Malnutrition is a condition most commonly arising from the inadequate consumption of nutrients necessary to maintain physiological health and is associated with the development of cardiovascular disease, osteoporosis, and sarcopenia. Malnutrition occurring in the hospital setting is caused by insufficient monitoring, identification, and assessment efforts. Furthermore, the ability of health care workers to identify and recognize malnourished patients is suboptimal. Therefore, interventions focusing on the identification and treatment of malnutrition are valuable, as they reduce the risks and rates of malnutrition within hospitals. Technology may be a particularly useful ally in identifying malnutrition due to scalability, timeliness, and effectiveness. In an effort to explore the issue, this scoping review synthesized the availability of technological tools to detect and identify hospital malnutrition.Our objective was to conduct a scoping review of the different forms of technology used in addressing malnutrition among adults admitted to hospital to (1) identify the extent of the published literature on this topic, (2) describe key findings, and (3) identify outcomes.We designed and implemented a search strategy in 3 databases . We completed a descriptive numerical summary and analyzed study characteristics. One reviewer independently extracted data from the databases.We retrieved and reviewed a total of 21 articles. We categorized articles by the computerized tool or app type: malnutrition assessment (n=15), food intake monitoring (n=5), or both (n=1). Within those categories, we subcategorized the different technologies as either hardware (n=4), software (n=13), or both (n=4). An additional subcategory under software was cloud-based apps (n=1). Malnutrition in the acute hospital setting was largely an unrecognized problem, owing to insufficient monitoring, identification, and initial assessments of identifying both patients who are already malnourished and those who are at risk of malnourishment. Studies went on to examine the effectiveness of health care workers (nurses and doctors) with a knowledge base focused on clinical care and their ability to accurately and consistently identify malnourished geriatric patients within that setting.Most articles reported effectiveness in accurately increasing malnutrition detection and awareness. Computerized tools and apps may also help reduce health care workers’ workload and time spent assessing patients for malnutrition. Hospitals may also benefit from implementing malnutrition technology through observing decreased length of stay, along with decreased foregone costs related to missing malnutrition diagnoses. It is beneficial to study the impact of these technologies to examine possible areas of improvement. A future systematic review would further contribute to the evidence and effectiveness of the use of technologies in assessing and monitoring hospital malnutrition. An inadequate diet can cause malnutrition, a condition where an individual is not consuming sufficient amounts of nutrients necessary to maintain their current level of physiological health .Malnutrition increases the risk of developing certain chronic diseases, such as cardiovascular disease, osteoporosis (a debilitating loss of bone density), and sarcopenia  ,2. AdditHospital malnutrition has been a historical problem as well as a current troubling issue, with documented prevalence rates as high as 60% in some hospitals . MalnutrAddressing, identifying, and monitoring malnutrition properly may improve the outlook for older hospitalized patients. Interventions that focus on identification and treatment of malnutrition have positive influences on decreasing the risks and rates of malnutrition in hospitals . FurtherThere are no known scoping reviews, to the best of our knowledge, that have synthesized the availability of technological tools to detect and identify hospital malnutrition. Therefore, we undertook a scoping review of the literature to identify the extent of the published literature on this topic, describe key findings, and identify outcomes.We followed Arksey and O’Malley’s  scoping The research questions were as follows: What is the extent of the published literature on using technology to monitor and assess malnutrition within the hospital setting? What is known from the existing literature about the impact and outcomes of implementing technology in such a manner?We initially developed the complete search in PubMed  and thenWe selected primary articles for inclusion in the scoping review if they discussed applicable technology-based approaches to monitor or assess malnutrition within the hospital or primary care setting. Articles not written in or translated into English were not included.The definition of “applicable” included systems that were described, designed, or in current use and application at the hospital or primary care setting. We screened articles to determine relevancy of the systems.AND(Monitoring [tw] OR Screening [tw] OR Technology-based dietary assessment [tw] OR Food record [tw] OR Recording [tw] OR Assessment [tw])ANDANDTechnology-based approaches referred to any tool or system that was technology driven or computer based, and that comprised a hardware component or a software component (including Web- and cloud-based apps). Essentially, technology-based approaches excluded any conventional nutrition support tools that only included paper-based methods traditionally used for nutrition assessment.We excluded studies that primarily considered nontechnologically driven or noncomputer-based solutions to address hospital malnutrition. We also excluded technologically driven or computer-based solutions based in hospitals, such as hospital accounting systems or inventory systems, that had no relevance to nutrition. For the purposes of our review, we excluded studies that primarily dealt with nutrition management systems focusing on prenatal and neonatal patients. The primary aim of this scoping review was to identify technologically relevant systems for use in hospitals for adults.We selected articles in the following 2 phases: (1) title, abstract, and keyword review phase, and (2) full-text review phase.Phase 1 review considered all search results. We developed a relevance form adapted from the template used by Griebel et al  to aid tWe organized the articles according to what the tool or app measured: malnutrition assessment, food intake monitoring, or both. Within these 3 categories, we subcategorized the articles by the type of technology used: software (including cloud-based apps), hardware based (including portable devices), or both.The goal of this scoping review was to analyze eligible articles to obtain an overview of the scientific literature on technological and computer-based approaches to nutrition monitoring and assessment in hospitals. With this goal in mind, we summarized and present the collection of key messages and concepts from eligible publications. We developed a data synthesis and characterization form to include the following study characteristics: authors; year of publication; country of origin; publication type; aims and purpose; description of the patients or participants; description of the article; type of technology used ; availability of the tool or app ; outcomes of the intervention; and cost implications (if available).The search returned 5444 articles. We deemed a total of 21 of those articles to be relevant after phase 1 and 2 reviews. Malnutrition assessment was the most frequent aim , followed by nutrition intake monitoring , followed by an app that measured both components  .Most of the malnutrition assessment articles discussed technology based on software created and incorporated within the hospital’s own computer system . Subcategorized within the software category was an article that proposed a cloud-based system for malnutrition assessment . Some studies directly used a hardware component (portable device) that assessed malnutrition .Among the food intake monitoring articles, 2 (40%) studies contained a hardware component and 3 (60%) used technology that contained both a hardware and a software component.One article mentioned an inclusive nutrition system that contained technology for both malnutrition assessment and food intake monitoring. The largest share of publications on the topic originated from the United States , followed by the United Kingdom , Spain , Taiwan, Philippines, the Netherlands, France, China, Australia, Argentina, and Israel, each with 1 article .Most of the articles reported semiexperimental studies (n=16), followed by descriptive studies (n=3), a randomized controlled trial , and a retrospective study (n=1). Semiexperimental studies may dominate the field because they all introduced a novel malnutrition assessment or nutrition intake monitoring tool, which was primarily being tested for accuracy and effectiveness  against universally accepted and standardized malnutrition assessment tools  or expert opinions.Most of the studies tested their tools and apps on patients or participants (n=14). Additionally, most of the studies reported that their tool or app was able to increase malnutrition detection or awareness (n=14). The same articles reported a degree of accuracy respective to their tool or app as determined by using validated tools  or clinical nutrition expert and dietician consultations or testing (n=15).A key concept mentioned in some of the articles that included a software component is automated data collection. For example, some software systems included features that allowed other departments within the hospital, such as the biochemical laboratory, to update a patient’s blood test results automatically -19. In aAnother feature of software apps was the ability to display a nutrition diagnosis , an automated warning, or an alert once relevant data parameters were assessed. Some apps provided automated alerts that informed health care workers when a patient was assessed as being at risk for malnutrition ,17,19,21Only 1 study had cloud-based technological components. It allowed health care workers to create an account, log in, and begin manually entering patient data, such as biochemical markers . AfterwaFor the hardware component, portable devices were used to assess malnutrition risk. Largely based in the 1980s, these portable devices were pocket computers, where physical, anthropometric, and laboratory results could be manually entered to produce a malnutrition assessment ,28. InclMost of the interventions had successful outcomes  ,29,31-34In addition to saving time and improving detection rates, 4 articles discussed the economic benefits and potential costs saved from incorporating the mentioned technology into practice ,23,31,34Of the tools and apps reviewed, less than half (n=9) were available for further clinical testing and implementation within other hospital systems ,31,33,34The 2 research questions formulated at the beginning of this scoping review were as follows: What is the extensiveness of the existing literature? What are the key impacts and outcomes? We discuss the outcomes in terms of effectiveness and accuracy of tools and apps; financial implications; efficiency and educational implications; and future and ethical implications.A total of 15 of the 21 tools and apps examined in this scoping review were effective in accurately increasing malnutrition detection and awareness using either malnutrition assessment apps or nutrition intake monitoring tools ,31-34,36only be effective, but they may also have a degree of accuracy similar to current and widely used conventional malnutrition assessment tools. However, only Brieux et al [Effectiveness was tested in a variety of ways, including evaluation studies, an RCT, and prototype testing conducted on a sample of patients or participants. The malnutrition assessment apps’ effectiveness and accuracy were tested against common practice-validated nutrition screening tools used globally by hospitals, such as the MNA-SF, SGA, and FNA tools; or they were directly assessed based on expert opinions of clinical dieticians and clinical nutrition experts. The nutrition intake monitoring tools’ accuracy and effectiveness were tested by comparing results from the estimated amount of food consumed with the actual amount of food consumed ,33,36. Tux et al  conducteThe results show that malnutrition assessment tools and apps were the dominant forms of technology used to measure malnutrition outcomes, while nutrition intake monitoring tools were used to a lesser extent. Malnutrition assessment tools and apps may dominate the literature because they may offer greater incentives and benefits than nutrition intake monitoring tools, which by their nature may require additional hospital expenditures on infrastructure (such as recording hardware or cameras). One possible incentive