 predictors, which helped provide the clearest evidence of which county-level factors in the model were contributing to the between-county variance in adult smoking. Last, model 4 (random intercepts and slopes model) built on the previous 2 models (models 2 and 3) by estimating the odds of being a current smoker with all level-1 and level-2 predictors accounted for simultaneously in the model. Model 4 also tested for specific interactions between the level-1 (respondents’ characteristics) and level-2 (county-level characteristics) variables. Hierarchical modeling was conducted by using HLM 7.02. . For results to qualify as significant as a whole, both levels had to be significant at P < .001) indicated significant spatial autocorrelation in the data — counties and their associated characteristics tended to be clustered together. Results of the spatial error regression model showed that 63.3% of the variability in county cigarette smoking was explained by the 6 county place-based characteristics included in the model. Of these place-based variables measured, percentage of population that was racial/ethnic minority, violent crime rate, and education level were significant.In P < .05) with similar high cigarette smoking prevalence as bordering counties; 3 counties were significant and negatively correlated with similar low smoking prevalence, whereas 96 counties that bordered some other studied counties were not spatially correlated.Forty-six states had at least 1 county represented in this study. Of 179 metropolitan counties in our study, 127 had borders with other counties in this study. Of these 127 counties, 28 were significant and positively correlated (P < .001). The intra-class correlation coefficient showed that 7.4% of the variance in smoking status was attributable specifically to the within-county level. This variance component in the null model indicated the significance of county characteristics on smoking behavior.The results of the hierarchical logistic regression analyses are presented in P < .001). The odds of being a current smoker were lower for increasing age , education level , and self-reported good health . Men had higher odds of being a current smoker than women . Hispanic , non-Hispanic black , and non-Hispanic Asian  adults had lower odds of being a current smoker than non-Hispanic white adults, whereas non-Hispanic other  adults had higher odds of being a current smoker than non-Hispanic white adults. Those with health insurance coverage had lower odds of being a current smoker than those without health insurance .In model 2, a random coefficients model with only individual participants’ variables (level-1) was performed with each level-1 predictor  being significant (P = .02) with increasing PCP density, as well as increasing percentage of minority population . Neither the type of metropolitan county (P = .06) nor the proportion of low-income residents without health insurance (P = .98) were significantly associated with smoking status.In model 3, the significance and direction of the relationship between the previously identified county-level (level-2) predictors and being a current smoker were assessed. The model showed that the PCP density and percentage of minority population of the county were significant with county-level smoking prevalence. The results showed the odds of being a current smoker were lower . This result suggests that a resident with a self-reported health status of good or better who lived in a county with high PCP density was less likely to be a current smoker than a resident with similar good or better self-reported health status who lived in a county with low PCP density.In model 4, the odds of being a current smoker were assessed when all significant residents’ characteristics (level-1) identified in model 2 and all significant metro county-level (level-2) factors identified in model 3 were simultaneously included in the model. The PCP density and minority population variables were added to the model simultaneously while maintaining the random effects of health and education. Results in model 4 showed a significant negative moderating effect of the county PCP density on the relationship between self-reported health status and smoking status ; thus, assessed counties are not representative of all metropolitan counties in the United States. Most (62.8%) US counties are nonmetropolitan . AlthougFindings from this study highlight the need for more novel approaches  in tobacco use prevention and control that consider local-level, place-based factors when addressing tobacco-related disparities. Our analysis explains the role of selected social and physical environmental characteristics for more than half of the variability in county adult cigarette smoking prevalence. The analysis examined both residents  and place-based  information to measure associations with cigarette smoking. To further understand how place-based characteristics influence cigarette smoking and mediate tobacco-related disparities, additional research at the micro (neighborhood) level is warranted. This type of information can help guide the placement of effective tobacco use prevention and control policies that consider the composition  and the context of places to optimize the effectiveness of tobacco control strategies.


