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Little is known about long-term fidelity of evidence-based interventions (EBIs) under changing conditions. This study examines how staff at 'mature' (eight or more years in operation) Housing First (HF) programs strategize to sustain EBI fit in different geographic areas in the Mid-Atlantic/Northeastern United States. Six focus groups (FGs) at three purposively selected HF programs were conducted with separate FGs for case managers and supervisors at each site. FG discussions elicited participants' service approaches and strategies in addressing fidelity amidst ongoing changes affecting each program. Thematic content analysis of FG transcripts was conducted using the five HF fidelity domains (housing choice/structure, separation of housing and services, service philosophy, service array, and program structure) as a priori themes with inductive content analyses conducted on data in each theme. Strategies for rigor were employed. Case managers (N = 17) and supervisors (N = 16) were predominantly white (76%) and female (60%). Across the themes, challenges included lack of affordable housing and choice, funders' restrictions and practice 'drift.' Strategies included community engagement and hiring, strong leadership and 'bending the rules.' There were no differences across sites. Later-stage implementation challenges show the need for continued vigilance in fidelity to EBIs. Among the strategies used to address fidelity in this study, the pursuit of pro-active community engagement to attract knowledgeable staff as well as increase local buy-in was considered pivotal at all three sites. These findings underscore the need to attend to the external setting as well as to internal program operations.With a career spanning more than half a century, Leonard Bickman has contributed to improving children's mental health through research on innovative interventions, such as measurement-based care, and service-level initiatives, including systems of care. Len's highly productive career in children's mental health services research is founded in his influence on the science of program evaluation, particularly in the area of program theory. This article provides an abridged and combined version of a video interview with Len dated April 16, 2019 and written responses to a series of questions posed to Len in advance of the festschrift held in his honor at Johns Hopkins Bloomberg School of Public Health on May 11, 2018.Recently, postmortem imaging is sometimes used as an alternative to conventional autopsy. However, there are few case reports of postmortem imaging of dialysis patients. Here, we report a fatal case of gas gangrene involving a 76-year-old man who underwent dialysis. He died suddenly before a diagnosis could be established. Immediately after his death, postmortem computed tomography (PMCT) revealed gas accumulation in his right upper extremity and ascending aorta. Gas gangrene progresses rapidly and may sometimes result in sudden death before it is diagnosed. In this case, PMCT findings were useful to diagnose gas gangrene. Intravascular gas is a common finding on PMCT and is generally caused by cardiopulmonary resuscitation and decomposition. However, the detection of gas in the ascending aorta by PMCT was not described previously. Moreover, Gram stain and culture of the exudate showed anaerobic Gram-positive bacilli which suggested that the gas generation in the blood was caused by Clostridia species. To the best our knowledge, this is the first report of a dialysis patient whose cause of death was determined as gas gangrene using PMCT.Abamectin (ABA) constitutes a big commodity for pharmaceutical companies because it generates about one billion dollar annual sale. Avermectins (AVMs) and their naturally occurring analogues, milbemycins (MILs), meilingmycins (MEIs), ivermectin (IVE), abamectin (ABA), and nemadectin (NEM), represent one of the most developed antiparasitic agents. Abamectin is a mixture of avermectin B1a and avermectin B1b. The production of abamectin by Streptomyces avermitilis is a complicated process and separation of two fractions is quite difficult; commercial product contains more than 80% of Bla and less than 20% of B1b components. The main goal of the study was the identification and optimization of fermentation conditions to raise the production of abamectin from Egyptian S. avermitilis. The qualitative and quantitative analysis of avermectins was carried out by thin layer chromatography (TLC) and 6538 Q-TOF with Agilent 1290 UHPLC. The process of identification was carried out by using production medium containing 30 g/L corn starch, and 0.725 g/L CaCO3, pH 7, 8% inoculum size and incubated at 32.5 °C. The enhancement of the production of abamectin is a big challenge with commercial and industrial importance, as its output is insufficient for human consumption.PURPOSE Minimally invasive surgery (MIS) has become the standard for many surgical procedures as it minimizes trauma, reduces infection rates and shortens hospitalization. However, the manipulation of objects in the surgical workspace can be difficult due to the unintuitive handling of instruments and limited range of motion. Apart from the advantages of robot-assisted systems such as augmented view or improved dexterity, both robotic and MIS techniques introduce drawbacks such as limited haptic perception and their major reliance on visual perception. METHODS In order to address the above-mentioned limitations, a perception study was conducted to investigate whether the transmission of intra-abdominal acoustic signals can potentially improve the perception during MIS. To investigate whether these acoustic signals can be used as a basis for further automated analysis, a large audio data set capturing the application of electrosurgery on different types of porcine tissue was acquired. A sliding window techniqueat potential to improve the surgical performance and to partly compensate the loss of haptic feedback.PURPOSE For laparoscopic