for using malnutrition assessment tools and apps may be their relative ease of implementation compared with nutrition intake monitoring tools. This may be due to the fact that most malnutrition assessment apps incorporated software programs, which may easily be adapted into a hospital’s existing electronic infrastructure ,31,32,34Some of the most simplified apps used Excel files that were tied into an algorithm developed by the authors ,31. McGuFrom an economic perspective, malnutrition is associated with increased LOS and readmission rates within hospitals . ParadoxA total of 3 of the reviewed articles mentioned economic incentives associated with implementing technology-based approaches for malnutrition assessment ,23,31. AAs health care costs in North America are on the rise and since the costs relating to malnutrition account for some of that expenditure, the results suggest that implementing such technology in the hospital setting could save costs . AdditioBecause older patients experience increased rates of deconditioning within the hospital, hospitals may find it beneficial to undertake efforts that identify malnutrition faster than conventional methods. Giovannelli et al  suggesteThe economic incentive is also extended to patients. They benefit not only physiologically from earlier malnutrition detection but also financially through decreased spending related to deconditioning outside of the hospital for homecare or nursing care .significantly greater financial reimbursements. Gout et al [In hospitals and other medical settings where there is a “pay-for-performance” infrastructure, the detection of malnutrition may result in ut et al  brought ut et al ; 1 Germaut et al ; and 1 Uut et al . The evimore cases of malnutrition [The results suggest that technological nutrition support tools and apps may help reduce health care workers’ workload and time spent assessing patients for malnutrition ,27,32-34utrition ,34; and utrition .The results also showed that certain tools and apps can collect relevant data either automatically or by being entered manually into the system. In our review, more articles discussed tools or apps that were able to automatically collect data. Some of the studies described their nutrition support technologies as being able to monitor, assess, and identify hospital malnutrition cases relatively independently or with minimal input from health care workers ,29,31,33Technology that has the ability to run independently or with minimal input may be beneficial in hospital areas where noise pollution is abundant, or in areas where there is relatively little time for health care workers to manually collect and analyze malnutrition information . Additionally, some hospitals choose to lay off health care workers, which increases the workload and patient to nurse ratio, adding further strain on malnutrition monitoring and assessment efforts . TherefoFurthermore, nutrition support tools and apps may have educational implications for health care workers, including nurses and doctors. Dieticians and clinical nutrition experts have more years of formal schooling and experience relating to malnutrition assessment and identification than do nurses and doctors . Nutritiactual usefulness in practical settings.However, none of the articles discussed the ease of use from the user’s perspective. The importance of establishing a usability rating may help determine the tool’s or app’s theoretical concept stage [It is common practice that scoping reviews do not address issues of quality appraisal relating to the sources of literature used. In this scoping review, we tried to use and capture peer-based research articles that directly tested their tool or app on a cohort of patients or participants. A few articles in this scoping review contained technology in the pt stage ,28. As sAdditionally, each of the reviewed research articles included different and unique types of software and hardware technologies respective to their study. Future research should seek to test the efficacy of one type of computer tool or app across different hospitals in the form of RCTs in order to contribute to a higher level of evidence for the field. It would also be interesting for future efforts to compare and test the outcomes of using malnutrition assessment tools and apps versus nutrition intake monitoring tools.It is likely that we excluded some relevant research articles from this review, as we screened only English-language publications. Some studies (n=8) did not pass phase 2 relevance screening because of the language restriction. These studies might have added further applications and outcomes in this scoping review. Perhaps future efforts to translate these publications will add value and knowledge to the field. Lastly, because this was a review study, we based our analysis solely on the information found in each included article, which was up-to-date only at the time of publication.The use of technologies for monitoring food intake and assessing malnutrition are beginning to be considered for future hospital processes that aim to identify, diagnose, and assess hospital malnutrition. Many computerized tools and apps are being developed worldwide to address the problem of hospital malnutrition. It is beneficial to study the impact of these technologies to examine their applicability and possible areas of improvement.


Harvest of orchid tubers for salep production is widespread in southwestern Asia and the Balkans and constitutes a major conservation risk for wild orchid populations. Synanthropic habitats, such as graveyards, are important refuges for orchids and other organisms and could offer protection from salep harvesting because of their special cultural role. However, little is known about the occurrence and factors influencing harvesting of salep in graveyards. During field surveys of 474 graveyards throughout Turkey, we observed 333 graveyards with orchids, 311 graveyards with tuberous orchids, and salep harvest in 14 graveyards. Altogether, 530 individuals of 17 orchid species were collected, representing 9% of the individuals recorded. Harvesting intensity was relatively low, and populations were usually not wholly destroyed. However, some species were clearly more affected than others. Salep harvesting risk of orchid species was significantly associated with flowering time, with early‐flowering species being more affected. A marginally significant positive relationship between harvesting risk and species‐specific tuber size was also detected. Our data suggest that graveyards might offer some protection against salep harvesting in Turkey, but they also show that some orchid taxa are much more affected than others. Overall, our observations add more weight to the conservation value of these special habitats. We hypothesized that specific traits of tuberous orchids, such as conspicuousness, tuber size, and flowering phenology, might predict salep harvesting. Conspicuousness of different orchids can be very different as a consequence of variation in height of flowering shoot. Mean tuber size is also highly variable between species. Specific variability of tuber size causes substantial differences in average weight of dried tubers of salep originated in different regions of Turkey Sezik, , charact22.1Himantoglossum Spreng. s.l. (incl. Barlia Parl. and Comperia K. Koch), where we followed the nomenclature of Sramkó, Molnár V., Hawkins, and Bateman  regardless of their spatial dimension, position within settlements, or presence of religious facilities in 2 years: 300 graveyards have been evaluated in 2014  L. C. M. Rich. lasts from beginning of April (10) to mid‐July (20); hence, average flowering time of this species is 15.Average flowering time of orchids was obtained from flowering intervals published in Kreutz and Çolak . These dAnacamptis and Ophrys in vegetative stage which were unidentifiable at the species level we excluded from the analyses.Excavated specimens of 2.3To understand which species characteristics affect salep harvesting, we used data from 14 graveyards in which salep harvesting was observed. For these graveyards, the number of harvested and unharvested orchids (treated separately for each species) was used as a bivariate response in a binomial Generalized Linear Mixed Model (GLMM). Plant height, volume of new tubers, and the average flowering time were included as explanatory variables. We also included genus as a random factor in these models to take into account the fact that closely related species are more similar to each other than expected by chance . Explanatory variables were Box‐Cox transformed and standardized to optimize model fit. We removed nonsignificant predictors from the complete model in a stepwise manner  in order to get a minimal model which contained only significant predictors. All models were built in the R Statistical Environment . We observed salep harvesting activity only in 14 graveyards (4.5%) of 311 graveyards hosting tuberous orchids . The highest frequency of salep collection in graveyards (in eight cases) was observed in Muğla province. The number of excavated individuals in a graveyard varied from 6 to 172. Himantoglossum robertianum (Lois.) P. Delforge  and Anacamptis pyramidalis (152) were collected in the highest individual number, while Himantoglossum robertianum (six graveyards), Himantoglossum jankae Somlyay, Kreutz, and Óvári (3), Anacamptis pyramidalis (3), and Ophrys holoserica subsp. heterochila Renz and Taubenheim (3) were harvested in most graveyards. The number of harvested species in a graveyard varied from 1 to 5. In those graveyards where salep harvesting occurred, mean ± SD = 37.0 ± 20.8% of species were excavated. In two graveyards, each visible individual of H. robertianum was excavated. This species was collected in both studied years in the settlements of Kemer and Meşelik (Muğla); in 2014, 50% of the individuals were removed, while in 2015, 100% in Meşelik, and 94% in Kemer was removed (Table Ophrys subfusca subsp. blithopertha (Paulus & Gack) Kreutz as a new taxon for salep harvesting from the graveyard of Bayır .We found orchids in 208 of 300 visited graveyards in 2014  suggest that harvesting intensity might be relatively low in graveyards, thereby providing some degree of protection to orchids inhabiting these seminatural anthropogenic habitats.First, although salep harvesting is widespread in Turkey, we detected excavation of orchid tubers in only 14 graveyards (4.5%) of a sample of 311 graveyards hosting tuberous orchids. As graveyards are places that are relatively highly frequented by the local inhabitants, this low intensity likely indicates lower preference for harvesting at these sites, rather than reduced detection ability. Second, in graveyards where salep collection was observed, the proportion of harvested individuals was nearly always smaller than the full population size, indicating that not all individuals were harvested . Third, compared to the average salep harvesting activity required for an economically sufficient amount of profit . The high frequency of harvested Himantoglossum individuals (39.5%), and the low frequency of Orchis (0%) within our sample of harvested individuals, contrasts with a previous study from Iran . In a wider outlook, enhancing long‐established burial practices and traditional management of Turkish graveyards (including minimization of human intervention) may allow survival of natural vegetation.Due intensification of agriculture and rapidly changing land use, the role and significance of graveyards in conservation of living natural heritage of Turkey will probably grow. Therefore, following disposes promoting long‐term maintenance of viable and valuable populations of orchids  are essentially required: (1) supporting awareness of sociocultural and conservational importance of graveyards among Turkish public; (2) In subsidizing of long‐term survival of orchids  it is especially important to keep on at least on recent low level of salep harvesting in graveyards or even reducing its intensity; (3) our dataset may help in designation of most important graveyards in orchid conservation. National official protection or at least local council protection of graveyards hosting more than five orchid species can be recommended; (4) Development of field and/or tissue culture cultivation of orchids is highly recommended to satisfy of increasing (partly foreign) commercial salep demand in favor and saving wild orchid populations. Based on our results, the highest yield is expected from the cultivation of the largest tuberous orchids (especially The authors declare that they have no conflict of interest.AMV conceived and designed the study; AMV, TN, VL, KS, and AT collected the data; TN and JT performed the analyses; JT, TN, and AMV led the writing with contributions from all authors. Click here for additional data file.