Spiking Neural Networks (SNNs) are fast becoming a promising candidate for brain-inspired neuromorphic computing because of their inherent power efficiency and impressive inference accuracy across several cognitive tasks such as image classification and speech recognition. The recent efforts in SNNs have been focused on implementing deeper networks with multiple hidden layers to incorporate exponentially more difficult functional representations. In this paper, we propose a pre-training scheme using biologically plausible unsupervised learning, namely Spike-Timing-Dependent-Plasticity (STDP), in order to better initialize the parameters in multi-layer systems prior to supervised optimization. The multi-layer SNN is comprised of alternating convolutional and pooling layers followed by fully-connected layers, which are populated with leaky integrate-and-fire spiking neurons. We train the deep SNNs in two phases wherein, first, convolutional kernels are pre-trained in a layer-wise manner with unsupervised learning followed by fine-tuning the synaptic weights with spike-based supervised gradient descent backpropagation. Our experiments on digit recognition demonstrate that the STDP-based pre-training with gradient-based optimization provides improved robustness, faster (~2.5 ×) training time and better generalization compared with purely gradient-based training without pre-training. In this era of data deluge with real-time content continuously generated by distributed sensors, intelligent neuromorphic systems are required to efficiently deal with the massive amount of data and computations in ubiquitous automobiles and portable edge devices. Spiking Neural Networks (SNNs), often regarded as third generation brain-inspired neural networks Maass, , can be Training strategy for SNNs can be broadly categorized into unsupervised and supervised algorithms. Unsupervised algorithms discover the characteristics and underlying structures of input patterns without using the corresponding output labels. Spike-Timing-Dependent-Plasticity (STDP)  is suitable for training the systems. Both the STDP and spike-based BP learning have been demonstrated to capture hierarchical features in SNNs  whose temporal dynamics are formulated below.We use the biologically plausible Leaky-Integrate-and-Fire (LIF) model , gets modulated by the synaptic weight (w) to produce resultant current that is integrated by the post-neuron in its membrane potential. The membrane potential leaks exponentially subsequent to the removal of the input spike. The time constant, τm, determines the rate of membrane leakage over time, where a smaller value incurs a faster membrane potential decay and vice versa. When the accumulated membrane potential reaches a certain firing threshold, the LIF neuron fires an output spike to the fan-out synapses and is thereafter reset. The non-linear membrane potential decay and reset mechanisms help regulate the spiking activities of the post-neurons.The incoming spike (Dirac-delta pulse) occurring at time instant D vector that is fully-connected to the output layer which produces inference decisions. The fully-connected layer acts as a classifier to effectively incorporate the composition of features resulting from the alternating convolutional and pooling layers into the final output classes.The recognition of high-dimensional input patterns necessitates multi-layer network topologies that can effectively learn hierarchical representations from input stimuli. In this work, we use a convolutional neural network model that consists of an input layer followed by intermediate hidden layers and the final output layer as illustrated in Figure The proposed semi-supervised learning methodology is comprised of unsupervised pre-training followed by supervised fine-tuning using a spike-based gradient descent BP algorithm in a global fashion. The concept of unsupervised pre-training was introduced in Hinton et al.  to efficoffset. The synaptic weight is depressed for larger spike timing differences. The STDP weight updates are applied to the synapses only at the time instances of post-synaptic firing. Specifically, we use the weight-dependent positive-STDP rule whose characteristic is formulated as follows.Spike-Timing-Dependent-Plasticity (STDP) is a biologically plausible unsupervised learning mechanism that self-learns synaptic weights based on the degree of temporal correlations between the pre- and post-synaptic spike events. As shown in Figure w is the change in the synaptic weight, ηSTDP is the learning rate, tpre–tpost is the timing difference between pre- and post-synaptic spikes, τpre is the time constant controlling the length of the STDP timing window, and wmax (wmin) is the maximum (minimum) bound on the synaptic weight. The amount of weight change has a non-linear dependence on the current weight (w), which is specified by the product of (wmax-w) and (w-wmin). Smaller the absolute value of the current weight, larger is the ensuing weight change and vice versa as illustrated in Figure where ΔIn convolutional SNNs, the weight kernels locally inter-connecting the successive layers stride over the pre-neuronal maps to construct the output feature maps at every time step. In an event of a post-spike, the time difference between corresponding pre- and post-neuronal spikes is used to conduct individual STDP update on the convolutional weights. In case of multiple post-neuronal spikes in an output feature map, averaged STDP updates are applied to the kernel weights. Accordingly, the STDP learning enables the weight kernels to self-learn useful features from the complex input patterns. In addition to performing STDP updates on the weight kernels, we modulate the firing threshold of the units in the corresponding feature map to enable kernels  to learn different representations of input patterns. In the event of a post-neuronal spike in a convolutional feature map, we uniformly increase the firing threshold of all the post-units constituting the feature map. In the period of non-firing, the firing threshold of the feature map exponentially decays over time. Such threshold adaptation, referred as homeostasis  learning that is a widely used first-order gradient descent algorithm for ANN  are weighted by inter-connecting synaptic weights th layer, nl denotes the number of neurons in lth layer, tk represents the time instant at which pre-neuron spikes. The post-neurons fire output spikes when the respective membrane potentials exceed a definite neuronal firing threshold, after which the potentials are reset and the spikes are broadcast to the subsequent layer. This process is successively carried out by the post-neurons in every layer based on the incoming spikes received from the preceding layer to produce spike trains over time as shown in Figure where aj, of an LIF neuron is computed by integrating the unit spikes [at time instants tk in (4)] and decaying the resultant sum in the time period between successive spikes. The time constant (τp), which determines the rate of decay of the neuronal activation, accounts for the non-linear membrane potential decay and reset mechanisms that influence the spiking dynamics of the post-neuron. The activation of the output neurons in the fully-connected layer (classifier) is normalized to obtain a probability distribution over all final class predictions for a given input pattern. The final error (ej) for each output neuron is evaluated by comparing the normalized output activation with the target label (labelj) of the presented input as shown in (5). The corresponding loss function [E in (6)] is defined as the mean square of the final error over all the output neurons.The activation, Next, we detail the gradient descent backpropagation algorithm that is used to minimize the output loss in SNNs. We first estimate the gradients of the output loss with maximum likelihood at the final output layer and back-propagate the gradients all the way down through the network using recursive chain rule ] by multiplying the final output error [e in (5)] with the derivative of the corresponding post-neuronal activation (a′(netL)) in (8). Note that “.” denotes element-wise multiplication while “*” indicates matrix multiplication in the Equations (3–10). The neuronal activation [as described in (4)] is non-differentiable with respect to input current because of discrete time series output signals. To overcome this, we obtain a pseudo-derivative of post-neuronal activation by adding a unity value to the time derivative of the corresponding activation as formulated in (8). The time derivative of neuronal activation reflects highly non-linear (leaky) characteristics of LIF neuron model and adding a unity value facilitates ignoring the discontinuity (step jump) that arises at each spike time. The error gradient, δh, at any hidden layer is recursively estimated by back-propagating the error gradient from the successive layer [(wh)T*δh+1] and multiplying it with the derivative of neuronal activation [(a′(neth)] as formulated in (9). It is worth mentioning here that the presented spike-based BP algorithm mitigates the vanishing gradient phenomena, because the derivatives of the spiking neuronal activation [shown in (8)] do not saturate unlike saturating activation functions.The quantity, δl and l+1 [△wl in (10)] is determined by multiplying the transposed error gradient at l+1 (δl+1) with the normalized activation of the neurons in layer l. In case of convolutional neural networks, we back-propagate the error in order to get the partial derivatives of the loss function with respect to the given output feature map. Then, we average the partial derivatives over the output map connections sharing the particular weight to account for the effective updates of kernel weights. Finally, the calculated partial derivatives of loss function are used to update the respective weights using a learning rate (ηBP) as illustrated in (11). Iteratively updating the weights over mini-batches of input patterns leads the network state to a local minimum, thereby enabling the network to capture hierarchical internal representations of the data.The derivative of the output loss with respect to the weights interconnecting the layers C5−2P−10FC and the deep network is 28 × 28−20C5−2P−50C5−2P−200FC−10FC. The initial synaptic weights are randomly assigned at each layer following the weights initialization scheme  are set proportional to the strength of the synaptic distribution as shown below.In this section, we demonstrate the capability of the proposed semi-supervised learning strategy on the handwritten digit MNIST dataset  procedures using the parameters listed in Table First, we discuss the effectiveness of our semi-supervised learning methodology by evaluating the classification performance of the shallow and deep multi-layer networks on the MNIST test dataset. We compare our proposed semi-supervised training strategy  against standalone gradient-based supervised optimization without pre-training  for both shallow and deep networks. The spike-based gradient descent training follows an identical criterion in both pre-trained and purely supervised models with the exception of parameter initialization . Figure To further quantify the benefits of the STDP-based pre-training method, we plotted the classification errors with respect to training efforts for both the purely supervised and pre-trained models that have identical weight initialization in the beginning of training. We quantify training effort as the total number of training iterations required for error convergence. The plots in Figure Lastly, lets try to answer the following question: Does the STDP-based pre-training also provide the benefits when the network is initialized with different random initialization? To address this question, we perform an experiment that initializes the parameters of deep multi-layer SNNs with another initialization scheme [“Glorot initialization” costs on testing and training data to highlight the performance gap between the two scenarios. The negative-log-likelihood function is formulated below.nL represents the size of final layer, x is the output target labels and p(x) denotes the normalized firing rate of final output neurons. Figure L1/L2 weight decay (Hanson and Pratt, where Recent efforts in spiking neural networks have been focused toward building multi-layer systems to hierarchically represent highly nonlinear and complex functions. However, training hierarchical systems remains a difficult problem because of their inherent high dimensionality and non-convexity. In this work, we have shown that the convolutional spiking neural network comprising multiple hidden layers can be pre-trained with layer-wise unsupervised STDP learning and fine-tuned with supervised gradient descent BP algorithm. The unsupervised pre-training extracts the underlying structures from high dimensional input patterns in order to better initialize the parameters and supervised gradient-based BP algorithm takes the hierarchical system to optimal local minima. The proposed semi-supervised strategy benefits the training procedure to be more invariant to randomly assigned initial parameters, yields faster training and better generalization compared to purely supervised optimization without pre-training. We believe that STDP-based unsupervised initialization scheme coupled with state-of-the-art deep learning backpropagation algorithm can pave the way toward effectively optimizing deep spiking neural networks.CL and KR conceived the theory and research direction and CL implemented the algorithm and conducted the experiments. CL, PP, and GS discussed about the results and analysis, and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


High-resolution images of finger joints with chemical-shift elimination can be obtained using an interleaved water-fat (IWF) sequence. This study assessed IWF imaging of finger joints in the delineation of bone structures by comparing images of cadaver fingers with those of microcomputed tomography (CT) that served as a standard reference.IWF images with spatial resolution of 176 µ × 176 µ × 300 µ were obtained from the distal and proximal interphalangeal joints of two cadaver finger specimens using a custom-built radiofrequency receive coil at 1.5T. Regular three-dimensional gradient-echo (GRE) images were also acquired with similar parameters and compared with the IWF images to evaluate the effects of chemical shift. Micro-CT scans were obtained and served as the standard reference. The image data were reviewed by two experienced musculoskeletal radiologists in consensus. The delineation of normal joint structures and abnormalities in the finger specimens as revealed by the magnetic resonance imaging (MRI) and micro-CT images were compared. The IWF and regular GRE images were assigned scores 0–3 for the depiction of apparent marginal bone defects, with zero being the same in appearance to the micro-CT image and three as having minimal resemblance to it. Statistical analysis of the scoring results was conducted to compare the two MRI techniques.The high-resolution IWF images provided accurate delineation of bone and calcified structures as seen in micro-CT. The thickness of subchondral bone was depicted similarly on the IWF water + fat and the micro-CT images but not on the regular GRE images. The regular GRE sequence showed false marginal bone defects not observed with IWF and micro-CT. In addition, the IWF water-only images facilitated the identification of bone cyst by revealing its water content.High-resolution IWF imaging should be useful for the early diagnosis and treatment assessment of arthritis and should also benefit basic research in the pathophysiology of the disease. However, MRI of finger joints is difficult due to their small size. Partial volume effects hinder the visualization of lesions and the bone. Accurate assessment of the bone is important as para-articular erosion portends irreversible joint damage. Patients with bone damage at an early stage of arthritis need to be identified and monitored closely. To provide