ablation to be successful, accurate placement of the needle to the tumor is essential. Laparoscopic ultrasound is an essential tool to guide needle placement, but the ultrasound image is generally presented separately from the laparoscopic image. We aim to evaluate an augmented reality (AR) system which combines laparoscopic ultrasound image, laparoscope video, and the needle trajectory in a unified view. METHODS We created a tissue phantom made of gelatin. Artificial tumors represented by plastic spheres were secured in the gelatin at various depths. The top point of the sphere surface was our target, and its 3D coordinates were known. The participants were invited to perform needle placement with and without AR guidance. Once the participant reported that the needle tip had reached the target, the needle tip location was recorded and compared to the ground truth location of the target, and the difference was the target localization error (TLE). The time of the needle placement was also recorded. We further tested the technical feasibility of the AR system in vivo on a 40-kg swine. RESULTS The AR guidance system was evaluated by two experienced surgeons and two surgical fellows. The users performed needle placement on a total of 26 targets, 13 with AR and 13 without (i.e., the conventional approach). The average TLE for the conventional and the AR approaches was 14.9 mm and 11.1 mm, respectively. The average needle placement time needed for the conventional and AR approaches was 59.4 s and 22.9 s, respectively. For the animal study, ultrasound image and needle trajectory were successfully fused with the laparoscopic video in real time and presented on a single screen for the surgeons. CONCLUSION By providing projected needle trajectory, we believe our AR system can assist the surgeon with more efficient and precise needle placement.PURPOSE Sustained delivery of regenerative retinal therapies by robotic systems requires intra-operative tracking of the retinal fundus. We propose a supervised deep convolutional neural network to densely predict semantic segmentation and optical flow of the retina as mutually supportive tasks, implicitly inpainting retinal flow information missing due to occlusion by surgical tools. METHODS As manual annotation of optical flow is infeasible, we propose a flexible algorithm for generation of large synthetic training datasets on the basis of given intra-operative retinal images. We evaluate optical flow estimation by tracking a grid and sparsely annotated ground truth points on a benchmark of challenging real intra-operative clips obtained from an extensive internally acquired dataset encompassing representative vitreoretinal surgical cases. RESULTS The U-Net-based network trained on the synthetic dataset is shown to generalise well to the benchmark of real surgical videos. When used to track retinal points of interest, our flow estimation outperforms variational baseline methods on clips containing tool motions which occlude the points of interest, as is routinely observed in intra-operatively recorded surgery videos. CONCLUSIONS The results indicate that complex synthetic training datasets can be used to specifically guide optical flow estimation. Our proposed algorithm therefore lays the foundation for a robust system which can assist with intra-operative tracking of moving surgical targets even when occluded.PURPOSE Basal cell carcinoma (BCC) is the most commonly diagnosed cancer and the number of diagnosis is growing worldwide due to increased exposure to solar radiation and the aging population. Reduction of positive margin rates when removing BCC leads to fewer revision surgeries and consequently lower health care costs, improved cosmetic outcomes and better patient care. In this study, we propose the first use of a perioperative mass spectrometry technology (iKnife) along with a deep learning framework for detection of BCC signatures from tissue burns. METHODS Resected surgical specimen were collected and inspected by a pathologist. With their guidance, data were collected by burning regions of the specimen labeled as BCC or normal, with the iKnife. Data included 190 scans of which 127 were normal and 63 were BCC. A data augmentation approach was proposed by modifying the location and intensity of the peaks of the original spectra, through noise addition in the time and frequency domains. A symmetric autoencoder was built by simultaneously optimizing the spectral reconstruction error and the classification accuracy. Using t-SNE, the latent space was visualized. RESULTS The autoencoder achieved an accuracy (standard deviation) of 96.62 (1.35%) when classifying BCC and normal scans, a statistically significant improvement over the baseline state-of-the-art approach used in the literature. The t-SNE plot of the latent space distinctly showed the separability between BCC and normal data, not visible with the original data. Augmented data resulted in significant improvements to the classification accuracy of the baseline model. CONCLUSION We demonstrate the utility of a deep learning framework applied to mass spectrometry data for surgical margin detection. We apply the proposed framework to an application with light surgical overhead and high incidence, the removal of BCC. The learnt models can accurately separate BCC from normal tissue.PURPOSE Eye gaze tracking is proving to be beneficial in many biomedical applications. The performance of systems based on eye gaze tracking is very much dependent on how accurate their calibration is. It has been reported that the gaze tracking accuracy deteriorates cumulatively and significantly with usage time. This impedes the wide use of gaze tracking in user interfaces. METHODS Explicit re-calibration, typically requiring the user's active attention, is time-consuming and can interfere with the user's main activity. Therefore, we propose an implicit re-calibration method, which can rectify the deterioration of the gaze tracking accuracy without bringing about the user's deliberate