Extended Wireless pH Monitoring Significantly Increases Gastroesophageal Reflux Disease Diagnoses in Patients With a Normal pH Impedance Study

Background/Aims@#Extended wireless pH monitoring (WPM) is used to investigate gastroesophageal reflux disease (GERD) as subsequent or alternative investigation to 24-hour catheter-based studies. However, false negative catheter studies may occur in patients with intermittent reflux or due to catheter-induced discomfort or altered behavior. We aim to investigate the diagnostic yield of WPM after a negative 24-hour multichannel intraluminal impedance pH (MII-pH) monitoring study and to determine predictors of GERD on WPM given a negative MII-pH. @*Methods@#Consecutive adult patients (> 18 years) who underwent WPM for further investigation of suspected GERD following a negative 24-hour MII-pH and upper endoscopy between January 2010 and December 2019 were retrospectively included. Clinical data, endoscopy, MII-pH, and WPM results were retrieved. Fisher’s exact test, Wilcoxon rank sum test, or Student’s t test were used to compare data.Logistic regression analysis was used to investigate predictors of positive WMP. @*Results@#One hundred and eighty-one consecutive patients underwent WPM following a negative MII-pH study. On average and worst day analysis, 33.7% (61/181) and 34.2% (62/181) of the patients negative for GERD on MII-pH were given a diagnosis of GERD following WPM, respectively. On a stepwise multiple logistic regression analysis, the basal respiratory minimum pressure of the lower esophageal sphincter was a significant predictor of GERD with OR = 0.95 (0.90-1.00, P = 0.041). @*Conclusions@#WPM increases GERD diagnostic yield in patients with a negative MII-pH selected for further testing based on clinical suspicion. Further studies are needed to assess the role of WPM as a first line investigation in patients with GERD symptoms.

Trismus therapy devices: A systematic review.

BACKGROUND: There is a wide range of commercial and custom-made devices available for the treatment of trismus (restricted jaw opening). They are used often in conjunction with a prescribed exercise program with the aim of improving maximal inter-incisal opening (MIO). This study compared the efficacy (MIO and patient reported outcome results), adverse events, consumer experience and cost of the different types of devices available. METHODS: Four databases were searched between the years 2001-2021 using the terms 'trismus' and 'device'. Two independent authors assessed each paper for inclusion, then conducted a quality analysis. RESULTS: Thirty-two studies met the criterion required for inclusion. The majority (n = 27) were in the context of established trismus, where the remaining five used the device preventatively. The trismus device improved MIO in 23 of the rehabilitation programs (pooled mean MIO increased by 9.5 mm in the intervention arm compared to 2.4 mm for controls; p = 0.0001). Improved MIO was not observed in the prevention studies. The Therabite ® was the most common trismus device investigated and with a mean increase in MIO of 10.0 mm and cost of $499AUD. Forces applied by trismus devices were regulated by the perception of pain experienced by the patient, rather than a prescribed force by the treating health professional. Despite this guidance, several adverse events occurred (n = 8), including mandibular and molar fractures. Barriers experienced by consumers included pain, ill-fitting mouthpiece, adverse events, exercise adherence and cost. CONCLUSION: Trismus devices which use the application of force to the jaw can improve the MIO of patients with established trismus. However, their role is unproven in the setting of trismus prevention during radiotherapy and several significant barriers such as cost, exercise adherence and safety concerns have been demonstrated for the intervention setting.

A pilot study of peripheral blood DNA methylation models as predictors of knee osteoarthritis radiographic progression: data from the Osteoarthritis Initiative (OAI).

Knee osteoarthritis (OA) is a leading cause of chronic disability worldwide, but no diagnostic or prognostic biomarkers are available. Increasing evidence supports epigenetic dysregulation as a contributor to OA pathogenesis. In this pilot study, we investigated epigenetic patterns in peripheral blood mononuclear cells (PBMCs) as models to predict future radiographic progression in OA patients enrolled in the longitudinal Osteoarthritis Initiative (OAI) study. PBMC DNA was analyzed from baseline OAI visits in 58 future radiographic progressors (joint space narrowing at 24 months, sustained at 48 months) compared to 58 non-progressors. DNA methylation was quantified via Illumina microarrays and beta- and M-values were used to generate linear classification models. Data were randomly split into a 60% development and 40% validation subsets, models developed and tested, and cross-validated in a total of 40 cycles. M-value based models outperformed beta-value based models (ROC-AUC 0.81 ± 0.01 vs. 0.73 ± 0.02, mean ± SEM, comparison p = 0.002), with a mean classification accuracy of 73 ± 1% (mean ± SEM) for M- and 69 ± 1% for beta-based models. Adjusting for covariates did not significantly alter model performance. Our findings suggest that PBMC DNA methylation-based models may be useful as biomarkers of OA progression and warrant additional evaluation in larger patient cohorts.

High affinity soluble ILT2 receptor: a potent inhibitor of CD8(+) T cell activation

Using directed mutagenesis and phage display on a soluble fragment of the human immunoglobulin super-family receptor ILT2 (synonyms: LIR1, MIR7, CD85j), we have selected a range of mutants with binding affinities enhanced by up to 168,000-fold towards the conserved region of major histocompatibility complex (MHC) class I molecules. Produced in a dimeric form, either by chemical cross-linking with bivalent polyethylene glycol (PEG) derivatives or as a genetic fusion with human IgG Fc-fragment, the mutants exhibited a further increase in ligand-binding strength due to the avidity effect, with resident half-times (t(1/2)) on the surface of MHC I-positive cells of many hours. The novel compounds antagonized the interaction of CD8 co-receptor with MHC I in vitro without affecting the peptide-specific binding of T-cell receptors (TCRs). In both cytokine-release assays and cell-killing experiments the engineered receptors inhibited the activation of CD8(+) cytotoxic T lymphocytes (CTLs) in the presence of their target cells, with subnanomolar potency and in a dose-dependent manner. As a selective inhibitor of CD8(+) CTL responses, the engineered high affinity ILT2 receptor presents a new tool for studying the activation mechanism of different subsets of CTLs and could have potential for the development of novel autoimmunity therapies.