Immune cell-intrinsic Ah receptor facilitates the expression of antimicrobial REG3G in the small intestine.

The intestinal epithelial layer is susceptible to damage by chemical, physiological and mechanical stress. While it is essential to maintain the integrity of epithelium, the biochemical pathways that contribute to the barrier function have not been completely investigated. Here we demonstrate an aryl hydrocarbon receptor (AHR)-dependent mechanism facilitating the production of the antimicrobial peptide AMP regenerating islet-derived protein 3 gamma (REG3G), which is essential for intestinal homeostasis. Genetic ablation of AHR in mice impairs pSTAT3-mediated REG3G expression and increases bacterial numbers of Segmented filamentous bacteria (SFB) and Akkermansia muciniphila in the small intestine. Studies with tissue-specific conditional knockout mice revealed that the presence of AHR in the epithelial cells of the small intestine is not required for the production of REG3G through the phosphorylated STAT3-mediated pathway. However, immune-cell-specific AHR activity is necessary for normal expression of REG3G in all regions of the small intestine. A diet rich in broccoli, capable of inducing AHR activity, increases REG3G production when compared to a semi-purified diet that is devoid of ligands that can potentially activate the AHR, thus highlighting the importance of AHR in antimicrobial function. Overall, these data suggest that homeostatic antimicrobial REG3G production is increased by an AHR pathway intrinsic to the immune cells in the small intestine.

Complex chemical signals dictate Ah receptor activation through the gut-lung axis.

The aryl hydrocarbon receptor (AHR) mediates intestinal barrier homeostasis. Many AHR ligands are also CYP1A1/1B1 substrates, which can result in rapid clearance within the intestinal tract, limiting systemic exposure and subsequent AHR activation. This led us to the hypothesis that there are dietary substrates of CYP1A1/1B1 that functionally increase the half-life of potent AHR ligands. We examined the potential of urolithin A (UroA), a gut bacterial metabolite of ellagitannins, as a CYP1A1/1B1 substrate to enhance AHR activity in vivo. UroA is a competitive substrate for CYP1A1/1B1 in an in vitro competition assay. A broccoli-containing diet promotes the gastric formation of the potent hydrophobic AHR ligand and CYP1A1/1B1 substrate, 5,11-dihydroindolo[3,2-b]carbazole (ICZ). In mice, dietary exposure to UroA in a 10% broccoli diet led to a coordinated increase in duodenal, cardiac, and pulmonary AHR activity, but no increase in activity in the liver. Thus, CYP1A1 dietary competitive substrates can lead to enhanced systemic AHR ligand distribution from the gut, likely through the lymphatic system, increasing AHR activation in key barrier tissues. Finally, this report will lead to a reassessment of the dynamics of distribution of other hydrophobic chemicals present in the diet.

Most Publications Regarding Platelet-Rich Plasma Use in the Knee Are From Asia, Investigate Injection for Osteoarthritis, and Show Outcome Improvement: A Scoping Review.

PURPOSE: To evaluate and synthesize the available literature related to platelet-rich plasma (PRP) treatment of knee pathologies and to provide recommendations to inform future research in the field. METHODS: PubMed, CINAHL, and Scopus databases were queried on October 6, 2023. All identified citations were collated and uploaded into Covidence for screening and data extraction. Studies were included if they were human studies published in English with adult cohorts that received PRP as a procedural injection or surgical augmentation for knee pathologies with patient-reported outcome measures (PROMs) and level of evidence Levels I-IV. RESULTS: Our search yielded 2,615 studies, of which 155 studies from 2006 to 2023 met the inclusion criteria. Median follow-up was 9 months (±11.2 months). Most studies (75.5%) characterized the leukocyte content of PRP, although most studies (86%) did not use a comprehensive classification scheme. In addition, most studies were from Asia (50%) and Europe (32%) and were from a single center (96%). In terms of treatment, 74% of studies examined PRP as a procedural injection, whereas 26% examined PRP as an augmentation. Most studies (68%) examined treatment of knee osteoarthritis. Many studies (83%) documented significant improvements in PROMs, including 93% of Level III/IV evidence studies and 72% of Level I/II evidence studies, although most studies (70%) failed to include minimal clinically important difference values. The visual analog scale was the most-used PROM (58% of studies), whereas the Short Form Health Survey 36-item was the least-used PROM (5% of studies). CONCLUSIONS: Most published investigations of knee PRP are performed in Asia, investigate procedural injection for osteoarthritis, and show significant outcome improvements. In addition, this review highlights the need for better classification of PRP formulations. LEVEL OF EVIDENCE: Level IV, scoping Review of level I-IV studies.

