Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity.

AIMS/HYPOTHESIS: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly connected 'hub' cells, important for the propagation of intercellular Ca2+ waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes. At present, the molecular mechanisms through which beta cell hierarchy is established are poorly understood. Changes at the level of the epigenome provide one such possibility, which we explore here by focusing on the imprinted gene Nnat (encoding neuronatin [NNAT]), which is required for normal insulin synthesis and secretion. METHODS: Single-cell RNA-seq datasets were examined using Seurat 4.0 and ClusterProfiler running under R. Transgenic mice expressing enhanced GFP under the control of the Nnat enhancer/promoter regions were generated for FACS of beta cells and downstream analysis of CpG methylation by bisulphite sequencing and RNA-seq, respectively. Animals deleted for the de novo methyltransferase DNA methyltransferase 3 alpha (DNMT3A) from the pancreatic progenitor stage were used to explore control of promoter methylation. Proteomics was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal imaging of Cal-520 AM and Cal-590 AM. Insulin secretion was measured using homogeneous time-resolved fluorescence imaging. RESULTS: Nnat mRNA was differentially expressed in a discrete beta cell population in a developmental stage- and DNA methylation (DNMT3A)-dependent manner. Thus, pseudo-time analysis of embryonic datasets demonstrated the early establishment of Nnat-positive and -negative subpopulations during embryogenesis. NNAT expression is also restricted to a subset of beta cells across the human islet that is maintained throughout adult life. NNAT+ beta cells also displayed a discrete transcriptome at adult stages, representing a subpopulation specialised for insulin production, and were diminished in db/db mice. 'Hub' cells were less abundant in the NNAT+ population, consistent with epigenetic control of this functional specialisation. CONCLUSIONS/INTERPRETATION: These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development. We therefore hypothesise that changes in methylation at this locus may contribute to a loss of beta cell hierarchy and connectivity, potentially contributing to defective insulin secretion in some forms of diabetes. DATA AVAILABILITY: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD048465.

Incidental Coronary Artery Calcium: Opportunistic Screening of Previous Nongated Chest Computed Tomography Scans to Improve Statin Rates (NOTIFY-1 Project).

BACKGROUND: Coronary artery calcium (CAC) can be identified on nongated chest computed tomography (CT) scans, but this finding is not consistently incorporated into care. A deep learning algorithm enables opportunistic CAC screening of nongated chest CT scans. Our objective was to evaluate the effect of notifying clinicians and patients of incidental CAC on statin initiation. METHODS: NOTIFY-1 (Incidental Coronary Calcification Quality Improvement Project) was a randomized quality improvement project in the Stanford Health Care System. Patients without known atherosclerotic cardiovascular disease or a previous statin prescription were screened for CAC on a previous nongated chest CT scan from 2014 to 2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental CAC were randomly assigned to notification of the primary care clinician and patient versus usual care. Notification included a patient-specific image of CAC and guideline recommendations regarding statin use. The primary outcome was statin prescription within 6 months. RESULTS: Among 2113 patients who met initial clinical inclusion criteria, CAC was identified by the algorithm in 424 patients. After chart review and additional exclusions were made, a radiologist confirmed CAC among 173 of 194 patients (89.2%) who were randomly assigned to notification or usual care. At 6 months, the statin prescription rate was 51.2% (44/86) in the notification arm versus 6.9% (6/87) with usual care (P<0.001). There was also more coronary artery disease testing in the notification arm (15.1% [13/86] versus 2.3% [2/87]; P=0.008). CONCLUSIONS: Opportunistic CAC screening of previous nongated chest CT scans followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is needed to determine whether this approach can reduce atherosclerotic cardiovascular disease events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04789278.

3D-Printed Microelectrodes for Biological Measurement.