attention. We make use of hand-eye coordination, with the reasonable assumption that the eye gaze follows the pointer during a selection task, to acquire additional calibration points during normal usage of a gaze-contingent system. We construct a statistical model for the calibration and the hand-eye coordination and apply the Gaussian process regression framework to perform the re-calibration. RESULTS To validate our model and method, we performed a user study on ultrasonography tasks on a gaze-contingent interface for ultrasound machines. Results suggest that our method can rectify the tracking accuracy deterioration for [Formula see text] of all cases where deterioration occurs in our user study. With another benchmark dataset, our method can redress tracking accuracy to a level comparable to the initial calibration in more than [Formula see text] of the cases. CONCLUSIONS Our implicit re-calibration method is a practical and convenient fix for tracking accuracy deterioration in gaze-contingent user interfaces, and in particular for gaze-contingent ultrasound machines.PURPOSE Surgical simulations play an increasingly important role in surgeon education and developing algorithms that enable robots to perform surgical subtasks. To model anatomy, finite element method (FEM) simulations have been held as the gold standard for calculating accurate soft tissue deformation. Unfortunately, their accuracy is highly dependent on the simulation parameters, which can be difficult to obtain. METHODS In this work, we investigate how live data acquired during any robotic endoscopic surgical procedure may be used to correct for inaccurate FEM simulation results. Since FEMs are calculated from initial parameters and cannot directly incorporate observations, we propose to add a correction factor that accounts for the discrepancy between simulation and observations. We train a network to predict this correction factor. RESULTS To evaluate our method, we use an open-source da Vinci Surgical System to probe a soft tissue phantom and replay the interaction in simulation. We train the network to correct for the difference between the predicted mesh position and the measured point cloud. This results in 15-30% improvement in the mean distance, demonstrating the effectiveness of our approach across a large range of simulation parameters. CONCLUSION We show a first step towards a framework that synergistically combines the benefits of model-based simulation and real-time observations. It corrects discrepancies between simulation and the scene that results from inaccurate modeling parameters. This can provide a more accurate simulation environment for surgeons and better data with which to train algorithms.PURPOSE Neuronavigation systems making use of augmented reality (AR) have been the focus of much research in the last couple of decades. In recent years, there has been considerable interest in using mobile devices for AR in the operating room (OR). We propose a complete system that performs real-time AR video augmentation on a mobile device in the context of image-guided neurosurgery. METHODS MARIN (mobile augmented reality interactive neuronavigation system) improves upon the state of the art in terms of performance, allowing real-time augmentation, and interactivity by allowing users to interact with the displayed data. The system was tested in a user study with 17 subjects for qualitative and quantitative evaluation in the context of target localization and brought into the OR for preliminary feasibility tests, where qualitative feedback from surgeons was obtained. RESULTS The results of the user study showed that MARIN performs significantly better in terms of both time ([Formula see text]) and accuracy ([Formula see text]) for the task of target localization in comparison with a traditional image-guided neurosurgery (IGNS) navigation system. Further, MARIN AR visualization was found to be more intuitive and allowed users to estimate target depth more easily. CONCLUSION MARIN improves upon previously proposed mobile AR neuronavigation systems with its real-time performance, higher accuracy, full integration in the normal workflow and greater interactivity and customizability of the displayed information. The improvement in efficiency and usability over previous systems will facilitate bringing AR into the OR.Sirtuin-2 (Sirt2) is a member of the NAD (+)-dependent protein deacetylase family involved in neuroprotection, cellular metabolism, homeostasis, and stress responses after injury of the nervous system. So far, no data have been published describing the role of SIRT2 in motor functional recovery after damage. We found that SIRT2 expression and deacetylase activity were increased within motoneurons after axotomy. To shed light onto the biological relevance of this change, we combined in vitro and in vivo models with pharmacological and genetic ablation approaches. We found that SIRT2 KO (knockout) mice exhibited improved functional recovery after sciatic nerve crush. SIRT2 activity blockage, using AK7, increased neurite outgrowth and length in organotypic spinal cord cultures and human cell line models. SIRT2 blockage enhanced the acetyltransferase activity of p300, which in turn increased the levels of an acetylated form of p53 (Ac-p53 k373), histone 3 (Ac-H3K9), and expression of GAP43, a downstream marker of regeneration. Lastly, we verified that p300 acetyltransferase activity is essential for these effects. Our results suggest that bolstering an epigenetic shift that promotes SIRT2 inhibition can be an effective therapy to increase functional recovery after peripheral nerve injury.Cortical spreading depolarizations (SD) are strongly associated with worse tissue injury and clinical outcomes in the setting of aneurysmal subarachnoid hemorrhage (SAH). Animal studies have suggested a causal relationship, and new therapies to target SDs are starting to be tested in clinical studies. A recent set of single-center randomized trials assessed the effect of the phosphodiesterase