Approximately 10-30% of brain arteriovenous malformations (AVM) have associated arterial aneurysms (AAA), and the management of these lesions can be challenging. In this video technical note, we demonstrate the microsurgical treatment of an unruptured, Spetzler-Martin grade I AVM in the distal Sylvian fissure with two AAAs arising proximally from the inferior M2 trunk immediately distal to the middle cerebral artery (MCA) bifurcation. First, we resected the superficially located AVM to normalize the blood flow through the Sylvian vein. Next, we performed a Sylvian fissure dissection to access and clip the two MCA AAAs. We also discuss the technical nuances of tandem surgical intervention for AVMs with AAAs as it pertains to this case, particularly with respect to the order of lesion treatment, Sylvian fissure dissection, nidal resection, and aneurysm clipping. Brain arteriovenous malformations (AVM) harbor associated aneurysms arising from feeding arteries in approximately 10-30% of cases . RedekopThe preoperative imaging, critical portions of the procedure, and postoperative imaging are shown and narrated in Video A 77-year-old male presented with seizures, and noninvasive neuroimaging showed an unruptured vascular malformation. Preoperative catheter cerebral angiography showed a right-sided, Spetzler-Martin grade I AVM located in the distal Sylvian fissure. The AVM was supplied by distal branches of the MCA, and drained both anteriorly through the Sylvian vein and posteriorly through the vein of Labbe. At the junction of the two draining veins, there was a venous varix. There were also two prenidal AAAs arising proximally from the inferior M2 trunk, immediately distal to the MCA bifurcation, with the larger of two AAAs located closer to the bifurcation. After discussing the management options with the patient, he elected to undergo concurrent surgical treatment of both the Sylvian AVM and MCA AAAs.The patient was positioned in a standard fashion for a right-sided pterional craniotomy, as previously described , except Upon dural opening, the AVM’s venous varix was immediately noted at the distal end of the Sylvian fissure. Since the varix was overlying the AVM nidus, we initially performed a subarachnoid dissection of the distal Sylvian fissure around the two superficial draining veins and varix. As we circumferentially dissected the AVM’s superficial venous components, elevation of the varix revealed the underlying nidus. Using standard microsurgical technique, we sequentially dissected, coagulated and sharply divided the arterial feeders while preserving the two primary draining veins. Upon adequate devascularization of the nidus, the anterior vein draining into the Sylvian vein was coagulated and divided, which allowed posterior and inferior mobilization of the nidus. Lastly, the posterior vein draining into the vein of Labbe, which was the final vessel tethering the nidus, was ligated. This allowed completion of the AVM resection.After extirpation of the AVM, we then turned our attention to the MCA AAAs. Since dissection of the AVM had already released cerebrospinal fluid (CSF) from, and hence deflated, the Sylvian fissure, a subfrontal retractor was placed. This maneuver provided gentle tension on the proximal Sylvian fissure and stretched its superficial arachnoid bands taut, which facilitated subsequent dissection. Once the superficial arachnoid of the Sylvian fissure was opened sharply, the fissure was split in an inside-to-out direction. Dissection of the deep portion of the Sylvian fissure exposed the MCA M1 segment, which was followed distally by the MCA bifurcation and both M2 trunks. Both AAAs arose from the inferior M2 trunk, and their anatomy was exposed using standard microsurgical technique. The larger, more proximal M2 AAA had an atherosclerotic neck, so it was under-clipped with a J-shaped aneurysm clip. Finally, the smaller, more distal M2 AAA was clipped with a straight mini-clip.Intraoperative indocyanine green (ICG) video angiography showed normal filling of both M2 trunks, as well as occlusion of both AAAs. Postoperative angiogram showed complete obliteration of AVM and occlusion of both MCA AAAs. The patient had an uncomplicated postoperative course, and was discharged home on postoperative day 7 without focal neurological deficits.In light of the recent findings from A Randomized Trial of Unruptured Brain AVMs and the Scottish Audit of Intracranial Vascular Malformations prospective AVM cohort study , 5, the We present a unique case of a distal Sylvian AVM with two proximal prenidal AAAs arising from the inferior M2 trunk. In the following, we will seek to delineate the following technical nuances: (1) order of AVM and AAA treatment, (2) Sylvian fissure dissection, (3) AVM resection, and (4) AAA clipping. While AAAs are always related to the feeding arteries of the nidus, in the present case, the AVM’s venous drainage affected the approach to the AAA. That is, the Sylvian vein comprised the anterior component of the nidal venous drainage, and dissection of the Sylvian fissure deep to this vein was necessary to expose the two AAAs. Therefore, while the AAAs could have been treated first, injury to the arterialized Sylvian vein draining the AVM would have resulted in considerable bleeding. Furthermore, inadvertent occlusion of the Sylvian vein during Sylvian fissure dissection, prior to AVM resection, would have increased the intranidal pressure and potentially caused an intraoperative rupture of the AVM before adequate dissection of the nidus and control of its arterial feeders.Thorough dissection of the Sylvian fissure was crucial to minimizing pial transgression and parenchymal injury during exposure of both the AVM and AAAs. We utilize the “inside-out” technique of Sylvian fissure dissection when feasible, which has been endorsed and described in detail by numerous experienced cerebrovascular surgeons . In brieResection of the AVM in our case was fairly routine, except that one had to be prepared to circumdissect and mobilize the venous varix in order to expose the underlying nidus. In the process of dissecting the arachnoid surrounding the varix, it was critically important to preserve the venous outflow of the nidus until it could be thoroughly devascularized. Additionally, any en passage arteries within the distal Sylvian fissure had to be protected, in order to avoid collateral damage to normal cortex. With respect to the AAAs, we noted significant atherosclerosis within the neck of the larger aneurysm, and therefore decided to under-clip this one. For atherosclerotic aneurysms, attaining what appears externally to be the ideal clip placement can, in fact, internally push atheroma into the parent vessel, causing flow-limiting stenosis, parenchymal ischemia, and thromboembolic complications. Under-clipping, as was employed in our case, preserved normal flow through the parent M2 trunk while completely occluding the AAA, as evidenced by both intraoperative ICG and postoperative catheter angiography.Only a minority of AVMs harbor AAAs, and these uncommon cases can present unusual technical challenges to the cerebrovascular surgeon, particularly when the AVM and AAA are anatomically distant, such that both lesions cannot be exposed with the same microsurgical dissection. We critically assess the technical nuances of resecting a distal Sylvian AVM and clipping two proximal prenidal AAAs arising from the MCA inferior M2 trunk, with a focus on the order of lesion treatment, as well as dissection of the Sylvian fissure, AVM, and AAAs. Patient, AVM, and AAA factors must be considered in the management of AVMs with AAAs. For appropriately selected AVMs with AAAs, surgical intervention can concurrently afford nidal obliteration and aneurysm occlusion in the same procedure.


Voluntary medical male circumcision (VMMC) has been successfully implemented in 14 countries as an additional HIV prevention intervention. As VMMC programs mature in most countries, the focus is now on how to sustain the HIV prevention gains realised from VMMC. As part of preparations for the sustainability phase, countries are either piloting or preparing to pilot early infant male circumcision (EIMC). This qualitative study explored the acceptability and feasibility of EIMC in Malawi in order to inform pilot implementation., policy-makers, programme managers and health-care workers. Audio recordings were transcribed, translated into English (where necessary), and thematically coded using NVivo 10.In 2016, 23 focus group discussions were held across Malawi with participants from several ethnicities and religions/faiths. Additionally, 21 key informant interviews were held with traditional and religious leaders, traditional circumcisers Discussions highlighted the socio-cultural significance of MC in Malawi. Knowledge or experience of EIMC was poor although acceptability was high among most ethnic/religious groups and key informants. Participants identified EIMC's comparative HIV benefits although a few health-care workers expressed scepticism. All participants said EIMC should be offered within a clinical setting. In addition to fathers, maternal uncles and traditional leaders were deemed key decision-makers. Potential barriers to EIMC included concerns about procedure safety as well as cultural considerations. Key informants felt it was feasible to offer EIMC in Malawi. Participants' recommendations, including phased implementation, engagement of traditional leaders, use of external mobilisers and initially reaching out to influential parents, will be taken into account when designing a pilot EIMC program.EIMC is potentially an acceptable and feasible HIV prevention intervention for most ethnic/religious groups in Malawi if wide-ranging, culturally appropriate demand-creation activities are developed, piloted, evaluated and appropriately implemented. Malawi registers approximately 33,000 new HIV infections each year . AlthougMalawi is one of the last countries to scale up VMMC as responsible authorities were sceptical of VMMC's protective effect. The understandable scepticism was due to the fact that the country's 2010 Demographic and Health Survey had included statistics of HIV infection from a sample of 6,834 men, reporting an HIV prevalence of 10.3% in circumcised men, but only 7.9% in non-circumcised men . HoweverAs VMMC programs mature in most countries, the focus is now on how to sustain the HIV prevention gains realised from VMMC –10. As pThe Malawi Ministry of Health (MoH) has developed an EIMC Roadmap to oversee pilot implementation of EIMC in the country. As part of the Roadmap, the MoH and its implementing partners commissioned a feasibility and acceptability study of EIMC in Malawi. Here we report qualitative findings from the study which will inform the design of a pilot EIMC program.Between January and March 2016 we collected data using focus group discussions (FGDs) and key informant interviews (KIIs). Previous research showed religion and culture as main determinants of MC in Malawi . The samngalibas) (n = 3), policy-makers, programme managers and health-care workers (n = 11). Leaders of traditional and religious groups were purposively sampled to include several ethnicities and religions/faiths. Traditional circumcisers were from Mangochi and Mulanje.FGD participants included: expectant mothers (n = 7 FGDs); expectant fathers (n = 6 FGDs); grandmothers/mothers-in-law (n = 5 FGDs); grandfathers/fathers-in-law/ maternal uncles (n = 5 FGDs). FGD participants belonged to a wide range of ethnicities including: Chewa, Yao, Tumbuka, Lomwe, Sena, Ngoni and Nkhonde. Additionally, some FGD participants identified themselves as either Christian or Muslim. We also held key informant interviews (KIIs) with traditional leaders (n = 3), religious leaders (n = 4), traditional circumcisers (Although a few key informant interviews were held in English (n = 5), Tumbuka (n = 1) and Yao (n = 2), discussions were mostly in Chichewa, the main indigenous language. Facilitators first explained that EIMC was medically performed during the first 60 days of life and subsequently explored perceptions around its acceptability and feasibility. All discussions were audio-recorded; hand-written notes were taken as back-up. Key informant interviews took approximately 1 hour and FGDs lasted approximately 2 hours.Data were transcribed and translated verbatim into English. Interview summaries were then written for each KII and FGD and used to come up with a provisional coding framework. Five key informant interviews and four FGDs were then independently coded using the coding framework. Discrepancies were resolved through discussion until consensus was reached. Any additional codes identified from the first set of transcripts were added to the coding framework. Names and other personal identifiers were removed from transcripts before they were entered into NVivo 10 , a qualitative data storage and retrieval program. Transcripts were then coded using the modified coding framework; care was taken to identify any additionally emerging codes. Codes were grouped and emerging themes were then identified.Ethics approval was given by the Malawi National Health Sciences Research Committee. Written informed consent, including for audio recording, was obtained from all participants prior to their participation in the study.A total of 247 participants aged 18–80 years took part in the 23 FGDs. Of these, 133 (54%) were female. In addition, 21 key informants were interviewed. Discussions highlighted the socio-cultural significance of MC in Malawi. EIMC acceptability was high among most ethnic groups although knowledge or experience of EIMC was sub-optimal. Health-care workers felt it was feasible to offer EIMC in Malawi. Participants articulated some concerns and recommendations which should be taken into account when designing a pilot EIMC program. We present these themes in more depth below.'