Microelectrodes are useful electrochemical sensors that can provide spatial biological monitoring. Carbon fiber has been by far the most widely used microelectrode; however, a vast number of different materials and modification strategies have been developed to broaden the scope of microelectrodes. Carbon composite electrodes provide a simple approach to making microelectrodes with a wide range of materials, but manufacturing strategies are complex. 3D printing can provide the ability to make microelectrodes with high precision. We used fused filament fabrication to print single strands of carbon black/polylactic acid (CB/PLA) and multiwall carbon nanotube/polylactic acid (MWCNT/PLA), which were then made into microelectrodes. Microelectrodes ranged from 70 µm in diameter to 400 µm in diameter and were assessed using standard redox probes. MWCNT/PLA electrodes exhibited greater sensitivity, a lower limit of detection, and stability for the measurement of serotonin (5-HT). Both CB/PLA and MWCNT/PLA microelectrodes were able to monitor 5-HT overflow from the ex vivo ileum tissue. MWCNT/PLA microelectrodes were utilized to show differences in 5-HT overflow from ex vivo ileum and colon following exposure to odorants present in spices. These findings highlight that any conductive thermoplastic material can be fabricated into a microelectrode. This simple strategy can utilize a wide range of materials to make 3D-printed microelectrodes for a diverse range of applications.

Evaluating diverse electrode surface patterns of 3D printed carbon thermoplastic electrochemical sensors.

Electrochemical sensing techniques rely on redox reactions taking place at the electrode surface. The configuration of this surface is of the utmost importance in the advancement of electrochemical sensors. The majority of previous electrode manufacturing methods, including 3D printing have produced electrodes with flat surfaces. There is a distinct potential for 3D printing to create intricate and distinctive electrode surface shapes. In the proposed work, 3D printed carbon black polylactic acid electrodes with nine different surface morphologies were made. These were compared to a flat surface electrode. To evaluate the performance of the electrodes, measurements were conducted in three different redox probes (ferrocene methanol, ferricyanide, and dopamine). Our findings highlighted that when electrodes were normalised for the geometric surface area of the electrode, the surface pattern of the electrode surface can impact the observed current and electron transfer kinetics. Electrodes that had a dome and flag pattern on the electrode surface showed the highest oxidation currents and had lower values for the difference between the anodic and cathodic peak current (ΔE). However, designs with rings had lower current values and higher ΔE values. These differences are most likely due to variations in the accessibility of conductive sites on the electrode surface due to the varying surface roughness of different patterned designs. Our findings highlight that when making electrodes using 3D printing, surface patterning of the electrode surface can be used as an effective approach to enhance the performance of the sensor for varying applications.

Efficient adversarial debiasing with concept activation vector - Medical image case-studies.

BACKGROUND: A major hurdle for the real time deployment of the AI models is ensuring trustworthiness of these models for the unseen population. More often than not, these complex models are black boxes in which promising results are generated. However, when scrutinized, these models begin to reveal implicit biases during the decision making, particularly for the minority subgroups. METHOD: We develop an efficient adversarial de-biasing approach with partial learning by incorporating the existing concept activation vectors (CAV) methodology, to reduce racial disparities while preserving the performance of the targeted task. CAV is originally a model interpretability technique which we adopted to identify convolution layers responsible for learning race and only fine-tune up to that layer instead of fine-tuning the complete network, limiting the drop in performance RESULTS:: The methodology has been evaluated on two independent medical image case-studies - chest X-ray and mammograms, and we also performed external validation on a different racial population. On the external datasets for the chest X-ray use-case, debiased models (averaged AUC 0.87 ) outperformed the baseline convolution models (averaged AUC 0.57 ) as well as the models trained with the popular fine-tuning strategy (averaged AUC 0.81). Moreover, the mammogram models is debiased using a single dataset (white, black and Asian) and improved the performance on an external datasets (averaged AUC 0.8 to 0.86 ) with completely different population (primarily Hispanic patients). CONCLUSION: In this study, we demonstrated that the adversarial models trained only with internal data performed equally or often outperformed the standard fine-tuning strategy with data from an external setting. The adversarial training approach described can be applied regardless of predictor's model architecture, as long as the convolution model is trained using a gradient-based method. We release the training code with academic open-source license - https://github.com/ramon349/JBI2023_TCAV_debiasing.

Impact of tertiary lymphoid structures on prognosis and therapeutic response in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is known to have a heterogeneous desmoplastic tumour microenvironment (TME) with a large number of immunosuppressive cells. Recently, high B-cell infiltration in PDAC has received growing interest as a potential therapeutic target. METHODS: Our literature review summarises the characteristics of tumour-associated tertiary lymphoid structures (TLSs) and highlight the key studies exploring the clinical outcomes of TLSs in PDAC patients and the direct effect on the TME. RESULTS: The location, density and maturity stages of TLSs within tumours play a key role in determining the prognosis and is a new emerging target in cancer immunotherapy. DISCUSSION: TLS development is imperative to improve the prognosis of PDAC patients. In the future, studying the genetics and immune characteristics of tumour infiltrating B cells and TLSs may lead towards enhancing adaptive immunity in PDAC and designing personalised therapies.