inhibitor cilostazol in patients with SAH. Cilostazol led to improved functional outcomes and SD-related metrics in treated patients through a putative mechanism of improved cerebral blood flow. Another promising therapeutic approach includes attempts to block SDs with, for example, the NMDA receptor antagonist ketamine. SDs have emerged not only as a therapeutic target but also as a potentially useful biomarker for brain injury following SAH. Additional clinical and preclinical experimental work is greatly needed to assess the generalizability of existing therapeutic trials and to better delineate the relationship between SDs, SAH, and functional outcome.Abnormal neural activity, particularly in the rostrodorsal anterior cingulate cortex (rdACC), appears to be responsible for intense alcohol craving. Neuromodulation of the rdACC using cortical implants may be an option for individuals with treatment-resistant alcohol dependence. This study assessed the effectiveness and feasibility of suppressing alcohol craving using cortical implants of the rdACC using a controlled one-group pre- and post-test study design. Eight intractable alcohol-dependent participants (four males and four females) were implanted with two Lamitrode 44 electrodes over the rdACC bilaterally connected to an internal pulse generator (IPG). The primary endpoint, self-reported alcohol craving reduced by 60.7% (p = 0.004) post- compared to pre-stimulation. Adverse events occurred in four out of the eight participants. Electrophysiology findings showed that among responders, there was a post-stimulation decrease (p = 0.026) in current density at the rdACC for beta 1 band (13-18 Hz). Results suggest that rdACC stimulation using implanted electrodes may potentially be a feasible method for supressing alcohol craving in individuals with severe alcohol use disorder. However, to further establish safety and efficacy, larger controlled clinical trials are needed.PURPOSE To determine the association between coronal Cobb's angle and Nash-Moe index in patients with adolescent idiopathic scoliosis. We also attempted to determine whether apical vertebral derotation depended upon the curve flexibility. OVERVIEW OF LITERATURE The three-dimensional nature of adolescent idiopathic scoliosis (AIS) is well established. Knowledge of all components of this complex deformity is essential to formulate effective treatment strategies. Though the importance of quantifying all the components of the deformity, in AIS, has been analysed in detail, very few studies have been done to ascertain the relationship between the coronal plane deformity and apical vertebral rotation. METHODS Digitalised standing and supine stretch anteroposterior (AP) radiographs of 158 patients with AIS were analysed. The standing and supine stretch AP radiographs were compared to calculate the percentage reduction of Cobb's angle to determine curve flexibility. The derotation of the apical vertebra on applicatiourves, when stretched.BACKGROUND All drug marketing authorization holders have the legal obligation to collect data on the use of the products they market and to keep the labels of those products updated. As demonstrated by previous studies, many generic products have labels that are discrepant from the labels of their reference (originator) products. This fact may cause inconsistent messages to be disseminated to healthcare professionals and patients for the same active ingredient. OBJECTIVE These potential label discrepancies led us to investigate the degree of difference between labels for generic and originator products, the possible consequences of this discrepancy for patients, and its implications for risk minimization. PRODUCTS AND METHODS Drugs from different Anatomical Therapeutic Chemical classes were randomly selected from the Electronic Medicines Compendium. For each drug, the consistency and discrepancies between the summaries of product characteristics (SmPCs) for originator and generic products were analyzed for ea have a severe patient outcome were noted for 11 (35.5%) of the selected drugs, and label misalignments that could have a medium impact on the patient were seen for 6 (19.35%) of the selected drugs. The label misalignments observed for 10 (32.25%) of the selected drugs would potentially lead to only a minor or no effect on the patient. Almost half (15, 48.4%) of the selected drugs presented label misalignments that could have a critical (fatal, life-threatening, severe) influence on the patient. CONCLUSIONS In this sample, SmPC alignment between generic and originator medicinal products was found to be inefficient for established drugs, and could lead to the diffusion of discrepant messages to healthcare professionals and patients. In order to address this SmPC alignment problem, health authorities such as the EMA and the FDA must conduct retrospective analyses of all drugs on the market as a first step towards realigning labels. These analyses could be performed during the evaluation of aggregate reports.Although bacteria have diverse membrane proteins, the function of many of them remains unknown or uncertain even in Escherichia coli. In this study, to investigate the function of hypothetical membrane proteins, genome-wide analysis of phenotypes of hypothetical membrane proteins was performed under various envelope stresses. Several genes responsible for adaptation to envelope stresses were identified. Among them, deletion of YhcB, a conserved inner membrane protein of unknown function, caused high sensitivities to various envelope stresses and increased membrane permeability, and caused growth defect under normal growth conditions. Furthermore, yhcB deletion resulted in morphological aberration, such as branched shape, and cell division defects, such as filamentous growth and the generation of chromosome-less cells. The analysis of antibiotic susceptibility showed that the yhcB mutant was highly susceptible to various anti-folate antibiotics. Notably, all phenotypes of the yhcB mutant were completely or