the optimal signal and image resolution for MRI of finger joints, dedicated radiofrequency (RF) coils were developed.Magnetic resonance imaging (MRI) is more sensitive than plain radiographs in detecting arthritis that will benefit from early aggressive treatment.,12 and at times resemble erosive changes.,13 Studies found mismatches in erosion detection between MRI and computed tomography (CT).,15 In addition, chemical-shift artifacts alter the appearance of subchondral bone,13,16 and may affect the early detection of osteoarthritis. To eliminate chemical-shift artifacts, an interleaved water-fat (IWF) sequence had been developed and applied to high-resolution finger imaging. It acquires both water-only (fat-suppressed) and fat-only images and eliminates chemical-shift artifacts in the combined water + fat (nonfat-suppressed) images. The objective of this study was to evaluate high-resolution IWF imaging of finger joints in the depiction of bone structures by acquiring images of cadaver fingers and compared with micro-CT.Another obstacle to finger MRI is chemical-shift artifacts that hinder the evaluation of bone and other structuresTwo cadaver finger specimens obtained from the National Disease Research Interchange  were used. According to the information provided by NDRI, they were harvested from two donors – a normal finger from a 68-year-old male and an arthritic finger from a 71-year-old male with unspecified arthritis. These fingers were among the second-to-fourth digits of the hand. They were preserved in a freezer and were thawed at room temperature before the use. The Institutional Biosafety Committee of our institution approved this study.MR imaging was conducted on a General Electric  1.5T scanner with maximum gradient amplitude of 40 mT/m and maximum slew rate of 150 T/m/s. An RF receive coil specially developed for finger joints was used to obtain high-resolution images. The coil consisted of a copper tape loop 2.9 cm in diameter and 2.0 cm in width and had a similar design as the one described in Reference 10. For scanning, the coil was placed with its axis perpendicular to the main magnetic field. The finger specimen was inserted through the coil with the joint being imaged centered in the coil. The distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints were imaged separately.,18 It excited and acquired water-only and fat-only signals in an interleaved manner during each repetition time (TR) period ), and this was also the case when each imaging plane  was considered separately . The regular GRE sequence showed false marginal bone defects not observed with IWF and micro-CT [For the comparison of apparent marginal bone defects  and 2, tmicro-CT , which wThe ability of IWF to reveal other abnormalities in finger joints was also demonstrated in this study. Articular cartilage calcification was observed on IWF water + fat images as seen with micro-CT . A bone This study demonstrated the ability of high-resolution IWF technique to accurately delineate bone structures in finger joints by comparing IWF and regular GRE images of cadaver finger specimens with micro-CT that served as the reference standard.Our results indicate that, with the removal of chemical-shift artifacts, high-resolution IWF imaging can improve the depiction of bone and calcified structures in finger joints and avoid the false appearance of marginal bone defects as observed in the regular GRE images. In addition, IWF also provides water-only images that enable water content inside bone structures such as bone cyst to be clearly identified and distinguishes them from the fatty bone marrow in trabecular structures without the need of any signal intensity/density measurements as in CT. can eliminate chemical-shift artifacts, they require multiple acquisitions that increase scan time.Although utilizing higher receive bandwidth can reduce chemical-shift artifacts, this approach is not desirable for high-resolution imaging due to the associated decrease in signal-to-noise ratio (SNR) and the increase in gradient amplitude that limits spatial resolution. On the other hand, while pulse sequence techniques such as IDEAL Besides, micro-CT offers several advantages over histology. It can be used to visualize the whole finger joint, and its 3D data acquired with resolution in tens of microns can be reformatted to match closely with the corresponding MRI in any plane. In contrast, histology provides only a limited number of cross sections in a given plane, and the FOV may cover only a small portion of the joint. Furthermore, micro-CT is noninvasive and does not damage or change the joint structures as in histology.In this study, micro-CT was used as the reference standard instead of histology since our focus was in bone and calcified structures, and CT-based techniques are often considered the gold standard for bone evaluation.While CT can provide clear depiction of bone structures in finger joints, it is less desirable for clinical use due to its ionizing radiation and its relatively low image contrast in soft and connective tissues. On the other hand, although ultrasound has been used for imaging finger joints, it is less sensitive in detecting bone erosions compared to MRI. In a study comparing ultrasound with CT of finger joints, small erosive lesions of <2 mm were found to cause false-negative results in ultrasound, whereas osteophytes mimic erosive lesions and led to false-positive results. The minimum scan time for the regular nonfat-suppressed and fat-suppressed scans is 6.4 min and 11.0 min using the minimum TR of 23 ms and 40 ms, respectively, resulting in a combined minimum scan time of 17.4 min that is longer than the IWF scan of 14.2 min. The scan time for IWF may be reduced by using partial echo acquisition, though the effect to SNR and image quality will need to be assessed.A potential limitation of the high-resolution IWF imaging in this study is the relatively long scan time of 14.2 min. It results from the use of the 3D matrix size of 256 × 256 × 64 and longer TR to achieve the high image resolution. For the regular nonfat-suppressed and fat-suppressed scans, the minimum TR values are 23 ms and 40 ms, respectively. For the IWF scan, the minimum TR is further lengthened to 52 ms to accommodate the separate water and fat acquisitions in each TR period . Despite the longer associated scan time, the longer TR is actually advantageous in that it provides higher signal to support the high-resolution acquisition. We found in a separate test that by increasing TR from the minimum value of 23 ms to 52 ms in the regular nonfat-suppressed GRE scan, SNR in the muscle was increased by about 50%. Furthermore, the IWF sequence provides both water + fat and water-only images in a single scan, thus saving the time to acquire both the conventional nonfat-suppressed and fat-suppressed scans. Dedicated hand/fingers phased array coils such as this may enable high-resolution IWF imaging of multiple fingers.Another limitation of the technique used in this study is that each finger joint was imaged separately due to the custom single-loop RF coil used, and this restricts its potential clinical applications. Recently, a new flexible hand coil that provides high signal and full coverage for all fingers in a hand has been reported.This study has characterized and verified the high-resolution IWF imaging findings in the bony and calcified structures of finger joints. This technique is able to reveal detailed structural information of finger joints that may not be seen with conventional MRI, and its elimination of chemical-shift artifacts provides accurate depiction of bone structures and avoids the false appearance of erosions. Potential applications of the technique include early diagnosis, monitoring of disease progression, and evaluation of the effects of early treatment of arthritis. This technique should also be useful for basic research in the pathophysiology of arthritis, such as early disease mechanisms in bone and cartilage, which may lead to improved treatment of the disease.