…We consider it [MC] as something new because here it is only those from Mangochi who get circumcised. We, the Ngonis and Chewas, do not do that' . Another female participant maintained, 'Our culture does not allow male circumcision. Yes, we are not Muslim here, it is only Muslims who do that' .Despite VMMC roll out in Malawi over the last 5–6 years, male circumcision continues to be associated with religion and ethnicity. Some participants felt that MC was a practice specific to certain ethnic or religious groups. Ongwanjulidwa is a derogatory term which denotes that one's foreskin has been brutally severed. Conversely, circumcised men use terms such as osatchena when referring to an uncircumcised man. Literally, the term implies that one is not smart but the underlying inference is that he is unclean/impure. Among traditionally circumcising groups, there is no terminology that specifically refers to male circumcision since the procedure is part of a comprehensive ‘rites of passage’ ritual; therefore terminology  holistically refers to the entire ritual.Terminology used to refer to traditional MC by some groups also mirrors attitudes towards the procedure. 'What I would want to see is that after circumcising the boys at the hospital, they should then go tojando. Maybe they should go tojandoto be taught good manners and then towards the end of the initiation, they should be taken to the hospital for male circumcision' .As part of the traditional MC ritual, the initiate is taken to a temporary shelter which is isolated from the community . There, '…Removing the foreskin "tells" the boy that he must leave bad habits…If they remove the whole foreskin, it might suggest that the boy did not have any good manners before and that is why they leave some foreskin' . Evident in this assertion is the fact that some ethnicities only perform partial as opposed to complete circumcision—a factor which likely explains the discordance between reported male circumcision status and HIV prevalence observed in some Malawian communities  should not be taken to thejandobut to the hospital…It needs to be breastfed' . Traditional circumcisers were especially unwilling to provide EIMC as the infant's mother would need to be close by as they performed the procedure, which is considered taboo. One traditional circumciser even mentioned that he sends his wife away whenever he needs to perform any male circumcisions from home.Contrary to parents' perceptions that traditional circumcisers may also want to be involved in EIMC, all who took part in this study said the procedure was acceptable as long as they were not asked to perform it themselves. 'It is mostly the fathers after discussing with the boy’s eldest uncle from the mother’s side…We cannot really make the decision without consulting the maternal uncles' . In some traditionally circumcising communities, participants felt that since male circumcision is sanctioned by the chief, it would be difficult for them to adopt EIMC without consulting the traditional leader.When participants were asked to envisage who would be involved in the process of deciding about EIMC, younger participants (expectant parents) felt that this would involve a discussion between the infant’s parents. Nonetheless, male and female participants of all age groups highlighted the importance of the father in the decision-making process. Younger men from matrilineal communities noted that although they were key decision-makers, they could not make the ultimate decision without consulting maternal uncles. 'I think there are chances that more foreskin than required is removed in infants… You look at an infant’stiti(little penis) and all you see is just foreskin' . As has been found in previous EIMC acceptability studies ['We do not know what the hospital or the health-care workers will do with the [discarded] foreskins' . When asked why they were not as concerned with adolescent and adult men's discarded foreskins, one woman responded, 'I think that infants’ foreskins are very tender and so they will be more effective in rituals than boys’ and men’s foreskins' .Despite highlighting several advantages of EIMC, participants also articulated possible disadvantages of the procedure, including physical harm.  studies , 36–37, 'Clinical officers and medical assistants are performing major procedures in women and male circumcision is just a minor procedure' (policy-maker). When asked to give opinions on the facilities that should offer EIMC, most health-care workers noted that it should be offered only at provincial and district hospitals as these already had some operating theatres/rooms and substantial equipment. They however, highlighted the fact that there is a critical shortage of health personnel and the current providers are overstretched.On the whole, key informants felt that it was feasible to introduce EIMC in Malawi. Unlike parents, all health-care workers felt that a wide range of health-care cadres including doctors, clinical officers, nurses and medical assistants could safely perform EIMC with adequate training. Overall, they felt that EIMC was less complicated than some of the procedures they perform. 'They should first discuss with chiefs so that the chiefs are able to understand what it is all about and then they will tell their people that male circumcision is a useful means of protecting male infants and men from HIV' . A female participant also recommended engagement of chiefs in creating EIMC awareness. 'The first important step is for the chief to choose some people who will sensitise the villagers so that they know the benefits of infant male circumcision and what it is all about…' . Some participants, however, felt that local mobilisers are often not taken seriously and recommended use of external personnel. 'Mostly, those that give out information about male circumcision are from within the village. People therefore do not take such information seriously. It would therefore be helpful if the various organisations sensitised villagers directly' .When asked to suggest how to successfully introduce EIMC in Malawi, FGD participants made at least three recommendations: engagement of chiefs, use of external mobilisers and initially reaching out to influential parents. 'I think the first people to take their infants for male circumcision should be people who are influential, people who are well-educated so that the rest of us will take on from them' . Related to this issue, participants mentioned that there is often a 'wait and see' tendency for most new initiatives. 'I think they [parents] would want to first see…You know, most people wait to see what happens to others. So if they see that other people’s infants who have been circumcised are fine, they will also have theirs circumcised' .In addition, participants recommended mobilising influential community members first as they often influence uptake of services. 'First of all, when you want to implement something, you do it on a small scale and then you analyse and see whether or not it works. You will then adjust the programme until you offer it on a larger scale' . Moreover, key informants suggested intensive campaigns to educate parents and the wider community about the procedure. One key informant mentioned that there might be undesirable consequences if women thought, for example, that EIMC was being compulsorily offered. 'Women will refrain from giving birth at the hospital and go to the traditional birth attendants instead' .Although health-care workers felt that it was feasible to introduce EIMC in Malawi, they recommended a phased, cautious implementation. Findings from FGDs and key informant interviews suggest that EIMC is both acceptable and feasible in Malawi. Since some stakeholders  do not understand the public health rationale behind EIMC, awareness campaigns need to explain the benefits of EIMC on vulnerability to HIV as well as the non-HIV benefits and the advantages of EIMC compared to male circumcision conducted later in life. Moreover, since findings suggest a general lack of knowledge of how EIMC is performed, explaining that the procedure does not require sutures, is characterised by non life-threatening minimal bleeding, easy wound care and faster healing , 20–21 wThe high EIMC hypothetical acceptability found in this study is encouraging but should be interpreted with caution. Studies conducted within the region have shown poor concordance between hypothetical and actual EIMC acceptability. In Zambia and Zimbabwe, actual uptake was lower than previously suggested by hypothetical acceptability studies  , 38–39. FGD and KII findings support the now well-recognised notion that cultural beliefs should be taken into consideration when providing male circumcision , 40–41. Importantly, both EIMC introduction and subsequent roll-out should be done in a manner that does not suggest any compulsion especially since discussions suggested this could possibly result in avoidance of formal health services. A key consideration for introducing EIMC is integration within routine health services for mothers and their children, such as maternal, newborn, and child health (MNCH) services, thereby strengthening these services , 42. EnsKey informants raised concerns around shortage of equipment and operating theatres/rooms in health facilities which are not necessarily applicable to EIMC. When EIMC is offered using devices, it requires minimal space  and equipment , 20–21. A major strength of this study is that it collected data through a triangulation of FGDs and key informant interviews for a nuanced understanding of the perceived acceptability and feasibility of EIMC in Malawi. There was largely concordance between data obtained through these two methods, highlighting the likely validity of the results and the value of triangulation. Furthermore, the study adds to the growing body of literature on acceptability and feasibility of EIMC. A potential limitation of this study is that it explored EIMC acceptability in the absence of widely-available services or any communication campaign that specifically provides information about EIMC. As stated earlier, hypothetical acceptability may be quite different from actual acceptance when EIMC is eventually rolled-out ,14,17,38In conclusion, study findings suggest that EIMC is potentially an acceptable and feasible intervention in Malawi among most ethnic and religious groups. While findings suggest possible barriers to EIMC, these are potentially surmountable given time. Wide-ranging, culturally appropriate demand-creation activities to promote EIMC need to be developed, piloted and appropriately evaluated in order to support introduction of EIMC in Malawi.