significantly restored by YhcB without the transmembrane domain, indicating that the localization of YhcB on the inner membrane is dispensable for its function. Taken together, our results demonstrate that YhcB is involved in cell morphology and cell division in a membrane localization-independent manner.Mongolian sheep are an indigenous ruminant raised for wool and meat production in China. The gut microbial community plays an important role in animal performance and metabolism. The objective of this study was to investigate the effects of two feeding regimens on the diversity and composition of gut microbiota and metabolite profiles of feces and plasma from Mongolian sheep. A total of 20 Mongolian sheep were assigned to one of two feeding regimens free grazing (FG) and barn confinement (BC). When samples were collected, the average live weights of the sheep were 31.28 ± 1.56 kg and 34.18 ± 1.87 kg for the FG and BC groups, respectively. At the genus level, the FG group showed higher levels of Bacteroides, RC9_gut_group, Alistipes, Phocaeicola, Barnesiella, and Oscillibacter, and lower levels of Succinivibrio, Treponema, and Prevotella, compared to the BC group. The butyric acid content in feces was lower in the FG group (P > 0.05). Higher levels of palmitic acid, oleic acid, alpha-linolenic acid, L-carnitine, L-citrulline, and L-histidine, and lower levels of L-tyrosine, L-phenylalanine, and L-kynurenine were found in the plasma of the FG sheep. Moreover, there were substantial associations between several gut microbiota genera and alterations in feces and plasma metabolites especially those involved in the metabolism of butyric acid, linolenic acid, and L-tyrosine. Feeding regimens can not only influence the composition of gut microbiota, but also alter metabolic homeaostasis in sheep.Crystal structures of enoyl-coenzyme A (CoA) isomerase from Bosea sp. PAMC 26642 (BoECI) and enoyl-CoA hydratase from Hymenobacter sp. PAMC 26628 (HyECH) were determined at 2.35 and 2.70 Å resolution, respectively. BoECI and HyECH are members of the crotonase superfamily and are enzymes known to be involved in fatty acid degradation. Structurally, these enzymes are highly similar except for the orientation of their C-terminal helix domain. Analytical ultracentrifugation was performed to determine the oligomerization states of BoECI and HyECH revealing they exist as trimers in solution. However, their putative ligand-binding sites and active site residue compositions are dissimilar. Comparative sequence and structural analysis revealed that the active site of BoECI had one glutamate residue (Glu135), this site is occupied by an aspartate in some ECIs, and the active sites of HyECH had two highly conserved glutamate residues (Glu118 and Glu138). Moreover, HyECH possesses a salt bridge interaction between Glu98 and Arg152 near the active site. This interaction may allow the catalytic Glu118 residue to have a specific conformation for the ECH enzyme reaction. This salt bridge interaction is highly conserved in known bacterial ECH structures and ECI enzymes do not have this type of interaction. Collectively, our comparative sequential and structural studies have provided useful information to distinguish and classify two similar bacterial crotonase superfamily enzymes.Multiple transcriptional regulators play important roles in the coordination of developmental processes, including asexual and sexual development, and secondary metabolism in the filamentous fungus Aspergillus nidulans. In the present study, we characterized a novel putative C2H2-type transcription factor (TF), RocA, in relation to development and secondary metabolism. Deletion of rocA increased conidiation and caused defective sexual development. In contrast, the overexpression of rocA exerted opposite effects on both phenotypes. Additionally, nullifying rocA resulted in enhanced brlA expression and reduced nsdC expression, whereas its overexpression exerted the opposite effects. These results suggest that RocA functions as a negative regulator of asexual development by repressing the expression of brlA encoding a key asexual development activator, but as a positive regulator of sexual development by enhancing the expression of nsdC encoding a pivotal sexual development activator. Deletion of rocA increased the production of sterigmatocystin (ST), as well as the expression of its biosynthetic genes, aflR and stcU. Additionally, the expression of the biosynthetic genes for penicillin (PN), ipnA and acvA, and for terrequinone (TQ), tdiB and tdiE, was increased by rocA deletion. Thus, it appears that RocA functions as a negative transcriptional modulator of the secondary metabolic genes involved in ST, PN, and TQ biosynthesis. Taken together, we propose that RocA is a novel transcriptional regulator that may act either positively or negatively at multiple target genes necessary for asexual and sexual development and secondary metabolism.A Gram-negative aerobic bacterium, designated RR4-38T, was isolated from a biofilter in a seawater recirculating aqua-culture system (RAS) in Busan, South Korea. The bacteria were irregular, short, rod-shaped, non-motile, oxidase-positive, and catalase-negative. Growth of the strain RR4-38T was observed at 15-35·C (optimum, 25-30·C), pH 5.5-9.5 (optimum, pH 8.0), and in the presence of 0-5% (w/v) NaCl (optimum, 3%). Phylogenetic analysis based on the 16S rRNA gene sequences showed that the strain RR4-38T formed a distinct lineage with close genera Ulvibacter (≤ 95.01% 16S rRNA gene sequence similarity), Aureitalea (94.74%), Aureisphaera (≤ 93.27%), and Jejudonia (93.07%) that all belong to the family Flavobacteriaceae. Whole-genome sequence comparison revealed that the ANI (average nucleotide identity) and digital DDH (DNA-DNA hybridization) values between strain RR4-38T and the two closest strains, Ulvibacter antarcticus DSM 23424T and Aureitalea marina S1-66T, were 68.96-69.88% and 17.4-19%, respectively. The genome analysis revealed that the strain might be involved in biodegradation of