Three quantitative structure-activity relationship (QSAR) models for predicting the affinity of mu-opioid receptor (μOR) ligands have been developed. The resulted models, exploiting the accessibility of the QSAR modeling, generate a useful tool for the investigation and identification of unclassified fentanyl-like structures. The models have been built using a set of 115 molecules using Forge as a software, and the quality was confirmed by statistical analysis, resulting in being effective for their predictive and descriptive capabilities. The three different approaches were then combined to produce a consensus model and were exploited to explore the chemical landscape of 3000 fentanyl-like structures, generated by a theoretical scaffold-hopping approach. The findings of this study should facilitate the identification and classification of new μOR ligands with fentanyl-like structures. Papaver somniferum were widely used as a medicine DAMGO from the human μOR was used for the determination of all of the Ki values, were selected. The binding affinity data were converted into their negative decimal logarithm pKi (pKi = −logKi).The chemical structures of all the molecules were retrieved from the ChEMBL database selecting only those tested for their affinity for the human μOR (available online: zerland)  was usedThe two-dimensional structures of the dataset were built using Marvin Sketch . The protonation states of the molecules were calculated assuming a neutral pH, and the Merck molecular force field (MMFF94) was used for a first 3D geometry optimization. Subsequently, the geometry of the resulting 3D structures was optimized at a semi-empirical level using the parameterized model number 3 (PM3) Hamiltonian as implemented in the MOPAC package  ,32.Ki range from 10.1 to 5.3. Ten different splits were tried and the results were consistent to the reported ones. All the fentanyl-like molecules were aligned using fentanyl in its previously reported conformation [All the fentanyl-like 3D-optimized structures were imported into the software Forge   to set tormation . The fieormation ,35. The The present study explores the development of three QSAR models exploitable for the prediction of a ligand affinity to the μOR, and for the identification of new molecules that could efficiently interact with such receptor class. Forge was employed to build a statistically robust QSAR evaluating methodology using a set of 115 fentanyl-analogs covering a wide range of known μOR ligands. An activity cliff analysis followed by a scaffold-hopping approach has been performed to provide a theoretical route for the exploration of novel unidentified fentanyl-analogs with high potency. The QSAR models reported here will guarantee, prospectively, fruitful applications to speed up the design and the identification process of new μOR ligands with tunable activities. Since μOR fentanyl-like ligands currently represent a well-explored class of synthetic opioids, often associated with fatal cases worldwide, this proposed ligand-based tool could be considered by the DEA, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), and other regulatory bodies for speeding-up the classification of novel fentanyl-like NPS. Likewise, the newly identified libraries may potentially aid the interpretation of toxicological analyses where the presence of novel synthetic opioids is postulated.