Subsets of Nanometer Vesicles in the Fly Release Differential Fractions of Vesicular Serotonin Content during Exocytosis.

Serotonin, a monoamine neurotransmitter, is important in both the central nervous system (CNS) and the peripheral nervous system. Malfunction of serotonin signaling leads to various disorders. We studied serotonin signaling from serotonergic neurons inside the ventral nerve cord of Drosophila melanogaster. Serotonergic neurons and stimulated release were visualized and achieved with mCherry and channelrhodopsin-2 (an optogenetically transfected ion channel), respectively, and two electrochemical techniques quantified serotonin release and vesicular content. Mean vesicular serotonin content released during exocytosis from these neurons was 84 %, considerably higher than reported in previous studies regarding octopamine (4.5 %) and glutamate release (31 %). Serotonin content within all vesicles is uniformly changed when serotonin concentration is inhibited or enhanced. However, serotonin release exhibits two Gaussian distributions: higher frequency of small release events, and similar or slightly higher frequency of large events, resulting in differential release fractions ranging from partial (13-18 %) to full (100 %) release after treatment with agents to either enhance or diminish release. This is the first example of consistent full exocytotic release events we have observed in any system. We suggest one pool of vesicles can release significantly diverse fractions of transmitter load during exocytosis, a potentially novel pathway to regulate exocytosis and neuronal signaling.

Quantitative Pathologic Analysis of Digitized Images of Colorectal Carcinoma Improves Prediction of Recurrence-Free Survival.

BACKGROUND & AIMS: To examine whether quantitative pathologic analysis of digitized hematoxylin and eosin slides of colorectal carcinoma (CRC) correlates with clinicopathologic features, molecular alterations, and prognosis. METHODS: A quantitative segmentation algorithm (QuantCRC) was applied to 6468 digitized hematoxylin and eosin slides of CRCs. Fifteen parameters were recorded from each image and tested for associations with clinicopathologic features and molecular alterations. A prognostic model was developed to predict recurrence-free survival using data from the internal cohort (n = 1928) and validated on an internal test (n = 483) and external cohort (n = 938). RESULTS: There were significant differences in QuantCRC according to stage, histologic subtype, grade, venous/lymphatic/perineural invasion, tumor budding, CD8 immunohistochemistry, mismatch repair status, KRAS mutation, BRAF mutation, and CpG methylation. A prognostic model incorporating stage, mismatch repair, and QuantCRC resulted in a Harrell's concordance (c)-index of 0.714 (95% confidence interval [CI], 0.702-0.724) in the internal test and 0.744 (95% CI, 0.741-0.754) in the external cohort. Removing QuantCRC from the model reduced the c-index to 0.679 (95% CI, 0.673-0.694) in the external cohort. Prognostic risk groups were identified, which provided a hazard ratio of 2.24 (95% CI, 1.33-3.87, P = .004) for low vs high-risk stage III CRCs and 2.36 (95% CI, 1.07-5.20, P = .03) for low vs high-risk stage II CRCs, in the external cohort after adjusting for established risk factors. The predicted median 36-month recurrence rate for high-risk stage III CRCs was 32.7% vs 13.4% for low-risk stage III and 15.8% for high-risk stage II vs 5.4% for low-risk stage II CRCs. CONCLUSIONS: QuantCRC provides a powerful adjunct to routine pathologic reporting of CRC. A prognostic model using QuantCRC improves prediction of recurrence-free survival.

Monitoring Gut Epithelium Serotonin and Melatonin Overflow Provides Spatial Mapping of Inflammation.

Electrochemical arrays were used to measure the overflow of serotonin (5-HT) and melatonin (MEL) from the entire colon of healthy mice and mice with chemical-induced inflammatory bowel disease (IBD), to understand the interplay between inflammation and colonic function. We show that 5-HT overflow is increased, whilst MEL levels are reduced, in inflamed tissues. The levels of MEL are increased at the interface between healthy and inflamed regions within the colon and may limit the spread of inflammation. Understanding the interplay between inflammation and mucosal epithelial signalling can provide key insight into colonic function and aid the development of effective therapeutic strategies to treat gastrointestinal diseases.