organic debris produced by farmed fish in aquaculture systems. The predominant respiratory quinone was menaquinone MK-6 and the major cellular fatty acids were iso-C150 (26.5%), iso-C170 3-OH (16.4%), iso-C151 G (15%), and iso-C160 3-OH (9.6%). The major cellular polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, unidentified aminolipids, and glycolipids. Based on phenotypic, chemotaxonomic, and phylogenetic features, strain RR4-38t represents a novel genus and species in the family Flavobacteriaceae, for which the name Pukyongia salina gen. nov., sp. nov. is proposed. The type strain is RR4-38T (= KCTC 52651T = DSM 108068T).INTRODUCTION Teneligliptin, a dipeptidyl peptidase 4 inhibitor, was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. However, clinical trials of teneligliptin involved limited numbers of elderly patients. Therefore, we investigated the safety and efficacy of teneligliptin in elderly patients with T2DM. METHODS This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. Data were analysed for patients in three age subgroups ( less then  65, ≥ 65 to less then  75, or ≥ 75 years old). Safety was assessed as the incidence of ADRs and efficacy was assessed in terms of glycaemic control, for up to 3 years. RESULTS The ADRs and serious ADRs occurred in 3.35% and 0.65% of 4596 patients aged less then  65 years, in 4.42% and 1.22% of 3371 patients aged ≥ 65 to less then  75 years, and glucose levels in all three age subgroups, and the changes were maintained for up to 3 years in many individuals in each age subgroup. We found no additional safety or efficacy concerns among elderly patients beyond those already described in the package insert. The present results support the use of teneligliptin for the treatment of elderly patients with type 2 diabetes mellitus in real-world clinical practice.INTRODUCTION Adequate bowel preparation is a vital determinant for the success of colonoscopy. However, individuals who undergo bowel preparation for colonoscopy can experience major discomfort. To solve this problem, adding prucalopride to the prepared solution may reduce intake volume, decreasing discomfort and side effects. We performed meta-analyses and systematic review of available randomized controlled trials. METHODS Meta-analyses were conducted to evaluate the overall relative risk and 95% confidence intervals in the combined studies for the assessment of primary outcome, which is the efficacy of bowel preparation with the addition of prucalopride. RESULTS Four randomized controlled trials involving 581 patients were included. When data were pooled for all patients in two non-inferiority studies, no significant difference in the quality of bowel preparation was observed between patients receiving prucalopride plus bowel preparation solution at a lower volume and those receiving the existing solution (relative risk 0.94; 95% confidence interval 0.86-1.03). The effects of prucalopride on acceptability, adverse events, adenoma detection rate, and polyp detection rate did not significantly differ from those of traditional solutions. CONCLUSIONS The combination of prucalopride and bowel preparation solution at a lower volume has similar effects on bowel preparation, and its use did not increase the occurrence of adverse effects.Rivaroxaban exposure and patient characteristics may affect the rivaroxaban benefit-risk balance. This study aimed to quantify associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation (NVAF), using data from the phase 3 ROCKET AF trial (NCT00403767). In ROCKET AF, 14,264 patients with NVAF were randomized to rivaroxaban (20 mg once daily [OD], or 15 mg OD if creatinine clearance was 30-49 mL/min) or dose-adjusted warfarin (median follow-up 707 days); rivaroxaban plasma concentration was measured in a subset of 161 patients. In this post hoc exposure-response analysis, a multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event efficacy and safety outcomes in 7061 and 7111 patients, respectively. There was no significant association between model-predicted rivaroxaban trough plasma concentration (Ctrough) and efficacy outcomes. Creatinine clearance and history of stroke were significantly associated with efficacy outcomes. Ctrough was significantly associated with the composite of major or non-major clinically relevant (NMCR) bleeding (hazard ratio [95th percentile vs. median] 1.26 [95% confidence interval 1.13-1.40]) but not with major bleeding alone. The exposure-response relationship for major or NMCR bleeding was shallow with no clear threshold for an acceleration in risk. History of gastrointestinal bleeding had a greater influence on safety outcomes than Ctrough. These results support fixed rivaroxaban 15 mg and 20 mg OD dosages in NVAF. Therapeutic drug monitoring is unlikely to offer clinical benefits in this indication beyond evaluation of patient characteristics.Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. The study objective was to assess the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism (VTE) prophylaxis (VTE-P) after hip/knee replacement surgery. Post hoc exposure-response analyses were conducted using data from the phase 3 RECORD1-4 studies, in which 12,729 patients were randomized to rivaroxaban 10 mg once daily or enoxaparin for ≤ 39 days. Multivariate regression approaches were used to correlate model-predicted individual rivaroxaban exposures and patient characteristics with outcomes. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and by making use of the known correlation between rivaroxaban plasma concentration and dynamics of PT. No significant associations between rivaroxaban exposure and total VTE or major bleeding were identified. A significant association between exposure and a composite of major or non-major clinically relevant (NMCR) bleeding from day 4 after surgery was observed. The relationship was shallow, with an approximate predicted absolute increase in a composite of major or NMCR bleeding from 1.08 [95% confidence interval (CI) 0.76-1.54] to 2.18% (95% CI 1.51-3.17) at the 5th and 95th percentiles of trough plasma concentration, respectively. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Hence, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-P.We report a rare case of fatal intoxication in a 40-year-old man caused by injection of a fluid containing organic mercury, allegedly in an attack with a syringe fixed to the tip of an umbrella. The man suffered from severe neurological symptoms and progressive multiorgan failure and died 10 months later in refractory status epilepticus. Autopsy revealed severe brain atrophy and non-specific kidney damage. Neuropathological examination showed neuronal loss especially in the occipital lobe, distinct granule cell necrosis in the cerebellum and Wallerian degeneration in the brainstem. Postmortem toxicological analysis revealed extremely increased levels of mercury in liver and kidney tissue as well as methylmercury levels in peripheral blood.Urinothorax is a cause of pleural effusion that is often missed due to its perceived rarity. Here, we present a case of urinothorax secondary to percutaneous nephrolithotomy resulting in lung collapse and death. This case highlights urinothorax as a cause of death, its biochemical profile, and diagnostic features on autopsy. A 39-year-old female presented to the ED with low back pain and dysuria. Abdominal and pelvic CT showed a large staghorn calculus in the right kidney which was then treated with percutaneous nephrolithotomy. On post-operative day (POD) 1, the patient was febrile, had decreased breath sounds, and complained of pain with deep inspiration. Chest x-ray revealed increased right pleural fluid. On POD 3, the patient continued to have difficulty breathing and was eventually found apneic. Resuscitation was unsuccessful. Autopsy revealed a collapsed right lung associated with a 1200 mL pleural effusion, which was cloudy, yellow, and smelled like urine. The cause of death was listed as complications of percutaneous nephrolitotomy, with urinothorax and collapse of lung. While rare, urinothoraces must be considered as a cause of pleural effusion due to risk of respiratory failure and death. Diagnosis relies on pleural fluid analysis and history, especially with regard to genitourinary obstruction and surgeries.Multiple organ dysfunction syndrome (MODS), also referred to as external challenge-induced multiple organ injury, is characterized by dysfunction of two or more organs during infection or following shock or trauma. The pathogenesis of MODS is multifactorial and involves systemic inflammation and cell stress responses including cell death; sepsis is defined as an infection with MODS. Gut microbiota contributes significantly to organ dysfunction and to the pathobiology of sepsis. However, the relationship between the development of sepsis and the composition of gut microbiota is equivocal and is only now starting to be elucidated. Recent studies by our group and others reveal that enteric microbial composition and function are disrupted during sepsis, and that microbial products can either promote or alleviate the progression of sepsis. Here, we summarize the current research on the functional link between gut microbiota and sepsis, and argue the point that gut microbiota is a potential therapeutic target in the management of sepsis.The gut microbiota consists of a dynamic multispecies community living within a particular niche in a mutual synergy with the host organism. Recent findings have revealed roles for the gut microbiota in the modulation of host immunity and the development and progression of immune-mediated diseases. Besides, growing evidence supports the concept that some metabolites mainly originated from gut microbiota are linked to the immune regulation implicated in systemic inflammatory and autoimmune disorders. In this chapter, we describe the recent advances in our understanding of how host-microbiota interactions shape the immune system, how they affect the pathogenesis of immune-associated diseases and the impact of these mechanisms in the efficacy of disease therapy.The gut microbiome contains trillions of commensal microorganisms that maintain a symbiotic relationship with the host, and its profound effects on gastrointestinal diseases have been widely described. Recently, gut microbiota have emerged as important factors in endocrine system diseases. Disruption of the gut microbiota affects neuroendocrine homeostasis and promotes peripheral endocrine system diseases, including obesity, diabetes, and hyperuricemia. This chapter provides a comprehensive overview of the biological mechanisms of gut microbiota that participate in endocrine system pathologies and discusses potential novel therapies for these diseases.The gut microbiota plays an important role in maintaining human health. Accumulating evidence has indicated an intimate relationship between gut microbiota and cardiovascular diseases (CVD) which has become the leading cause of death worldwide. The alteration of gut microbial composition (gut dysbiosis) has been proven to contribute to atherosclerosis, the basic pathological process of CVD. In addition, the metabolites of gut microbiota have been found to be closely related to the development of CVD. For example, short-chain fatty acids are widely acclaimed beneficial effect against CVD, whereas trimethylamine-N-oxide is considered as a contributing factor in the development of CVD. In this chapter, we mainly discuss the gut microbial metabolite-involved mechanisms of CVD focusing on atherosclerosis, hypertension, diabetes, obesity, and heart failure. Targeting gut microbiota and related metabolites are novel and promising strategies for the treatment of CVD.Renal injury, especially chronic kidney disease (CKD), is closely associated with gut microbiota. It is well known that renal injury development could cause enteric microbial compositional disruption. On the other hand, gut microbial composition, as well as their function, would directly influence the renal disease