Toxicodendron radicans (poison ivy) as well as other Toxicodendron species. They are alk-(en)-yl catechol derivatives with a 15- or 17-carbon side chain having different degrees of unsaturation. Although several methods have been developed for analysis of urushiols in plant tissues, the in situ localization of the different urushiol congeners has not been reported. Here, we report on the first analysis of urushiols in poison ivy stems by matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI). Our results show that the urushiol congeners with 15-carbon side chains are mainly localized to the resin ducts, while those with 17-carbon side chains are widely distributed in cortex and vascular tissues. The presence of these urushiols in stem extracts of poison ivy seedlings was confirmed by GC-MS. These novel findings provide new insights into the spatial tissue distribution of urushiols that might be biosynthetically or functionally relevant. Urushiols are the allergenic components of  Toxicodendron radicans (poison ivy) and Toxicodendron diversilobum (poison oak) are well known for causing contact dermatitis in sensitive individuals + ions with a mass tolerance less than 10 ppm for all selected ions. For an urushiol standard, and to evaluate the behavior of the molecules in MALDI-MS, extracts obtained from the Japanese lacquer tree (T. vernicifluum) were also spotted on a glass slide, coated by DHB matrix via sublimation and analyzed by MALDI-MS using the same conditions as with the tissue sections. MALDI-MS images were generated using ImageQuest software ; intensity of the selected ions were normalized to the total ion count before generating the images. The MALDI-MSI method was similar to that described in Woodfield et al. . Lyophi


Although cerebral fat embolism syndrome is a clinical diagnosis, Diffusion weighted-MRI (DW-MRI) of the brain showing a “Star Field” pattern of multiple small high-intensity lesions with diffusion restriction supports the diagnosis.An 89-year-old male patient was diagnosed with degenerative osteoarthritis of the left knee joint and admitted for unilateral total knee replacement arthroplasty (TKR). Postoperatively (on day 2), the consciousness of the patient rapidly deteriorated with the Glasgow Coma Scale (GCS) falling to 7/15, and he required ventilation and intubation to maintain oxygen saturation level.A chest radiograph showed bilateral lower lobe opacities Figure . ComputeThe diagnosis of fat embolism syndrome (FES) is a clinical one and related to the release of fat droplets into the systemic circulation after for example an orthopedic intervention. The diagnosis is based on Gurd’s and Wilson’s criteria which require the presence of at least one major and at least four minor criteria Table .The pathophysiology of the fat embolism is not clearly established. Two mechanisms have been postulated . First, The diagnosis of fat embolism syndrome is characterized by the classical triad of petechial rash, respiratory distress, and neurological dysfunction. MRI of the brain is a very sensitive technique to confirm the diagnosis of cerebral fat embolism; DWI, in particular, can show the typical “Star Field” pattern with multiple, non-confluent, small hyper-intense foci in the cerebral white matter and deep grey matter in a symmetric distribution.


To investigate the relationship between anterior capsule polish and visual function.Data were obtained from Pubmed, Embase, Web of Science, WanFang, VIP and CNKI up to the end of May 2018, without any date or language restrictions for trials. The modified Jadad scale and the newcastle-ottawa scale were used to assess the quality of included studies. Uncorrected visual acuity (UCVA) and posterior capsule opacification (PCO) were used as outcome variables. Data on anterior capsule polish were pooled using weighted, random-effect meta-analysis.One randomized controlled trial and 4 observational cohort studies involving 2533 patients were included in the analyses. There was a statistically significant difference of UCVA  between the polish group and the control group, indicating that anterior capsule polish improved UCVA. Further studies with continuous data also suggested that anterior capsule polish was associated with good UCVA . Posterior capsule opacification rate for 1-year or longer follow-up were extracted for 2561 eyes in 3 studies. Posterior capsule opacification rate was lower in the anterior capsule polish group according to summary odds ratio on PCO rate (OR 0.42 95% CI 0.24–0.73).Anterior capsule polish prevents complication of modern cataract surgery and benefits on visual function in short term follow-up period. Age-related cataract is lens opacification and the common cause of blindness for elders in the world. The Chinese Center for Disease Control and Prevention estimated that 2.91 million Chinese aged 50 years or older had cataract in one or both eyes in 2010. ApproximThe incidence of PCO could be prevented by multiple methods, including anterior capsule polish, the sharp rim of IOLs, the material of IOLs, posterior capsulorhexis and medicine.–14 HowevAlthough many studies have characterized the effectiveness of anterior capsule polish on PCO, there was little concentration on the effect of polish on visual function. In this study, we performed a meta-analysis to investigate the effect of anterior capsule polish on visual function.This systematic review and meta-analysis were performed in an academic medical setting according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Cataract” and “polishing” were the main terms used for comprehensive literature search to identify relevant studies. A hand search by reading references of identified studies was performed by 2 authors (HMY and YJ) independently. The detailed searching strategy for Pubmed was listed as followed: ("cataract "[MeSH Terms] OR ("cataract"[All Fields]) AND ("anterior capsule"[MeSH Terms] OR "anterior capsule"[All Fields]) AND "polishing"[All Fields].The reports of anterior capsule polish were searches in consultation with Pubmed, Embase, Web of Science, WanFang, VIP, China National Knowledge Internet (CNKI) electronic databases for the reports of anterior capsule polishing up to the end of May 2018. No date or language restriction was used in the electronic searches for the trials. Neither was study design. “The eligibility of studies was assessed by 2 authors (HMY and YJ) independently via reading titles and abstracts. Endnote was used as the literature manager system to remove the duplicated publications. After that, 2 authors (HMY and YJ) independently screened the full-text papers with the inclusion criteria for the meta-analysis: (1) Participants, population of interest were patients with age-related cataract; (2) intervention, anterior capsule was polished intraoperatively; (3) outcome variables, at least 1 of primary outcome was reported: PCO rate, uncorrected visual acuity (UCVA).The methodological quality of identified studies was assessed by 2 reviewers (HMY and YJ) independently to reduce the influence of different bias. The