Infection responsive coatings to reduce biofilm formation and encrustation of urinary catheters.

AIMS: The care of patients undergoing long-term urethral catheterization is frequently complicated by Proteus mirabilis infection. This organism forms dense, crystalline biofilms, which block catheters leading to serious clinical conditions. However, there are currently no truly effective approaches to control this problem. Here, we describe the development of a novel theranostic catheter coating, to simultaneously provide early warning of blockage, and actively delay crystalline biofilm formation. METHODS AND RESULTS: The coating comprises of a pH sensitive upper polymer layer (poly(methyl methacrylate-co-methacrylic acid); Eudragit S 100®) and a hydrogel base layer of poly(vinyl alcohol), which is loaded with therapeutic agents (acetohydroxamic acid or ciprofloxacin hydrochloride) and a fluorescent dye, 5(6)-carboxyfluorescein (CF). The elevation of urinary pH due to P. mirabilis urease activity results in the dissolution of the upper layer and release of cargo agents contained in the base layer. Experiments using in vitro models, which were representative of P. mirabilis catheter-associated urinary tract infections, demonstrated that these coatings significantly delay time taken for catheters to block. Coatings containing both CF dye and ciprofloxacin HCl were able to provide an average of ca. 79 h advanced warning of blockage and extend catheter lifespan ca. 3.40-fold. CONCLUSIONS: This study has demonstrated the potential for theranostic, infection-responsive coatings to form a promising approach to combat catheter encrustation and actively delay blockage.

Do You Really Need a Hand Surgeon? Distal Radius Fractures.

Distal radius fractures are one of the most common injuries treated by orthopaedic surgeons. As the number of distal radius fractures grows and practice patterns demonstrate more of these fractures are treated surgically, it is incumbent for orthopaedic surgeons to understand the fundamentals of evaluation, treatment, and rehabilitation.

Nerve Compression Syndromes of the Upper Extremity.

Nerve compression syndromes of the upper extremity are among the most common pathologies encountered in orthopaedic surgery. Symptoms can be debilitating for patients-affecting their work, activity level, sleep patterns, and overall quality of life. The community orthopaedic specialist should be familiar with the anatomy, etiology, and presentation of upper extremity nerve entrapment. Furthermore, knowledge of current evidence surrounding the management of these common syndromes can prove valuable for treating clinicians. Treatment ranges from nonsurgical (including medication and splinting) to surgical (when symptoms are severe). Although the gold standard treatment for nerve compression syndromes of the upper extremity is typically surgical release, nonsurgical methods should also be reviewed and understood because these can play an important role for patients as well. Community orthopaedic specialists should be well aware of the risks and complications associated with surgical releases.

Incidence of wound dehiscence in patients undergoing laparoscopy or laparotomy: a systematic review and meta-analysis.

Surgical wound dehiscence (SWD) is a serious complication-with a 40% estimated mortality rate-that occurs after surgical intervention. Since the implementation of advanced recovery protocols, the current global incidence of SWD is unknown. This systematic review and meta-analysis estimated the worldwide incidence of SWD and explored its associated factors in general surgical patients. Eligible full-text cross-sectional, cohort and observational studies in English, between 1 January 2010 to 23 April 2021, were retrieved from MEDLINE, CINAHL, EMBASE and the Cochrane Library. Data extraction and quality appraisal were undertaken independently by three reviewers. Random effects meta-analytic models were used in the presence of substantial inconsistency. Subgroup, meta-regression and sensitivity analyses were used to explore inconsistency. Publication bias was assessed using Hunter's plots and Egger's regression test. Of 2862 publications retrieved, 27 studies were included in the final analyses. Pooled data from 741,118 patients across 24 studies were meta-analysed. The 30-day cumulative incidence of SWD was 1% (95% Confidence Interval (CI): 1-1%). SWD incidence was highest in hepatobiliary surgery, at 3% (95% CI: 0-8%). Multivariable meta-regression showed SWD was significantly associated with duration of operation and reoperation (F=7.93 (2-10); p=0.009), explaining 58.2% of the variance. Most studies were retrospective, predated the agreed global definition for SWD and measured as a secondary outcome; thus, our results likely underestimate the scope of the problem. Wider uptake of the global definition will inform the SWD surveillance and improve the accuracy of reporting.