progression. Here, in the present chapter, we will summarize the crosstalk between intestinal microbiota and renal disease and discuss some potential therapeutic approaches based on this topic.The brain-gut axis is a bidirectional communication pathway connecting the central nervous system (CNS) and the gastrointestinal tract via nerve transmission, hormone, immune system, and other molecular signals. The bacterial flora of the human gut contributes direct and indirect signals to the CNS along the brain-gut axis. Alterations in gut flora, a state known as dysbiosis, has been tied to systemic inflammation, increased bacterial translocation, and increased absorbance of microbial by-products. An increase in recent literature has highlighted the role of the gut-brain axis in CNS pathology. This chapter reviews the association between gut flora dysbiosis and disorders of the central nervous system including autoimmune disease, developmental disorders, physiologic response to traumatic injury, and neurodegenerative disease.Gut microbiota are known to impact multiple organs including the lung. The cross talk between gut microbes and lungs, termed as the "gut-lung axis," is vital for immune response and homeostasis in the airways. In this chapter, we summarized the coordinated development of microorganisms in the gut and lung, exogenous and endogenous factors related to the cross talk, the mechanisms of the gut-lung axis and their dysbiosis in lung diseases. Although the current understanding of the gut-lung axis is in its infancy, several gut microbiota-associated strategies have been designed to treat and prevent lung diseases.Chronic liver injury mainly comprises viral hepatitis, fatty liver disease, autoimmune hepatitis, cirrhosis and liver cancer. It is well established that gut microbiota serves as the key upstream modulator for chronic liver injury progression. Indeed, the term "gut-liver axis" was mostly applied for chronic liver injury. In the current chapter, we will summarize the relationship between gut microbiota and chronic liver injury, including the interaction between them based on latest clinic and basic research.Over the last few decades, intestinal microbial communities have been considered to play a vital role in host liver health. Acute liver injury (ALI) is the manifestation of sudden hepatic injury and arises from a variety of causes. The studies of dysbiosis in gut microbiota provide new insight into the pathogenesis of ALI. However, the relationship of gut microbiota and ALI is not well understood, and the contribution of gut microbiota to ALI has not been well characterized. In this chapter, we integrate several major pathogenic factors in ALI with the role of gut microbiota to stress the significance of gut microbiota in prevention and treatment of ALI.The gastrointestinal (GI) tract is inhabited by a diverse array of microbes, which play crucial roles in health and disease. Dysbiosis of microbiota has been tightly linked to gastrointestinal inflammatory and malignant diseases. Here we highlight the role of Helicobacter pylori alongside gastric microbiota associated with gastric inflammation and cancer. We summarize the taxonomic and functional aspects of intestinal microbiota linked to inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and colorectal cancer in clinical investigations. We also discuss microbiome-related animal models. Nevertheless, there are tremendous opportunities to reveal the causality of microbiota in health and disease and detailed microbe-host interaction mechanisms by which how dysbiosis is causally linked to inflammatory disease and cancer, in turn, potentializing clinical interventions with a personalized high efficacy.In the past decade, research focusing on the gut microbiota has attracted a growing number of scientists. We increasingly realize that the gut microbiota plays a key role in both maintaining host homeostasis and affecting the progression of multiple diseases, which means that the microorganisms living in the intestines would not only influence the gastrointestinal tract but also impact other important organs such as the liver, brain, kidney, and lung. The underlying modulatory mechanism is complicated; however, we can expand the existing insight on the development of organ damage pathogenesis and discover novel therapeutic targets for organ injury-related diseases by investigating this "hot-topic". In this chapter, we will present a broad overview of the gut microbiota and organ injury, as well as the latest research achievements regarding the linkage between them.Sugary drinks and processed foods are associated with negative health outcomes in adults, including weight gain, and their consumption should be limited. However, they may be difficult to avoid if they are ubiquitously available in the retail environment. This study aimed to quantify the availability of such products for sale throughout New York City (NYC) at both food and non-food retailers. In 2018, ten one-mile retail-dense NYC street segments were selected for the sample. Data collectors canvassed each segment and visited all retailers, recording the type (food/non-food) and presence of processed food and beverages for sale. Descriptive statistics were analyzed for availability of products sold in retailers overall and by retailer type. In total, 491 retailers were identified (191 food, 300 non-food). Sugary drinks were available at 83% of food retailers and 19% of non-food retailers, while processed foods were available at 61% of food retailers and 16% of non-food retailers. Eighty-five percent of food retailers and 21% of non-food retailers sold sugary drinks and/or processed foods. This study supports and builds on results of previous research examining the availability of food and beverages in the retail environment. Sugary drinks and processed foods are ubiquitous at food and non-food retailers, providing pervasive cues to consume energy-dense, nutrient-poor products. Restrictions on where such products can be sold merit consideration.