quality of randomized controlled trials (RCTs) was identified by the modified Jadad scale with a scale of 0 to 7. The modified Jadad scale included the following domains: randomization, blinding and patient attrition. Studies with scores higher than 4 were regarded as high quality. The qualThe data were extracted from high quality studies by 2 authors (HMY and YJ) independently. The characteristics of eligible studies were recorded as first author, year of publication, study design, participants number, the period of follow-up, polish area, IOL type and outcome variables. We contacted the correspond authors for the missing information. The primary outcomes were recorded at different time points, such as one-month or one-year. Visual function variables including PCO rate and UCVA were extracted at different time points. If there were published studies on the same group of patients, more recent and complementary data were used in the meta-analysis.I2 and the chi-square statistic. I2<50% was considered to no heterogeneity among the included studies in a meta-analysis. We evaluated the pooled summary effect in random effect model. Publication bias was assessed using the funnel plot.All statistical analyses were performed using RevMan 5.2 software . Studies defined as the publication year were classified into different subgroups, depending on the follow-up periods. We pooled dichotomous data in odds ratio (OR) with 95% confidence intervals (CI), such as PCO rate and patient number of good uncorrected visual acuity. Continuous data were pooled using mean differences (MD) with 95% CI, such as visual acuity. Heterogeneity was analyzed through chisquare test. Heterogeneity was calculated by Our search strategy identified 266 articles through electronic searches of multiple databases up date to May 2018. After deduplication, irrelevant articles were removed by screening titles and abstracts, excluding case reports, review and other objectives. A total of 35 full-text articles were selected for potential inclusion in the meta-analysis. Finally, 5 full-text articles were included in the meta-analysis with the inclusion criteria, of which 1 study identified RCT and the others were observational cohort studies. There were 3 Chinese studies and 2 English studies in the meta-analysis.,19–22 WeThe characteristics of the included articles are shown in the I2 = 0%). Based on 2 studies that evaluated uncorrected visual acuity after anterior capsule polish, there are more events in the polish group than unpolish group at both one-month  and longer follow-up period time points .[The meta-analysis aimed at effects of anterior capsule polish on visual function. The primary outcomes for the meta-analysis were UCVA and PCO rate. Uncorrected visual acuity as UCVA of more than 0.8 was defined as good. The number of patients with good UCVA was little at one time point, therefore we discussed UCVA in different subgroups at depended on different time points and pooled summary effects together. Our results showed that UCVA was improved by anterior capsule polish. The meta-analysis results comparing patient numbers of good UCVA between anterior capsule polish group and unpolish group were shown in to 3.55).,22 The sto 3.55).,19We defined the PCO as flaggy or schistose opacification appeared on the posterior capsule after phacoemulsification. The PCO Visual inspection of funnel plots by follow-up and patient number of good UCVA did not reveal any asymmetry At present, cataract is the leading cause of blindness in the world and PCO remains the most common complication of modern cataract surgery. If the LECs were removed completely, PCO would be avoided possibly. There were controversial conclusions about anterior capsule polish in different studies. Therefore, a meta-analysis is required to evaluate the effects of anterior capsule polish on visual function. Our meta-analysis showed that the surgical method of polish was associated with visual function. The results of meta-analysis indicated that anterior capsule polish improved visual function.In the meta-analysis, the PCO rates and visual acuity were performed as outcome variables based on the 5 included studies. Anterior capsule polish improved UCVA in 3-years follow-up period. The following factors are considered as reasons for good UCVA in polish group: anterior capsule opacification, capsule contraction, capsule stability, effective lens position.,26 The pin vivo was presented in style of PCO, which was not directly obtained from human clinically. PCO impairs visual function after modern cataract surgery by reducing visual acuity and increasing intra-ocular straylight. Capsule opacification leads to scattered light.[The migration of LECs on the posterior capsule leads to PCO. The presented study assessed the short-term influence of anterior capsule polish on PCO rates. The results of our meta-analysis found that incidence of PCO in polish group was less than that of unpolish group in short-term follow-up period. The longest follow-up among included studies was 3 years, indicating unclear effects of anterior capsule polish on longer follow-up period. A study showed that was no statistically significance different in 5-years follow-up between polish group and unpolish groups. The diffed light. The degrin vivo should be investigated in future.Many complications of modern cataract surgery are associated with the proliferation of LECs. Various means to destroy LECs, such as mitosis, heating, freezing, laser and trypsin, are not applicable. In animaMany studies investigated the relationship between anterior capsule polish and PCO occurrence. Our meta-analysis focused on the effects of anterior capsule polish on visual function. In addition, our meta-analysis was performed in an academic medical setting according to PRISMA guidelines.One limitation of our review was that 4 included studies were observational cohort studies. We hope that more RCTs about anterior capsule polishing will be performed in future. Another limitation was the short-term follow-up period. A longer follow-up period will help the clinicians better understand the surgical method of polish on visual function. The article number of our meta-analysis is also limited. Although we conducted a thorough electronic search and a manual search of the relevant publications, there were only 1 RCTs on the relationship between anterior capsule polish and visual function. More relevant RCTs would enrich our understanding on the effects of polish on visual function.Anterior capsule polish prevents complication of modern cataract surgery and has good effects on visual function in short term follow-up period. Future studies are required to identify the relationship between anterior capsule polishing and refractive error.Anterior capsule polishing would prevent complication of modern cataract surgery and have good effect on visual function in short term follow-up period. Future studies are required to relationship between anterior capsule polishing and refractive error.S1 Checklist(DOC)Click here for additional data file.