The elderly population following the improvement in health status and life expectancy in developing countries is increasing. Malnutrition causes decreased quality of life and increased mortality in elderly. This study aimed to review systematically and meta-analysis of studies assessing the prevalence of malnutrition among Iranian elderly people over 60 yr of age using Mini Nutritional Assessment (MNA).This systematic review and meta-analysis was conducted in 2016 to estimate the overall malnutrition prevalence. Data were collected using the following keywords: prevalence, elderly, aging, malnutrition, nutrition, nutritional assessment, nutritional status, health status, mini nutritional assessment, MNA and Iran in PubMed, Scopus, Google Scholar, Iranmedex, Magiran, and SID. Computer software CMA: Two were applied to estimate the overall prevalence of malnutrition.Seventeen of 811 articles were included in our analyses. The overall estimated prevalence of malnutrition among elderly based on the random effect model was 12.2% (95% CI 8–18.5). In subgroups, the prevalence of malnutrition among elderly living in home based on the fixed effect model was 9.2% (95% CI 7.1–11.9) and prevalence of malnutrition among elderly residents of nursing homes based on the random effect model was 21.6% (95% CI 12–38.6).Given the increase in the elderly population in future and the prevalence rate of malnutrition among them as well as the higher prevalence of malnutrition in elderly care centers, more attention to this population group is a matter of necessity. Given the improvement in health status and medical services and accordingly increased life expectancy, the elderly population is increasing . The popThis systematic review and meta-analysis were conducted in 2016 using the approach described in “A Systematic Review to Support Evidence-Based Medicine ”. First,Two reviewers (MM and AM) independently screened titles and abstracts for relevance. The full text of potentially relevant articles that evaluated malnutrition in elderly were obtained and assessed for eligibility. During this stage, in the case of conflicts between these two reviewers, consensus was reached using a third reviewer’s opinion. Studies were selected and included in the analyses based on the following inclusion criteria: original research, studies that focused on the prevalence of malnutrition in elderly over 60 yr of age, published in English or Persian and conducted in Iran. Conference presentations, case reports, and interventional and qualitative studies were excluded from the analysis. Subsequently, articles independently evaluated on the basis of the ‘Strengthening the Reporting of Observational Studies in Epidemiology’ (STROBE) checklist , 21.Two reviewers extracted the data using a standard data collection form . The fol2 statistic  was displayed using the forest plot so that the size of each square represents the sample size and the lines on each side of the square indicate the confidence interval. Microsoft Office Excel 2010 was used to draw graphs. Funnel plot was applied to evaluate the possibility of publication bias   applied to perform the meta-analysis and estimated the overall malnutrition prevalence. The presence of heterogeneity across the studies was assessed by the Itatistic . Statistion bias .Three foFirst, analysis of all articles was conducted. Then two sub-groups were formed: one composed of articles related to the elderly living at home, and the other of the elderly residents of nursing homes.P<0.001, I2= 65.7).Of 811 studies identified in the initial search, 17 studies with 8140 persons were included in the final analysis. These studies were conducted between 2007 and 2015. Of 17 studies, seven studies were related to the prevalence of malnutrition among elderly residing in elderly home. While the lowest percentage of prevalence of malnutrition among elderly was associated with the study conducted (3%) in Isfahan , the higFor the meta-analysis of the prevalence of malnutrition among elderly living in home  and eldeP=0.43, I2=0).In the meta-analysis of nine studies consisting of 6572 elderly over 60 yr old, the overall prevalence of malnutrition based on the fixed effect model was 9.2% (95% CI 7.1–11.9). 95% CI for the prevalence was drawn for each study in the horizontal line format .In the meta-analysis of eight studies consisting of 1568 elderly over 60 yr old, the overall prevalence of malnutrition based on the random effect model was 21.6% (95% CI 12–38.6). Of 95% CI for the prevalence was drawn for each study in the horizontal line format  have been completely observed by the authors.


Par-4 knockdown or overexpression studies established that ectopic Par-4 along with ER stress are not sufficient to downregulate p21 in PC-3 cells but are adequate for DU-145 cells and that the ER stress inflicted activation of JNK, inhibition of AKT and Par-4 induction are all crucial to p21 downmodulation by 3-AWA. By using isogenic cell lines, such as HCT-116 p53+/+ and HCT-116 p53−/−, we found that deceleration in p21 expression due to ER stress is p53 independent. Moreover, in orthotopic carcinogen-induced rat colorectal carcinoma model, we found that 3-AWA inhibits colorectal tumor growth and formation of colorectal polyps at a tolerable dose, similar to the first-line drug for colorectal cancer-5-fluorouracil.The double-edged role of p21 to command survival and apoptosis is emerging. The current investigation highlights ER stress-mediated JNK activation that plausibly triggers cell death by attenuating endogenous p21 level. Here, we demonstrated that ER stress activator 3-AWA diminishes the p21 levels in cancer cells by averting the senescent phenotype to commence G2/M arrest. In essence, the deceleration in p21 level occurs through ER stress/JNK/Caspase-3 axis via activation/induction of proapoptotic Par-4 and inhibition of AKT. The molecular dynamics studies identified important interactions, which may be responsible for the AKT inhibition and efficacy of 3-AWA towards AKT binding pocket. Interestingly, the p21 deceleration was rescued by incubating the cells with 3-AWA in the presence of an ER stress inhibitor, Salubrinal. Furthermore, we demonstrated that p21 expression decreases solitarily in Par-4 Together, it may not only provide new insights in cancer development but also profoundly impinge on the efficacy of various anticancer drugs that induce p21.The diverse biological functions of p21 are well known for its controversial role in predicting the prognosis of cancer patients. p21 levels are highly amplified in various cancers including prostate, cervical, colon, breast and squamous cell carcinomas. p21 activation directly correlates with tumor grade and invasiveness, although the mechanisms remain vague. The oncogenic function of cytoplasmic p21 is exerted through its non-traditional targets in the cytoplasm.3 Cell cycle arrest is an established role of p21 although many studies have reported otherwise. A plethora of reports suggest that p21 protects the cells from stress or p53-dependent and p53-independent apoptosis, although the mechanisms are poorly understood.7 Delayed treatment of cancer cells with genotoxic agents causes caspase-3-mediated p21 cleavage and subsequent inactivation, thereby triggering apoptosis.8 Moreover, p21 shields the cancer cells from death induced by DNA-damaging agents, and altered p21 expression increases sensitivity to treatment in vivo.9 Similarly, Martinez et al.7 reported that low doses of doxorubicin induced p21 expression in human CaP cells, while high doses abrogated p21 expression. Interestingly, p53 expression remained impassive in both stipulations.7 Further, the potential significance of p21 in cancer biology has been underscored in human melanoma cells and chronic myeloid leukemia wherein, the comparison between wild-type cells and p21 deleted cells underscored the dual nature of p21 owing to its ability to hamper cell proliferation and drug-induced apoptosis.11 Compelling recent evidences have suggested the involvement of AKT in ER stress-induced apoptosis. Hu and colleagues demonstrated sarcoplasmic reticulum calcium pump (SERCA) inhibitor, Thapsigargin or tunicamycin, to transiently activate AKT during ER stress, in MCF-7 cells. The importance of AKT activation as a pro-survival response during ER stress was concreted when MCF-7 cells with suppressed AKT activity were sensitized to ER stress-induced apoptosis.12The classical tumor-suppressor role of p21 has been recently complicated by its oncogenic activities.14 This withaferin derivative triggered apoptosis by disrupting Bcl2-Beclin 1 interaction through ER stress-mediated Par-4 induction in prostate cancer cells.15 3-Azido withaferin A (3-AWA), a novel derivative of withaferin A, is a strong inducer of Par-4,16 and several lines of evidence incriminate the proapoptotic and anti-invasive role of Par-4 in cancer.17 In addition, Par-4 suppression in cancer cells has also been implicated in resistance to chemotherapy.18 In the current study, we have demonstrated that 3-AWA downregulated p21 via ER stress/JNK/caspase-3 axis. This study, for the first time emphasizes the AKT-dependent cross talk between Par-4 and ER stress in mediating p53-independent p21 downmodulation.We have recently demonstrated a prospective therapeutic implication in prostate cancer cells through treatment of these cells by natural product derivative 3-AWA. The presence of α-β-unsaturated carbonyl moiety in natural products bestow them with enhanced chemo-preventive properties, thus rendering a higher degree of specificity to overcome drug resistance.15 Relevantly, our western blot data showed that 3-AWA induced ER stress was associated with the proapoptotic activation of JNK  at 1 to 3 μm 3-AWA. This was concomitant with the activation of JNK, upregulation of Par-4 and dephosphorylation of AKT in PTEN null PC-3 and Ras mutated HCT-116 cells (m MG132 (proteasome inhibitor) plus 3-AWA treatment had negligible effect in the reduction of p21 expression (m) was sufficient to trigger Par-4 induction15 (that too might be independently controlled mechanism), it seems that Salubrinal did not exhibit any pivotal role in maintaining Par-4 levels. On the other hand, elevated Par-4 spontaneously blocked cellular AKT activation,20 whereas, as the expression of p21 was reduced, Salubrinal could not prevent 3-AWA mediated caspase-3 activation but blocked the decline in XIAP expression. This provides an evidence that higher concentration of 3-AWA could promote apoptosis even in the presence of salubrinal through XIAP independent pathway. Of note, we checked the expression of AKT, JNK, Par-4 and p21 in salubrinal-treated cells, as given in the 21 Therefore, we sought to investigate the effect of 3-AWA on the interaction between these two proteins in a perspective concerning apoptosis resistance incurred by this interaction of p21 with JNK. The co-immunoprecipitation results demonstrated that a direct interaction between JNK and p21 existed in vehicle-exposed cells. Intriguingly, a drastic loss in the interaction between JNK and p21 was observed in 3-AWA treated PC-3 cells (22 we checked the effect of 3-AWA on the expression and activation of eukaryotic translation initiation factor-4E (eIF4E) in HCT-116 cells. Although 3-AWA was initially found to increase the phosphorylation of eIF4E, at higher concentrations, eIF4E dephosphorylation (inhibition of protein synthesis) accompanied by decreased expression of GRP78 and increased expression of p-eIF2α were observed. Interestingly, in the presence of salubrinal, 3-AWA could not inhibit the activity of eIF4E, as evident by its phosphorylation levels  by AKT is vital to retain p21 in the cytoplasm and execute its antiapoptotic activities. Furthermore, AKT hyperactivation also sequesters Par-4 to regulate it negatively.13 Therefore, we assumed that inhibition of AKT was required to intercede an intrication between Par-4 and ER stress/JNK in p21 regulation by 3-AWA. To validate this, western blot analysis of Par-4 overexpressing cells, incubated with 3-AWA/Thapsigargin and/or AT7867, showed that Thapsigargin and Par-4 alone or in combination and Thapsigargin plus AT7867 were unable to reduce p21 expression markedly in PC-3 