Aryl Hydrocarbon Receptor Activation Coordinates Mouse Small Intestinal Epithelial Cell Programming.

In the face of mechanical, chemical, microbial, and immunologic pressure, intestinal homeostasis is maintained through balanced cellular turnover, proliferation, differentiation, and self-renewal. Here, we present evidence supporting the role of the aryl hydrocarbon receptor (AHR) in the adaptive reprogramming of small intestinal gene expression, leading to altered proliferation, lineage commitment, and remodeling of the cellular repertoire that comprises the intestinal epithelium to promote intestinal resilience. Ahr gene/protein expression and transcriptional activity exhibit marked proximalHI to distalLO and cryptHI to villiLO gradients. Genetic ablation of Ahr impairs commitment/differentiation of the secretory Paneth and goblet cell lineages and associated mucin production, restricts expression of secretory/enterocyte differentiation markers, and increases crypt-associated proliferation and villi-associated enterocyte luminal exfoliation. Ahr-/- mice display a decrease in intestinal barrier function. Ahr+/+ mice that maintain a diet devoid of AHR ligands intestinally phenocopy Ahr-/- mice. In contrast, Ahr+/+ mice exposed to AHR ligands reverse these phenotypes. Ligand-induced AHR transcriptional activity positively correlates with gene expression (Math1, Klf4, Tff3) associated with differentiation of the goblet cell secretory lineage. Math1 was identified as a direct target gene of AHR, a transcription factor critical to the development of goblet cells. These data suggest that dietary cues, relayed through the transcriptional activity of AHR, can reshape the cellular repertoire of the gastrointestinal tract.

Third generation quinoline-3-carboxamide transcriptional disrupter of HDAC4, HIF-1α, and MEF-2 signaling for metastatic castration-resistant prostate cancer.

BACKGROUND: The quinoline-3-carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration-resistant prostate cancer(mCRPC), TasQ (1 mg/day) increased time-to-progression, but not overall survival. METHODS: TasQ analogs were chemically synthesized and tested for activity compared to the parental compound. These included HDAC4 enzymatic assays, qRT-PCR and western blot analyses of gene and protein expression following treatment, in vitro and in vivo efficacy against multiple prostate cancer models including PDXs, pharmacokinetic analyses,AHR binding and agonist assays, SPR analyses of binding to HDAC4 and NCoR1, RNAseq analysis of in vivo tumors, 3D endothelial sprouting assays, and a targeted kinase screen. Genetic knockout or knockdown controls were used when appropriate. RESULTS: Here, we document that, on this regimen (1 mg/day), TasQ blood levels are 10-fold lower than the optimal concentration (≥2 µM) needed for anticancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that TasQ is an arylhydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 µM to produce unwanted off-target side effects. Therefore, we screened a library of TasQ analogsto maximize on-target versus off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and 5-fold greater potency against prostate cancer patient-derived xenografts. CONCLUSION: This increased therapeuticindex nominates ESATA-20 as a lead candidate forclinical development as an orally active third generation quinoline-3-carboxamide analog thatretains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.

Radiation protection aspects for alpha therapies.

The use of alpha emitting radiotherapeutics is increasing, with further growth expected due to a number of clinical trials currently running involving new alpha emitters. However, literature concerning radiation safety aspects of alpha emitting radionuclides is limited and most of the available literature concerns 223Ra. In general, the occupational exposure from alpha emitting radionuclides is expected to be low, as are doses to the public from external exposure. However, care must be taken to avoid skin contamination, inhalation, and ingestion. Not all alpha emitting radionuclides are identical, they often have very different associated decay chains and emissions. The decay chains and the manufacturing process should be carefully examined to identify any long-lived progeny or impurities. These may have an impact on the radiation safety processes required to limit occupational exposure and for waste management. Doses to the public must also be assessed, either arising directly from exposure to patients treated with radiotherapeutics, or via waste streams. Risk assessments should be in place when starting a new service covering all aspects of the preparation and administration, as well as any foreseeable incidents such as skin contamination or patient death, and the appropriate steps to take in these instances. It is imperative that with the increase in the use of alpha emitting radiotherapeutics more literature is published on radiation safety aspects, especially for new alpha emitting radiotherapeutics which often have very different characteristics than the currently established ones.