Natural Language Processing Model for Identifying Critical Findings-A Multi-Institutional Study.

Improving detection and follow-up of recommendations made in radiology reports is a critical unmet need. The long and unstructured nature of radiology reports limits the ability of clinicians to assimilate the full report and identify all the pertinent information for prioritizing the critical cases. We developed an automated NLP pipeline using a transformer-based ClinicalBERT++ model which was fine-tuned on 3 M radiology reports and compared against the traditional BERT model. We validated the models on both internal hold-out ED cases from EUH as well as external cases from Mayo Clinic. We also evaluated the model by combining different sections of the radiology reports. On the internal test set of 3819 reports, the ClinicalBERT++ model achieved 0.96 f1-score while the BERT also achieved the same performance using the reason for exam and impression sections. However, ClinicalBERT++ outperformed BERT on the external test dataset of 2039 reports and achieved the highest performance for classifying critical finding reports (0.81 precision and 0.54 recall). The ClinicalBERT++ model has been successfully applied to large-scale radiology reports from 5 different sites. Automated NLP system that can analyze free-text radiology reports, along with the reason for the exam, to identify critical radiology findings and recommendations could enable automated alert notifications to clinicians about the need for clinical follow-up. The clinical significance of our proposed model is that it could be used as an additional layer of safeguard to clinical practice and reduce the chance of important findings reported in a radiology report is not overlooked by clinicians as well as provide a way to retrospectively track large hospital databases for evaluating the documentation of the critical findings.

3D-printed electrochemical pestle and mortar for identification of falsified pharmaceutical tablets.

Falsified medicines and healthcare supplements provide a major risk to public health and thus early identification is critical. Although a host of analytical approaches have been used to date, they are limited, as they require extensive sample preparation, are semi-quantitative and/or are inaccessible to low- and middle-income countries. Therefore, for the first time, we report a simple total analysis system which can rapidly and accurately detect falsified medicines and healthcare supplements. We fabricated a poly-lactic acid (PLA) pestle and mortar and using a commercial 3D printer, then made carbon black/PLA (CB/PLA) electrodes in the base of the mortar using a 3D printing pen to make an electrochemical cell. The pestle and mortar were able to crush and grind the tablets into a fine powder to the same consistency as a standard laboratory pestle and mortar. Using melatonin tablets to characterise the device, the 3D-printed pestle and mortar was able to detect the concentration of melatonin in the presence of insoluble excipients. The calibration plot showed a linear response from 37.5 to 300 µg/mL, where the limit of detection was 7 µg/mL. Electrochemical treatment was able to regenerate the CB/PLA working electrode allowing for repeated use of the device. In a blinded study, the device was able to accurately determine falsified melatonin tablets with recovery percentages between 101% and 105%. This was comparable to HPLC measurements. Overall, these findings highlight that our 3D-printed electrochemical pestle and mortar is an accessible and effective total analysis system that can have the ability to identify falsified medicines and healthcare supplements in remote locations.

Decreased 14-3-3 expression correlates with age-related regional reductions in CNS dopamine and motor function in the pond snail, Lymnaea.

Ageing is associated in many organisms with a reduction in motor movements. We have previously shown that the rate of feeding movements of the pond snail, Lymnaea, decreased with age but the underlying cause is not fully understood. Here, we show that dopamine in the cerebro-buccal complex is an important signalling molecule regulating feeding frequency in Lymnaea and that ageing is associated with a decrease in CNS dopamine. A proteomic screen of young and old CNSs highlighted a group of proteins that regulate stress responses. One of the proteins identified was 14-3-3, which can enhance the synthesis of dopamine. We show that the Lymnaea 14-3-3 family exists as three distinct isoforms. The expression of the 29 kDa isoform (14-3-3Lym3) in the cerebro-buccal complex decreased with age and correlated with feeding rate. Using a 14-3-3 antagonist (R18) we were able to reduce the synthesis of L-DOPA and dopamine in ex vivo cerebro-buccal complexes. Together these data suggest that an age-related reduction in 14-3-3 can decrease CNS dopamine leading to a consequential reduction in feeding rate.

Diagnostic performance of single-phase dual-energy CT to differentiate vascular and nonvascular incidental renal lesions on portal venous phase: comparison with CT.