cells, but did so efficiently by an assemblage of Par-4, AT7867, and Thapsigargin  cytoplasmic accumulation. To check whether the downstream p21 suppression in this potential ER stress/JNK/caspase-3 axis (due to 3-AWA treatment) is independent of the cellular status of p53, we used isogenic HCT-116 p53+/+ and HCT-116 p53−/− colon cancer cells. We observed that similar to DU-145 cells, Thapsigargin and Par-4 combination had a profound effect on p21 expression in both HCT-116 p53+/+ and HCT-116 p53−/− cell lines, which was further amplified with the addition of AT7867  along with colorectal polyps throughout the colorectal mucosa. However, the mean tumor volume reduced significantly in 3-AWA-treated (10 mg/kg of body weight (b.w.) group (158 mm3) compared with the vehicle-treated control group. Post treatment, the positive control 5-FU-treated (25 mg/kg b.w.) group contained mean tumor volume of 165 mm3. On the other hand, the number of polyps reduced significantly (6 to 10 polyps/rat in the control group versus one to three polyps per rat in treatment group) in the 3-AWA- as well as 5-FU-treated group , a derivative of the α-β-unsaturated functionality of ring A of withaferin A, has been well documented for its antiproliferative potential and is superior to its parent compound, withaferin A, in stalling cancer progression.38 Inhibitor of the c-Jun N-terminal kinase (JNK), SP600125, has been demonstrated to increase p21 expression and promote p21 phosphorylation via PI3K/AKT pathway, thus preventing p21 binding to PCNA and direct inactivation of caspase-3.39 Herein, we found that 3-AWA arbitrated p21 modulation was inhibited by SP600125 as well as by Fmk-z-VAD in the presence of 3-AWA, implying ER stress-mediated JNK activation rendered the suppression of p21 via caspase-3 stimulation  is considered as a major downstream activator in stress responses. JNK activation in response to diverse forms of stress is noted to impact the cell death machinery by regulating the Bcl2 family proteins.mulation . In addi3 As reported previously, phosphorylation of p21 (T145) by AKT is vital to retain p21 in the cytoplasm and execute its antiapoptotic activities.26 AKT hyperactivation also confiscates Par-4 and regulates it negatively and we have shown recently that 3-AWA dephosphorylates AKT and favors threshold induction of Par-4.40 But in the current consequence, we found that Par-4 induction and stimulation of ER stress on their own are not sufficient to destabilize p21. We expected that inhibition of AKT was too required to intercede an intrication between Par-4 and ER stress/JNK in p21 regulation by 3-AWA. Indeed, we found that the ER stress inflicted activation of JNK, AKT inhibition, and Par-4 induction are equally crucial to p21 downmodulation by 3-AWA in aggressive cancer cells. However, keeping in view that 3-AWA is a strong Par-4 inducer as well as a negative regulator of antiapoptotic p21, we investigated the physiologically relevant effects of 3-AWA on orthotopic tumor growth and we found that 3-AWA inhibits colorectal tumor growth and formation of colorectal polyps at a tolerable dose of 10 mg/kg, which was similar to the first-line drug for colorectal cancer-5-fluorouracil.Agents that selectively restrain AKT activation may not only divest tumors of the pro-survival functions of AKT but are also likely to subvert p21 leading to elevated apoptotic effects. A study where the DNA-damaging agent aminoflavone induced apoptosis of MCF-7 breast cancer cells by simultaneously blocking AKT activity as well as p21 stabilization supports this possibility.In conclusion, our findings unveil a novel mechanism of p21 regulation involving AKT/Par-4/JNK axis in the most aggressive type of cancers, as shown in Par-4+/+ and Par-4−/− MEFs; Dr Bert Vogelstein, Johns Hopkins University, Baltimore, MD gifted p53+/+ HCT-116 and p53−/− HCT-116 cell lines. These cell lines were cultured in RPMI 1640/DMEM medium  supplemented with 10% fetal bovine serum, 70 mg/l penicillin, 100 mg/l streptomycin, 6 mm HEPES and 2 mml-glutamine  at 37 °C and 5% CO2. The major inhibitors including ER stress inhibitor Salubrinal, JNK inhibitor SP600125 were purchased from Selleck Chemicals, Houston, TX, USA. AKT inhibitor AT7867, caspase inhibitor Fmk-z-VAD and ER stress inducer Thapsigargin were procured from Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA.The prostate cancer cell lines PC-3 and DU-145 were purchased from the ATCC; Dr Vivek Rangnekar, University of Kentucky, Lexington gifted m Tris-HCl pH 7.5, 1 mm EDTA, 400 mmNaCl, 0.5% NP-40 and 1 mm DTT) supplemented with protease inhibitor cocktail. Western blotting was carried out as described.41 The antibodies used—anti-phospho-JNK (#4668S), anti-phospho-AKT (#9271S), anti-phospho-PERK (#3191S), anti-eIF2α (#9722S), anti-phospho-eIF2α (#3597S), anti-Bcl2 (#2872S), cleaved-caspase-3 (#9661S) were purchased from Cell Signalling Technologies, Beverly, MA, USA; pro-caspase-3 ; anti-Par-4 (sc-1807), anti-p21 (sc-817), anti-AKT (sc-8312), anti-PERK (sc-13073), anti- FAS (sc-714), anti-CDK2 (sc-748), anti-XIAP, anti-PARP (sc-7150), anti-GRP78 (sc-13968), anti-JNK (sc-572), p53 (sc-6243), anti-GAAD (sc-575) antibody were from Santa Cruz Biotechnology, Inc. Anti-β-actin (A5316), anti-Rabbit (A6154) and anti-Mouse (A4416) monoclonal antibody were purchased from Sigma-Aldrich. The quantitative analysis of western blot results was based on ImageJ software version 1.44p . For co-immunoprecipitation, lysates were precleared by adding 20 μl of normal IgG conjugated to 50 μl of protein G-Sepharose beads. Twenty-five microliters of antibody conjugated to 50 μl of protein G-Sepharose beads was used to immunoprecipitate the precleared lysates.Following the treatments, the cell lysates were prepared with TEGN buffer . Transfections were carried out with Lipofectamine 2000 or Neon Transfection system (Invitrogen Life Technologies) as per the manufacturer’s protocol and as described previously.Par-4 siRNA was obtained from Dharmacon  and briefly, desired number of cells was seeded in appropriate dishes or wells and transfected with human specific Par-4. Oligofectamine (Invitrogen Life Technologies) was used for transfections as per the manufacturer's guidlines.4 cells/chamber. Following transfections or treatments with 3-AWA, the cells were incubated for set time points and immunocytochemistry was performed as described previously.17 The prepared slides were then analyzed with Zeiss LSM-510 metaconfocal microscope under × 40 magnification .For p-AKT and p21 protein immunostaining, the cells were seeded in the Lab-Tek chamber slides  at a seeding density of 5 × 1042 After treatment for set time points, the cells were collected and incubated in a hypotonic solution  for 30 min at room temperature in the dark. BD Diva software  was used for the subsequent FACS analysis.Cell cycle analysis was done as per described protocol.43 The score of 1–4 was assessed as weak to moderate expression and 6–9 as strong expression.For immunohistochemical detection of the specific proteins, paraffin-embedded sections from the tumors of treated and untreated mice were prepared. Primary antibody (dilution 1:100) incubated sections were detected with biotinylated secondary antibody. The specimens were then exposed to DAB , counterstained with hematoxylin and mounted for confocal microscopy. The extent of scoring of the stained proteins was scaled between 0 and 3. Final scores were computed using a composite of intensity scores multiplied by the extent of staining score as described previously.44 Briefly, the cells (5 × 104) were plated and treated for 6 days. Post washing with phosphate-buffered saline, the cells were fixed with 4% paraformaldehyde. Accordingly, freshly prepared senescence-associated β-Gal staining solution  per ml in 40 mm of citric acid, sodium phosphate (pH 6.0), 5 mm potassium ferrocyanide, 5 mm potassium ferricyanide, 150 mm NaCl and 2 mm MgCl2) was used to stain the cells for 24–48 h. The stained cells were then fixed with methanol, air dried and observed under bright field microscope for senescent phenotype. Quantification was done with ImageJ software.Senescence-associated β-galactosidase  assay was performed as per the standardized protocol.45 having resolution 2 Å were downloaded from Protein Data Bank. The crystal structure of the protein is bound with the 5--4,5,6,7-tetrahydro-1H-imidazopyridine inhibitor with 42 nm activity. The co-ordinates of the bound inhibitor were used to define the active site of the protein for performing docking studies. To perform molecular docking studies, initially the protein was prepared and docking protocol was standardized.Molecular docking studies of 3-AWA with AKT were carried out using the Schrodinger suite 2015-1 molecular modeling software. The three-dimensional co-ordinates of AKT protein with Protein Data Bank ID: 3CQW46 TIP3P solvent model with cubic boundary conditions of 10 Å distance was used, and the net charge of the system was neutralized. Production simulations were run in NPT ensemble with 1 bar pressure and 300 K temperature using Berendsen coupling scheme. Finally, 10 ns equilibration and production simulation were run for the protein–ligand complex and its co-ordinates were recorded after every 1.2 ps.It is important to analyze the behavior of the protein–ligand complex in aqueous environment of the biological system. Therefore, molecular dynamics simulation studies, of the docked conformation with maximum affinity for the target protein, were done by Desmond software .in vivo antitumor activity of 3-AWA, seven healthy male Wistar rats  per group were taken. The animals were fed standard pelleted chow, sterile water and kept in a pathogen-free condition. The animals were randomized into three groups and six animals were taken per group. For the orthotopic induction of colorectal tumors, the animals were given an intrarectal instillation of 0.5 ml of freshly prepared 0.4% aqueous solution of N-methyl-N-nitrosourea (MNU) three times weekly for 3 weeks by a method as described previously.47 Twenty-two weeks after the initiation of administration of MNU, treatment regimens were started. The test group of animals received 10 mg/kg b.w. of 3-AWA, the positive control group received 25 mg/kg b.w. of 5-FU and the negative control group animals were given 0.9% normal saline solution in alternate days for another 3 weeks. The experiment was terminated at the end of 25 weeks and the animals were killed through anesthesia followed by cervical dislocation. The large bowel was dissected carefully throughout its length and observed for shape, size and the location of the tumors. The tumor volume was calculated from the equation: V=(d1 × d2)2 × 0.6, where V is the tumor volume, d1 is the largest diameter of the tumor and d2 is the smallest diameter of the tumor. None of the animals injected with tumor cells was excluded from the analysis. No statistical method was used to predetermine sample size. The experiments were executed and analyzed in a non-randomized and non-blinded manner.Animal experiments were carried out according to the guidelines approved by the Institutional Animal Ethics Committee ‘CPCSEA’ (IAEC No. 51/02/15). To evaluate the P<0.05 was considered significant in all the cases. No statistical method was used to predetermine sample size. The experiments were executed and analyzed in a non-randomized and non-blinded manner. Comparisons between two groups were conducted using unpaired Student’s t-test. Experiments with more than two groups were compared by one-way analysis of variance followed by Tukey’s multiple comparison test. The tests were undertaken using SPSS, version 19.0, computer .Graph Pad Prism version 5  was used to perform statistical analyses. Data were expressed as the mean±s.e. of three independent experiments. A two-sided value of