Diagnosis and treatment strategies of the multiligament injured knee: a scoping review.

OBJECTIVE: To map the current literature evaluating the diagnosis and treatment of multiligament knee injuries (MLKIs). DESIGN: Scoping review. DATA SOURCES: Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews and Arksey and O'Malley frameworks were followed. A three-step search strategy identified relevant published literature comprising studies reporting on at least one aspect in the diagnosis or treatment of MLKI in adults. Data were synthesised to form a descriptive analysis and thematic summary. RESULTS: Overall, 417 studies were included. There was a substantial chronological increase in the number of studies published per year, with 70% published in the last 12 years. Of included studies, 128 (31%) were narrative reviews, editorials or technical notes with no original data. The majority of studies (n=239, 57%) originated from the USA; only 4 studies (1%) were of level I evidence. Consistent themes of contention included clinical assessment, imaging, operative strategy, timing of surgery and rehabilitation. There was a lack of gender and ethnic diversity reported within patient groups. CONCLUSIONS: There remains insufficient high-level evidence to support definitive management strategies for MLKI. There is considerable heterogeneity in outcome reporting in current MLKI literature, precluding robust comparison, interpretation and pooling of data. Further research priorities include the development of expert consensus relating to the investigation, surgical management and rehabilitation of MLKI. There is a need for minimum reporting standards for clinical studies evaluating MLKI.

The diagnosis of hip microinstability is correlated with ease of intra-operative hip distraction.

PURPOSE: Hip microinstability has emerged as a contributor to young adult, non-arthritic hip pain. There is a paucity of objective clinical data to identify patients with hip microinstability and guide surgical treatment. The purpose of this study was to identify the degree of distractibility in patients with and without microinstability undergoing hip arthroscopy. METHODS: A single-surgeon series of hip arthroscopies were retrospectively reviewed from 2014-2020. All procedures were performed with paralysis on a fracture table with a perineal post where 1 turn of fine traction equates to 4 mm of axial traction. Diagnosis was recorded as isolated instability, instability plus femoroacetabular impingement (FAI), and isolated FAI. Operative reports were reviewed to collect patient demographic data, number of turns of traction required for adequate distraction of the femoral head relative to the acetabulum (10 mm), and the presence of residual subluxation after initial traction was released. RESULTS: A total of 464 patients were identified, 26 (5.6%) with isolated microinstability, 183 (39.4%) with microinstability with FAI anatomy, and 255 (55.0%) with FAI. The concurrent diagnosis of microinstability was associated with decreased turns required to adequately distract the hip. Isolated microinstability patients required 6.9 turns (IQR 4.6-8.8) while those with instability plus FAI required 8.8 turns (IQR 6.5-11) and isolated FAI required 19.1 turns (IQR 15-22). Residual subluxation after removal of negative intra-articular pressure but before performing the hip arthroscopy was more commonly associated with instability, occurring in 84.6% of isolated instability and 86.9% of instability plus FAI as compared with 29.8% in the isolated FAI cohort. CONCLUSION: A diagnosis of hip microinstability, with or without features of FAI, is associated with decreased axial traction required to distract the hip. These data support the use of intra-operative ease of distraction as a method of identifying patients with hip microinstability. LEVEL OF EVIDENCE: Level III.

Design and Evaluation of an Alternative Control for a Quad-Rotor Drone Using Hand-Gesture Recognition.

Gesture recognition is a mechanism by which a system recognizes an expressive and purposeful action made by a user's body. Hand-gesture recognition (HGR) is a staple piece of gesture-recognition literature and has been keenly researched over the past 40 years. Over this time, HGR solutions have varied in medium, method, and application. Modern developments in the areas of machine perception have seen the rise of single-camera, skeletal model, hand-gesture identification algorithms, such as media pipe hands (MPH). This paper evaluates the applicability of these modern HGR algorithms within the context of alternative control. Specifically, this is achieved through the development of an HGR-based alternative-control system capable of controlling of a quad-rotor drone. The technical importance of this paper stems from the results produced during the novel and clinically sound evaluation of MPH, alongside the investigatory framework used to develop the final HGR algorithm. The evaluation of MPH highlighted the Z-axis instability of its modelling system which reduced the landmark accuracy of its output from 86.7% to 41.5%. The selection of an appropriate classifier complimented the computationally lightweight nature of MPH whilst compensating for its instability, achieving a classification accuracy of 96.25% for eight single-hand static gestures. The success of the developed HGR algorithm ensured that the proposed alternative-control system could facilitate intuitive, computationally inexpensive, and repeatable drone control without requiring specialised equipment.