We evaluated the feasibility of combined hippocampal- and scalp-sparing intensity-modulated radiotherapy (IMRT) plans. This study included 7 patients who received conventional palliative whole brain radiation treatment (WBRT) for brain metastasis. The brain, hippocampus, and scalp were contoured and replanned with intensity modulated radiation therapy. The prescription dose was 30 Gray (Gy) in 10 fractions with hippocampus and normal structure constraints per the Radiation Therapy Oncology Group (RTOG) 0933 protocol. Further planning was done to minimize the scalp dose while maintaining the dose constraints for the hippocampus. Dose volume histograms were obtained from conventional opposed lateral fields, IMRT and compared. Planning target volume (PTV) coverage for all plans fell within the RTOG 0933 critical structure acceptable variation category. When compared to traditional opposed lateral fields, the IMRT plan with combined hippocampal- and scalp-sparing constraints was able to significantly reduce the max and mean scalp dose as well as the percentage of scalp receiving 10 and 20 Gy by 46% and 35%, respectively, while maintaining acceptable RTOG 0933 hippocampal dose variations. We conclude that acceptable PTV coverage and sparing of the scalp and hippocampus can be accomplished using a 9-field non-coplanar IMRT plan. Prospective study is warranted to understand the impact on radiation induced alopecia. Brain metastases account for approximately 15% - 30% of all intracranial tumors, and it is estimated that 25% - 30% of patients with cancer and 50% of patients dying from their disease will develop brain metastases [WBRT, a mainstay in the treatment of brain metastases, has been shown to improve the 1 – 2 month median survival of patients with brain metastases treated with corticosteroids to approximately 6 months –5. This et al., patients reported that along with fatigue, hair loss was the most distressing physical symptom associated with the WBRT [In addition to neurologic side effects, WBRT causes distressing physical side effects, most notably iatrogenic alopecia. In a study by Irvine the WBRT . In an aet al. [Seven patients who had previously undergone CT simulation of the brain for conventional WBRT between June 2011 and December 2011 at Thomas Jefferson University Hospital for brain metastases were selected for repeat planning. Patients with metastases within 5 mm of either hippocampus were excluded. The patients had previously undergone non-contrast computed tomography (CT) scan with aquaplast mask fixation. Additionally, all patients had previously received MRI of the brain including T1 post-contrast, T2, and fluid attenuation inversion recovery (FLAIR) sequences. These scans were fused to the CT simulation images and contouring was subsequently performed using Xio FocalSim . The hippocampus was contoured as previously described by Gondi et al. . Additio® planning software  to cover the cranial contents with a 1 cm margin on the base-of-skull and extending into air around the cranial vault. The collimator was angled to follow the base-of-skull and the inferior border was blocked at the C1 and C2 vertebral body disk space. The chosen prescription point was mid-plane in the center of the clinical target volume (CTV). Cumulative dose-volume histograms were then produced for the PTV, hippocampi, and scalp.Standard opposed lateral fields using 6 MV photons were planned in XioPatients were simulated in the supine position with their arms down. CT images  for 30 degrees head holder angle were artificially generated by rotating CT scans derived with 0 degree position. Original CT scan was imported to MIM vista software system , rotated along left-right axis (pitch) by 30 degrees, and then re-sampled to create a new CT image that mimics a 30 degrees head angle position. The contours in the 0 degree CT image were then transferred to the rotated image by fusing two images together through rigid registration.® planning software (Elekta) and 6 MV photons. Clinical criteria and inverse planning algorithm constraints for the LINAC-based IMRT planning are listed in  The same data set previously used for the conventional plan was transferred to the inverse planning system. The number and directions of beams were chosen empirically in order to optimize scalp sparing and PTV dose conformality. The chosen geometry had a total of 9 non-coplanar beam angles. Optimization parameters were chosen in an attempt to obtain a homogenous coverage of the PTV and to minimize the dose to the scalp. The dose was scaled to cover 90% of the PTV to meet RTOG 0933 constraints.Inverse-planning was performed using Xiot-Test with an upper bound of p < 0.05.Comparisons of dose volume histogram parameters were assumed to be normally distributed and were analyzed with the Student’s paired .Acceptable PTV coverage is achievable with combined hippocampal- and scalp-sparing IMRT. We evaluated whole brain PTV coverage of 7 patients planned with opposed laterals, hippocampal-sparing IMRT, and combined hippocampal- and scalp-sparing IMRT plans by comparing values generated by their respective dose volume histograms. According to RTOG 0933, 90% of the PTV is required to be covered by the prescription dose of 30 Gy with 2% of the PTV receiving no more than 37.5 Gy and at least 98% receiving 25 Gy. Despite better PTV coverage and lower maximum point doses with the opposed lateral field arrangement, both hippocampal- sparing and combined hippocampal- and scalp-sparing IMRT met the RTOG 0933 constraints . We noted no significant difference in maximum, minimum, and mean hippocampal doses between the hippocampal- sparing  and combined hippocampal- and scalp-sparing   for IMRT plans. Both IMRT plans met the acceptable variations dose requirements of RTOG 0933  techniques are gaining momentum in the treatment of many sites given their quick delivery times. In our initial experience with these planning techniques, similar scalp dosimetry was achievable; however, dual sparing of the hippocampus and scalp was not, which may limit clinical utility of arc delivery.We demonstrate here for the first time the feasibility of combined hippocampal- and scalp-sparing IMRT. Reductions to the average scalp dose by approximately 45% while maintaining adequate PTV coverage and hippocampal-sparing are achievable. The clinical implications of such a technique could be addressed in future trials evaluating hippocampal-sparing as we show no change in dose reduction to the hippocampi or for PTV coverage.