Malnutrition is very prevalent in geriatric patients with hip fracture. Nevertheless, its importance is not fully recognized. The objective of this paper is to review the impact of malnutrition and of nutritional treatment upon outcomes and mortality in older people with hip fracture. We searched the PubMed database for studies evaluating nutritional aspects in people aged 70 years and over with hip fracture. The total number of studies included in the review was 44, which analyzed 26,281 subjects . Older people with hip fracture presented an inadequate nutrient intake for their requirements, which caused deterioration in their already compromised nutritional status. The prevalence of malnutrition was approximately 18.7% using the Mini-Nutritional Assessment (MNA) (large or short form) as a diagnostic tool, but the prevalence was greater (45.7%) if different criteria were used (such as Body Mass Index (BMI), weight loss, or albumin concentration). Low scores in anthropometric indices were associated with a higher prevalence of complications during hospitalization and with a worse functional recovery. Despite improvements in the treatment of geriatric patients with hip fracture, mortality was still unacceptably high (30% within 1 year and up to 40% within 3 years). Malnutrition was associated with an increase in mortality. Nutritional intervention was cost effective and was associated with an improvement in nutritional status and a greater functional recovery. To conclude, in older people, the prevention of malnutrition and an early nutritional intervention can improve recovery following a hip fracture. Hip fractures represent a significant health risk for older populations because the incidence of fractures increases notably with age .2, and age are among the independent risk factors for hip fractures [Hip fractures in geriatric patients have a negative impact on functional status and quality of life, and are associated with high mortality ,3. Despiractures . Poor nuractures . Among rractures . This reThe principal objective of this review is to describe how both nutritional status, as revealed by malnutrition biomarkers, influences the clinical evolution and mortality of older people with hip fracture, as well as the impact of nutritional intervention. We therefore structured this paper into four chapters concerning subjects with hip fracture: (1) prevalence of malnutrition and nutritional status aspects , (2) influence upon outcomes and complications, (3) mortality, and (4) effects of nutritional intervention.A search was carried out on the electronic database MEDLINE for papers published from January 1990 until December 2017. The search strategy is detailed in Supplementary data. The search was restricted to articles in English, Spanish, or Italian. The references of the selected articles were manually revised in the search for eligible articles. Whenever there were studies with multiple publications about the same population, the study with the largest sample was selected, as long as it respected our inclusion criteria.We included observational and cohort studies that evaluated the presence of malnutrition , and the influence of malnutrition, as revealed by nutritional biomarkers, on functional recovery, post-operative complications, and mortality in hip fracture patients. We considered as nutritional biomarkers: (1) anthropometric parameters, such as BMI, mid-arm circumference, and triceps skinfold; (2) blood concentrations of total proteins, albumin, and micronutrients such as vitamin D and calcium. We also included controlled clinical trials with nutritional intervention. We defined an intervention as cases where patients received supplements  or advice on the characteristics of the diet . We consider studies  carried out in populations with an average age of 70 years or above. Reviews and protocols that did not provide results were excluded.The title and abstract of papers compiled from the search were evaluated by two researchers who carried out data extraction. Doubts and queries were discussed and whenever these could not be solved, the opinion of a third reviewer was requested. Studies were grouped according to their main objective. When necessary we contacted the corresponding author to request data that did not appear in the paper.The quality of the selected studies was determined with both the National Institutes of Health (NIH) Quality Assessment tool for Observational Cohort and Cross-Sectional Studies and the Quality Assessment of Controlled Intervention Studies . These tThis review included 44 papers, which totaled 26,281 subjects with a mean age 83.6 ± 7.2 years. The population was mostly female (73.5%). The overall quality of the included studies was rated as fair .In all of the studies included, malnutrition was identified by a validated nutritional assessment tool. Nevertheless, the prevalence of malnutrition changed according to diagnostic tool used. The prevalence of malnutrition was 18.7% using the MNA (long or short form), but it was greater if other diagnostic criteria were used  (45.7%). The prevalence of malnutrition, of risk of malnutrition, and the diagnostic tool used in each study are presented in In this section we included 10 studies that assessed the nutritional status of older people with hip fracture, with a total of 1575 subjects . The design of the studies, the general characteristics of the populations studied, and the main results are presented in Patients with hip fracture present malnutrition, as demonstrated by the presence of low values of the anthropometric indices. Several studies showed that energy intake in older people is smaller than that required and recommended ,13,14,152, versus only one-fifth of patients with intertrochanteric fractures [The importance of a good nutritional status was backed up by studies that observed how higher BMI scores were associated with a lower incidence of hip fractures . An interactures .The general characteristics of the studies included in this section can be found in Espaulella et al. showed how after 6 months’ follow-up only slightly over half of the patients subject to follow-up had recovered the functional status they had before the fracture . The MNAMalnutrition is of double importance as it is a risk factor for hip fracture, and in patients with hip fracture it reduces the ability to recover pre-fracture functional capacity. Indeed, malnutrition is a risk factor for fracture, and malnourished older people generally present a worse functional status before the fracture and frequently recover only partially their pre-fracture level of independency in activities of daily living (ADL) following a hip fracture . ConversMalnutrition and risk of malnutrition are more prevalent in geriatric patients with a higher comorbidity , in addip < 0.001), longer hospital stay (p < 0.001), and higher prevalence of readmission (p = 0.054). The benefits of a good nutritional status were also observed in other studies [Albumin could be a good blood marker of malnutrition . In this studies .In this section we included those studies whose main objective was to assess the impact of malnutrition, as revealed by nutritional biomarkers, on mortality. In addition, we considered studies where a multivariable analysis was carried out and which included malnutrition biomarkers. A summary of the design, characteristics, and main results of the included studies can be found in p < 0.001) [2 were associated with an increase of almost seven times the mortality at 1 year, as compared to values higher than 25 kg/m2 (Hazard Ratio (HR) 7.25, 95% CI 1.6–33.7) [2 had a risk almost three times less of dying after 1 year from the fracture  [Mortality was inversely associated with pre-surgery albumin levels, and patients with hypoalbuminemia had a relative risk of dying of 1.52  1.37–1.70, < 0.001) . Regardl< 0.001) . Further.6–33.7) . Studies1.4–5.0) .Cenzer et al. showed that difficulty preparing meals after hip fracture predicts 1-year mortality (and this predictor factor has the same points as congestive heart failure) . Others Mortality increases progressively after a hip fracture, from an in-hospital mortality of 7%, to 11% in the first 6 months after the fracture, up to 30% in the first year and 40% at 3 years. To highlight the importance of this health problem, we summarized total mortality and the follow-up periods of the included studies in In this section we included the studies in which nutritional interventions were carried out. The general characteristics of the populations included, the design, and the main results of the studies included are presented in We included 18 studies, 14 of which were carried out in Europe, one in the USA, one in Australia, and two in Asia, totaling 2248 patients (each study including between 23 and 420 subjects), with an mean age of 81.6 ± 5.4. Five studies were carried out only on women, whereas the rest had mixed samples (66.8% women).n 14) used oral nutritional supplements. One was preceded by supplementation with parenteral nutrition. In one study the supplement was administered via naso-gastric tube, and in one other study only dietary advice was used. One study did not specify the type of intervention. The characteristics of the interventions, calories used, protein content, and duration of the treatment are summarized in A majority of the studies  should be modified with the values that have been shown to be associated with lower mortality in the elderly (23–29 kg/m2) [Despite this, the observed trend is uniform and shows that malnourished older people are at a greater risk of fracture and that the prevalence of malnutrition is high in geriatric patients admitted with hip fracture. Patients with intracapsular fracture usually have low BMI, while patients with trochanteric fracture tend to have high BMI ,64. Low 9 kg/m2) . It woul9 kg/m2) ,68. The 9 kg/m2) . On the 9 kg/m2) .Screening tools such as the Mini-Nutritional Assessment Short-Form (MNA-SF) were able to diagnose a nutritional problem before it manifested through changes in the biochemical markers of malnutrition  . FactorsAs well as the known effects of this deficiency on bone metabolism, there is a high concentration of vitamin D receptors in muscle tissue . This siThe high prevalence of malnutrition in people with dementia could be one of the pathophysiological mechanisms for the high risk of falls and fractures, as well as for their poor functional recovery after a fracture ,37,42,74Malnutrition, which is very prevalent in geriatric patients with hip fracture, is associated with the incidence of complications, with length of hospital stay (and thus increase in cost), and with mortality. Hip fracture continues to be a pathology with high mortality. In spite of the achievement of a reduction in the incidence of hip fractures, mortality has not decreased . Intra-hPatients with hip fracture show a state of hypercatabolism secondary to reduced intake, loss of blood, and inflammation, which leads to a reduction in plasma proteins, which are important mechanisms for the defense of oxidative stress. Cell regeneration determines an increase in the production of free radicals at the site of the fracture. Plasma oxidant markers malondialdehyde (MDA) and advanced oxidation protein products (AOPP) were significantly positively, while albumin and total antioxidant capacity (TAC) are significantly negatively associated with the duration of hospitalization.Several studies observed lower scores in nutritional indices, such as BMI, in geriatric patients who died following a hip fracture, as compared to those who lived . It may Therefore, the results of this review support the indications of the European Society of Parenteral and Enteral Nutrition (ESPEN) guidelines, according to which all older adult patients with hip fracture should receive nutritional supplements during hospitalization .The prevalence of malnutrition is very high in older people and increases further in older people with high comorbidities as well as in geriatric patients. Malnutrition is associated to functional alterations and this can be a cause as well as a consequence of fractures.Malnutrition prevention could be associated with a reduction in the incidence of fractures, and with a better functional recovery following hip fracture. Fall prevention campaigns as well as advice on healthy and active ageing have contributed to the reduction in the incidence of hip fractures. The inclusion in care plans for geriatric patients with hip fracture of both nutritional assessments and the treatment of malnutrition could contribute to a better functional recovery and a reduction of mortality.