Notchplasty is associated with decreased risk of anterior cruciate ligament graft revision.

PURPOSE: Despite influencing knee biomechanics and outcomes, the use of notchplasty at time of anterior cruciate ligament reconstruction (ACLR) has not been evaluated with regards to risk of secondary injury and revision. This study evaluates this association. METHODS: 42 patients (21.7-years, IQR = 19.0-27.5) that underwent primary then revision ACLR at a single institution were contrasted with a case matched control group of patients with grafts that did not fail. Patients were propensity score matched in a 1:2 ratio by age, gender, and date of index procedure. Post-hoc statistical correction was made for post-index procedure sports participation level. RESULTS: Notchplasty was performed in 2 of 42 cases that went on to revision, and in 31 of 84 cases in the control group (p < 0.001). This was associated with reduced rates of revision ACLR (OR = 0.085, 95%CI = 0.019-0.378). A significant difference was seen in the post-ACLR activity level between groups (p = 0.028), with post-hoc testing highlighting those returning to competitive sport to be more likely to require subsequent revision (OR = 9.647, 95%CI = 1.947-47.795). Notchplasty remained significantly associated with (reduced) risk of revision surgery, despite the observed variation in post-ACLR activity (p = 0.001). CONCLUSION: Individuals whose graft failed following ACLR were significantly less likely to have had notchplasty performed as part of their surgery than a control group who did not suffer graft reinjury. We propose that this may be due to decreased tensioning of the graft as the knee enters dynamic valgus, which may be of great relevance to athletes undergoing ACLR to enable return to sport.

Plasmid replication-associated single-strand-specific methyltransferases.

Analysis of genomic DNA from pathogenic strains of Burkholderia cenocepacia J2315 and Escherichia coli O104:H4 revealed the presence of two unusual MTase genes. Both are plasmid-borne ORFs, carried by pBCA072 for B. cenocepacia J2315 and pESBL for E. coli O104:H4. Pacific Biosciences SMRT sequencing was used to investigate DNA methyltransferases M.BceJIII and M.EcoGIX, using artificial constructs. Mating properties of engineered pESBL derivatives were also investigated. Both MTases yield promiscuous m6A modification of single strands, in the context SAY (where S = C or G and Y = C or T). Strikingly, this methylation is asymmetric in vivo, detected almost exclusively on one DNA strand, and is incomplete: typically, around 40% of susceptible motifs are modified. Genetic and biochemical studies suggest that enzyme action depends on replication mode: DNA Polymerase I (PolI)-dependent ColE1 and p15A origins support asymmetric modification, while the PolI-independent pSC101 origin does not. An MTase-PolI complex may enable discrimination of PolI-dependent and independent plasmid origins. M.EcoGIX helps to establish pESBL in new hosts by blocking the action of restriction enzymes, in an orientation-dependent fashion. Expression and action appear to occur on the entering single strand in the recipient, early in conjugal transfer, until lagging-strand replication creates the double-stranded form.

Hip Microinstability: Understanding a Newly Defined Hip Pathology in Young Athletes.

Microinstability is an increasingly recognized diagnosis in young athletes presenting with hip pain. Causes of microinstability may include abnormality of the hip bony anatomy, acetabular labral tears, joint capsule laxity or injury, and muscle dysfunction. Borderline hip dysplasia is an increasingly recognized factor predisposing to microinstability. The capsuloligamentous structures of the hip, particularly the iliofemoral ligament, provide important restraints to femoral head motion, and iatrogenic defects can predispose patients to instability after surgery. Injury to the acetabular labrum may disrupt its important hip-stabilizing properties including the suction seal and improved acetabular depth. Hip muscle weakness or imbalance may result in increased femoral head motion within the acetabulum. The diagnosis of hip microinstability can be challenging, and the history is often nonspecific. Physical examination maneuvers include the anterior apprehension, prone instability, axial distraction, and abduction-hyperextension-external rotation tests. Radiographic features may include borderline hip dysplasia, femoral head-neck junction cliff sign, and an elevated femoral-epiphyseal acetabular roof index. Magnetic resonance arthrography may demonstrate a capsular defect, capsular thinning, or labral pathology. Diagnostic intra-articular injection of anesthetic can confirm the intra-articular nature of the pathology. Management of hip microinstability focuses on strengthening the dynamic stabilizers of the hip through focused physical therapy. Surgery may be considered in recalcitrant cases where symptoms persist despite optimization of hip stabilizer strength. In such cases, addressing the primary source of instability through labral repair or reconstruction and capsular repair or plication can be considered. In highly selected cases, surgery can result in excellent outcomes.

Criteria for the Operating Room Confirmation of the Diagnosis of Hip Instability: The Results of an International Expert Consensus Conference.

PURPOSE: The purpose of this study was to establish an international expert consensus on operating room findings that aid in the diagnosis of hip instability. METHODS: An expert panel was convened to build an international consensus on the operating room diagnosis/confirmation of hip instability. Seventeen surgeons who have published or lectured nationally or internationally on the topic of hip instability were invited to participate. Fifteen panel members completed a pre-meeting questionnaire and agreed to participate in a 1-day consensus meeting on May 15, 2021. A review of the literature was performed to identify published intraoperative reference criteria used in the diagnosis of hip instability. Studies were included for discussion if they reported and intraoperative findings associated with hip instability. The evidence for and against each criteria was discussed, followed by an anonymous voting process. For consensus, defined a priori, items were included in the final criteria set if at least 80% of experts agreed. RESULTS: A review of the published literature identified 11 operating room criteria that have been used to facilitate the diagnosis of hip instability. Six additional criteria were proposed by panel members as part of the pre-meeting questionnaire. Consensus agreement was achieved for 8 criteria, namely ease of hip distraction under anesthesia (100.0% agreement), inside-out pattern of chondral damage (100.0% agreement), location of chondral damage on the acetabulum (93.3% agreement), pattern of labral damage (93.3% agreement), anteroinferior labrum chondral damage (86.7% agreement), perifoveal cartilage damage (97.6% agreement), a capsular defect (86.7% agreement), and capsular status (80.0% agreement). Consensus was not achieved for 9 items, namely ligamentum teres tear (66.7% agreement), arthroscopic stability tests (46.7% agreement), persistent distraction after removal of traction (46.7% agreement), findings of examination under anesthesia (46.7% agreement), the femoral head divot sign (40.0% agreement), inferomedial synovitis (26.7% agreement), drive-through sign (26.7% agreement), iliopsoas irritation (26.7% agreement) and ligamentum teres-labral kissing lesion (13.3% agreement). All experts agreed on the final list of 8 criteria items reaching consensus. CONCLUSION: This expert panel identified 8 criteria that can be used in the operating room to help confirm the diagnosis of hip instability. LEVEL OF EVIDENCE: Level V expert opinion.

Female gender, decreased lateral center edge angle and a positive hyperextension-external rotation test are associated with ease of hip distractability at time of hip arthroscopy.

PURPOSE: To identify factors associated with ease of hip distraction at the time of hip arthroscopy. METHODS: A retrospective review of patients 17-50 years old undergoing hip arthroscopy with a single high-volume hip arthroscopist was performed from 2014 to 2020. Demographics, clinical history, examination, and imaging findings were collected. Distractibility was quantified using turns of fine traction (1 turn = 4 mm axial distraction) with the patient paralyzed on a fracture table with a well-padded perineal post Fine axial traction was applied after the patient's perineum contacted the post. Demographic and clinical predictors of ease of distractibility were analyzed with simple linear regression models. Significant predictors were subsequently added to a multivariable linear regression model, estimating the effect of each variable. RESULTS: In total, 453 patients were included, with an average age of 31.6 years (± 9.2) and 45.9% females. In univariate analysis, gender, race, BMI, range of motion, hyperextension-external rotation (HEER) test, the abduction-extension-external rotation test, and lateral center edge angle (LCEA) were associated with the number of fine traction turns required to distract the hip. On multivariable analysis, lower LCEA (p = 0.002), female gender (p < 0.001), and a positive HEER test (p = 0.045) were associated with decreased turns required for adequate hip distraction. CONCLUSION: Female gender, decreased LCEA, and a positive HEER test are associated with decreased axial traction required for adequate hip distraction at the time of hip arthroscopy. As ease of distractibility has been associated with hip microinstability, these findings may allow pre-operative identification of hip instability patients and aid in pre-operative counseling, risk stratification and capsular management planning. LEVEL OF EVIDENCE: IV. CLINICAL RELEVANCE: Preoperative identification of risk factors for ease of hip distraction may raise pre-surgical suspicion and, when coupled with other intraoperative findings, may aid in the diagnosis and management of hip microinstability.