Shigella causes approximately 500,000 illnesses, 6000 hospitalizations, and 40 deaths in the United States annually, but incidence and populations at risk for severe shigellosis among adults are unclear. This study describes severe shigellosis among US adults.Shigella among adults ≥18 years old during 2002–2014. Criteria to define severe shigellosis included hospitalization, bacteremia, or death. We estimated annual incidence of shigellosis per 100,000 among adult populations, and conducted multivariable mixed-effects logistic regression to assess associations between severe shigellosis, demographic factors and Shigella species among adults with shigellosis.We analyzed Foodborne Diseases Active Surveillance Network data for infections caused by S. sonnei and S. flexneri, median annual incidence of severe shigellosis among adults was 0.56 and highest overall incidence was among black males 18–49 years old (1.58). Among adults with shigellosis, odds of severe disease were higher among males than females aged 18–49 years old  and among males than females with S. flexneri infections . The odds of severe shigellosis were higher among blacks than whites .Among 9968 shigellosis cases, 2764 (28%) were severe. Restricting to cases due to S. flexneri, and with black race. Future research should assess associations between severe shigellosis and sexual practices, antimicrobial resistance, comorbidities, and access to care.Among adults, men 18–49 years old, particularly blacks, have the highest incidence of severe shigellosis. Among adults with shigellosis, severe shigellosis was associated with being male in age group 18–49 years, with infections caused by  Shigella sonnei, S. flexneri, S. dysenteriae, or S. boydii. Shigellosis causes an estimated 500,000 illnesses, 6000 hospitalizations, and 40 deaths annually in the United States . None of the illnesses caused by S. dysenteriae or S. boydii resulted in death or bacteremia. Males with shigellosis had a higher proportion of severe illnesses compared with women (30% vs. 25%). More cases of shigellosis were reported among adults 18–49 years old (7658) than among adults ≥50 years old (2310). However, among all reported cases, the proportion of adults ≥50 years old with severe shigellosis (34%) was higher than the proportion of adults 18–49 years old with severe shigellosis (26%). By race, the proportion of severe infections was highest among blacks (35%) compared with whites (25%) or other (25%) race groups  and was higher for S. sonnei than for S. flexneri   for S. flexneri and 0.56 (IQR: 0.49–0.70) for the two species combined  had complete age, race, species and sex variables and were used in this analysis. The distributions of race and age were similar among the included and excluded cases, but the included group contained a higher proportion of males than the excluded group (53% vs. 49%). Overall, 7063 (71%) were caused by S. flexneri, black males 18–49 years old had the highest median annual incidence of severe shigellosis (1.58). Among infections caused by S. sonnei, black females 18–49 years old had the highest median annual incidence of severe shigellosis (1.08) (data not shown).When calculating the incidence of shigellosis by race (black vs white), sex, and age group combined ; black males 18–49 years old had the highest median annual incidence of severe shigellosis 2.76), whereas white females ≥50 years old had the lowest (0.32)  among adults with shigellosis. Thus, the associations between severity of infections and sex were presented by age group and Shigella species (Table p < 0.01). However, among adults ≥50 years old, no significant difference by sex was observed . The odds of severe disease were higher for males than females among infections caused by S. flexneri,  but not among infections caused by S. sonnei . Blacks had higher odds of severe disease compared with whites  and other race groups . The odds of severe shigellosis gradually increased by year during 2002–2014 . Site-level random effects were significant (p < 0.001), implying significant contextual influences on disease severity (data not shown).In multivariable logistic regression, we observed significant interactions between sex and age group and between sex and species (all es Table . Among 1S. sonnei caused the greatest number of severe infections, and black men 18–49 years old had the highest incidence of severe shigellosis compared to other race, age, and sex groups. Disparities by sex and race existed: odds of severe illness were higher among men 18–49 years than among women of the same age, among men compared with women infected with S. flexneri, and among blacks compared with whites or other races. Although a higher proportion of cases were severe among adults ≥50 years old than among those 18–49 years old, incidence of severe shigellosis was far lower, and no disparities were found by sex, in the older age group. Our data additionally suggest that the incidence of severe shigellosis in adults has been increasing since 2005, whereas shigellosis incidence overall has shown a general decrease from 2009 to 2013 [This study outlines the burden of severe illness from shigellosis among US adults, and shows significant differences in the risk of developing severe shigellosis by sex, age, race, and species of infection. Among adults in FoodNet, Race and ethnicity often correlate with social determinants of health, such as poverty, unemployment, and low educational attainment . Racial Shigella infections in MSM. Between 1975 and 1985, the median age of U.S. males infected with S. flexneri increased from 5 to 26 years of age, likely driven by transmission among MSM [In this analysis, men experienced higher incidence of both shigellosis and severe shigellosis than did women. The reason for the male predominance is unknown and we were unable to assess the impact of comorbidities and sexual practices in our findings. It is possible that the increased incidence could be driven by increases in mong MSM . In the mong MSM . Severalmong MSM , 26, andmong MSM , 27. Shimong MSM , 28, 29.mong MSM , 31. In mong MSM , 33. Shimong MSM , 13.Shigella generally have longer duration of bacterial shedding in feces, and may suffer from more severe illness [HIV infection is a risk factor for shigellosis , and shi illness , 28. In  illness . HIV inf illness .Shigella is classified as a “serious risk” pathogen by CDC [Shigella strains associated with outbreaks in MSM were significantly more likely to be resistant to the key therapeutic antimicrobials than were other Shigella strains [Although we could not assess the direct association between antimicrobial resistance and shigellosis severity, antimicrobial-resistant n by CDC , and datn by CDC –40. An a strains . Antimic strains , and can strains . With inOur findings suggest severe shigellosis is increasing, especially among men 18–49 years of age, and could be driven by increases among MSM. Shigellosis questionnaires used during public health investigations should incorporate information regarding sexual practices or orientation and concurrent STDs to better define risk groups and guide interventions for severe shigellosis. Because the increase in severe shigellosis may also be associated with increases in antimicrobial resistance, epidemiologic studies should include antimicrobial resistance, treatment and clinical outcome data to further characterize these associations.Lack of information about sexual orientation or practices, comorbidities such as HIV, and antimicrobial resistance limited our study. Small numbers of deaths and bacteremia cases prevented meaningful sub-analyses for these outcomes, and detailed information about clinical characteristics such as dysentery were not available. Limiting the dataset to cases with complete demographic variables underestimated incidence and may have introduced selection bias. However, since FoodNet is an active surveillance system, we assume no association between the absence of demographic data and disease severity. The racial disparities we found should be interpreted carefully, as non-severe cases of shigellosis may be underreported in groups with poor access to healthcare, including blacks , howeverShigella infections, they had higher odds of developing severe illness during Shigella infections, compared to others. The reasons for this are unclear, but may be associated with disparities in social determinants of health, sexual orientation or behaviors, antimicrobial resistance, comorbidities, or circulation of more pathogenic strains within certain populations. Based on these and previous findings, Shigella isolates from all persons requiring antimicrobial treatment should be tested for antimicrobial susceptibility. Effective public health interventions for targeted prevention of shigellosis among blacks and men 18–49 years old could dramatically reduce the burden of severe shigellosis. Counseling MSM about prevention of sexual transmission of shigellosis, including guidance about hygiene, use of barriers during sex, and avoiding sex while having diarrhea, is critical. Further studies are warranted to characterize potential associations between severe shigellosis and MSM, antimicrobial resistance, and comorbidities. Among shigellosis patients, clinicians should consider the increased possibility for severe illness among persons infected with S. flexneri, males aged 18–49 years old or anyone aged ≥50 years old, and blacks.In conclusion, blacks, particularly men 18–49 years old, experienced higher incidence of severe shigellosis compared to other subgrounds and during