Human Gait Modeling, Prediction and Classification for Level Walking Using Harmonic Models Derived from a Single Thigh-Mounted IMU.

The majority of human gait modeling is based on hip, foot or thigh acceleration. The regeneration accuracy of these modeling approaches is not very high. This paper presents a harmonic approach to modeling human gait during level walking based on gyroscopic signals for a single thigh-mounted Inertial Measurement Unit (IMU) and the flexion-extension derived from a single thigh-mounted IMU. The thigh angle can be modeled with five significant harmonics, with a regeneration accuracy of over 0.999 correlation and less than 0.5° RMSE per stride cycle. Comparable regeneration accuracies can be achieved with nine significant harmonics for the gyro signal. The fundamental frequency of the harmonic model can be estimated using the stride time, with an error level of 0.0479% (±0.0029%). Six commonly observed stride patterns, and harmonic models of thigh angle and gyro signal for those stride patterns, are presented in this paper. These harmonic models can be used to predict or classify the strides of walking trials, and the results are presented herein. Harmonic models may also be used for activity recognition. It has shown that human gait in level walking can be modeled with a harmonic model of thigh angle or gyro signal, using a single thigh-mounted IMU, to higher accuracies than existing techniques.

Posture Monitoring and Correction Exercises for Workers in Hostile Environments Utilizing Non-Invasive Sensors: Algorithm Development and Validation.

Personal protective equipment (PPE) is an essential key factor in standardizing safety within the workplace. Harsh working environments with long working hours can cause stress on the human body that may lead to musculoskeletal disorder (MSD). MSD refers to injuries that impact the muscles, nerves, joints, and many other human body areas. Most work-related MSD results from hazardous manual tasks involving repetitive, sustained force, or repetitive movements in awkward postures. This paper presents collaborative research from the School of Electrical Engineering and School of Allied Health at Curtin University. The main objective was to develop a framework for posture correction exercises for workers in hostile environments, utilizing inertial measurement units (IMU). The developed system uses IMUs to record the head, back, and pelvis movements of a healthy participant without MSD and determine the range of motion of each joint. A simulation was developed to analyze the participant's posture to determine whether the posture present would pose an increased risk of MSD with limits to a range of movement set based on the literature. When compared to measurements made by a goniometer, the body movement recorded 94% accuracy and the wrist movement recorded 96% accuracy.

ABC score: a new risk score that accurately predicts mortality in acute upper and lower gastrointestinal bleeding: an international multicentre study.

OBJECTIVES: Existing scores are not accurate at predicting mortality in upper (UGIB) and lower (LGIB) gastrointestinal bleeding. We aimed to develop and validate a new pre-endoscopy score for predicting mortality in both UGIB and LGIB. DESIGN AND SETTING: International cohort study. Patients presenting to hospital with UGIB at six international centres were used to develop a risk score for predicting mortality using regression analyses. The score's performance in UGIB and LGIB was externally validated and compared with existing scores using four international datasets. We calculated areas under receiver operating characteristics curves (AUROCs), sensitivities, specificities and outcome among patients classified as low risk and high risk. PARTICIPANTS AND RESULTS: We included 3012 UGIB patients in the development cohort, and 4019 UGIB and 2336 LGIB patients in the validation cohorts. Age, Blood tests and Comorbidities (ABC) score was closer associated with mortality in UGIB and LGIB (AUROCs: 0.81-84) than existing scores (AUROCs: 0.65-0.75; p≤0.02). In UGIB, patients with low ABC score (≤3), medium ABC score (4-7) and high ABC score (≥8) had 30-day mortality rates of 1.0%, 7.0% and 25%, respectively. Patients classified low risk using ABC score had lower mortality than those classified low risk with AIMS65 (threshold ≤1) (1.0 vs 4.5%; p<0.001). In LGIB, patients with low, medium and high ABC scores had in-hospital mortality rates of 0.6%, 6.3% and 18%, respectively. CONCLUSIONS: In contrast to previous scores, ABC score has good performance for predicting mortality in both UGIB and LGIB, allowing early identification and targeted management of patients at high or low risk of death.

HeadUp: A Low-Cost Solution for Tracking Head Movement of Children with Cerebral Palsy Using IMU.

Cerebral palsy (CP) is a common reason for human motor ability limitations caused before birth, through infancy or early childhood. Poor head control is one of the most important problems in children with level IV CP and level V CP, which can affect many aspects of children's lives. The current visual assessment method for measuring head control ability and cervical range of motion (CROM) lacks accuracy and reliability. In this paper, a HeadUp system that is based on a low-cost, 9-axis, inertial measurement unit (IMU) is proposed to capture and evaluate the head control ability for children with CP. The proposed system wirelessly measures CROM in frontal, sagittal, and transverse planes during ordinary life activities. The system is designed to provide real-time, bidirectional communication with an Euler-based, sensor fusion algorithm (SFA) to estimate the head orientation and its control ability tracking. The experimental results for the proposed SFA show high accuracy in noise reduction with faster system response. The system is clinically tested on five typically developing children and five children with CP (age range: 2-5 years). The proposed HeadUp system can be implemented as a head control trainer in an entertaining way to motivate the child with CP to keep their head up.

Adjustment of the iodine ICRP population pharmacokinetic model for the use in thyroid cancer patients after thyroidectomy.

Biokinetic models developed for healthy humans are not appropriate to describe biokinetics in thyroid cancer patients following thyroidectomy. The aim of this study was to adjust the population model for iodine proposed by the International Commission on Radiological Protection (ICRP) for the use in these patients. Rate constants of the ICRP publication 128 model for iodine were adjusted using the population modelling software package Monolix to describe activity retention in whole-body, thyroid, blood and protein-bound iodine observed in 23 patients. The new set of rate constants was compared to the four uptake scenarios proposed in ICRP publication 128. Flow from the inorganic iodide in blood compartment into the first thyroid compartment decreases to 0.15 d-1compared to a value of 7.27 d-1for the ICRP publication 128 model with a medium uptake. The transfer from first to second thyroid compartments and the outflow from the second thyroid compartment increases. An increased turnover rate of extrathyroidal organic iodine is observed. The rate constant from inorganic iodide in blood to kidney was also adjusted. Overall a good agreement was found between the adjusted model and the activity retention in thyroid cancer patients. The adjustment of population pharmacokinetic models to describe the biokinetic properties of specific patient populations for therapeutic radiopharmaceuticals is essential to capture the changes in biokinetics. The proposed set of rate constants for the established ICRP publication 128 model can be used to more accurately assess radiation protection requirements for the treatment of thyroid cancer patients using radioiodine.

Selective Ah receptor modulators attenuate NPC1L1-mediated cholesterol uptake through repression of SREBP-2 transcriptional activity.

The ability of the aryl hydrocarbon receptor (AHR) to alter hepatic expression of cholesterol synthesis genes in a DRE-independent manner in mice and humans has been reported. We have examined the influence of functionally distinct classes of AHR ligands on the levels of Niemann-Pick C1-like intracellular cholesterol transporter (NPC1L1) and enzymes involved in the cholesterol synthesis pathway. NPC1L1 is known to mediate the intestinal absorption of dietary cholesterol and is clinically targeted. AHR ligands were capable of attenuating cholesterol uptake through repression of NPC1L1 expression. Through mutagenesis experiments targeting the two DRE sequences present in the promoter region of the NPC1L1 gene, we provide evidence that the repression does not require functional DRE sequences; while knockdown experiments demonstrated that this regulation is dependent on AHR and sterol-regulatory element-binding protein-2 (SREBP-2). Furthermore, upon ligand activation of AHR, the human intestinal Caco-2 cell line revealed coordinate repression of both mRNA and protein levels for a number of the cholesterol biosynthetic enzymes. Transcription of NPC1L1 and genes of the cholesterol synthesis pathway is predominantly regulated by SREBP-2, especially after treatment with a statin. Immunoblot analyses revealed a significant decrease in transcriptionally active SREBP-2 levels upon ligand treatment, whereas the precursor form of SREBP-2 was modestly increased by AHR activation. Mechanistic insights indicate that AHR induces proteolytic degradation of mature SREBP-2 in a calcium-dependent manner, which correlates with the AHR ligand-mediated upregulation of the transient receptor potential cation channel subfamily V member 6 (TRPV6) gene encoding for a membrane calcium channel. These observations emphasize a role for AHR in the systemic homeostatic regulation of cholesterol synthesis and absorption, indicating the potential use of this receptor as a target for the treatment of hyperlipidosis-associated metabolic diseases.