OBJECTIVES: To determine whether single-phase dual-energy CT (DECT) differentiates vascular and nonvascular renal lesions in the portal venous phase (PVP). Optimal iodine threshold was determined and compared to Hounsfield unit (HU) measurements. METHODS: We retrospectively included 250 patients (266 renal lesions) who underwent a clinically indicated PVP abdominopelvic CT on a rapid-kilovoltage-switching single-source DECT (rsDECT) or a dual-source DECT (dsDECT) scanner. Iodine concentration and HU measurements were calculated by four experienced readers. Diagnostic accuracy was determined using biopsy results and follow-up imaging as reference standard. Area under the curve (AUC) was calculated for each DECT scanner to differentiate vascular from nonvascular lesions and vascular lesions from hemorrhagic/proteinaceous cysts. Univariable and multivariable logistic regression analyses evaluated the association between variables and the presence of vascular lesions. RESULTS: A normalized iodine concentration threshold of 0.25 mg/mL yielded high accuracy in differentiating vascular and nonvascular lesions (AUC 0.93, p < 0.001), with comparable performance to HU measurements (AUC 0.93). Both iodine concentration and HU measurements were independently associated with vascular lesions when adjusted for age, gender, body mass index, and lesion size (AUC 0.95 and 0.95, respectively). When combined, diagnostic performance was higher (AUC 0.96). Both absolute and normalized iodine concentrations performed better than HU measurements (AUC 0.92 vs. AUC 0.87) in differentiating vascular lesions from hemorrhagic/proteinaceous cysts. CONCLUSION: A single-phase (PVP) DECT scan yields high accuracy to differentiate vascular from nonvascular renal lesions. Iodine concentration showed a slightly higher performance than HU measurements in differentiating vascular lesions from hemorrhagic/proteinaceous cysts. KEY POINTS: • A single-phase dual-energy CT scan in the portal venous phase differentiates vascular from nonvascular renal lesions with high accuracy (AUC 0.93). • When combined, iodine concentration and HU measurements showed the highest diagnostic performance (AUC 0.96) to differentiate vascular from nonvascular renal lesions. • Compared to HU measurements, iodine concentration showed a slightly higher performance in differentiating vascular lesions from hemorrhagic/proteinaceous cysts.

Efficacy of Arthroscopic Surgery in the Management of Adhesive Capsulitis: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.

PURPOSE: To determine which interventions optimize clinical outcomes in adhesive capsulitis by performing a network meta-analysis of randomized controlled trials. METHODS: A systematic review was conducted of all clinical trials on adhesive capsulitis published since 2008. Patient cohorts were grouped into treatment categories; data collected included range of motion (ROM) and patient-reported outcome measures (PROMs). Interventions were compared across groups by means of arm-based Bayesian network meta-analysis in a random-effects model. RESULTS: Sixty-six studies comprising 4042 shoulders (57.6% female patients, age 54.8 ± 3.2 years [mean ± standard deviation]) were included. The most commonly studied interventions were physical therapy (PT) or shoulder injections. Network meta-analysis demonstrated that arthroscopic surgical capsular release was the most effective treatment in increasing ROM. This effect was apparent in forward flexion (effect difference [ED] versus placebo, 44°, 95% confidence interval [CI] 31° to 58°), abduction (ED 58°, 45° to 71°), internal rotation (ED 34°, 24° to 44°), and external rotation (ED 59°, 37° to 80°). Interventions most effective for pain relief included PT supplemented with either medical therapy (ED -4.50, -9.80 to 2.80) or ultrasound therapy (ED -5.10, -5.10 to -1.40). Interventions most effective for improvement of functional status included PT, manipulation under anesthesia (MUA), intra-articular or subacromial steroid injection, surgical capsular release, and supplementation of PT with alternative therapy. CONCLUSIONS: No one treatment emerged superior in regard to ROM, pain symptoms, and functional status. Surgery (after failure of conservative treatment) ranked highest across all ROM domains. Treatments that ranked highest for treatment of pain included PT supplemented with either medical therapy or ultrasound. Finally, treatments that ranked highest for improvements in functional status included MUA, PT with medical therapy, surgical intervention, PT with ultrasound, PT with injection, and injection alone. LEVEL OF EVIDENCE: II, systematic review and network meta-analysis of level I and II studies.

How can we define clinically important improvement in pain scores after biceps tenodesis?

BACKGROUND: Patient postoperative pain is an important consideration following biceps tenodesis. The visual analog scale (VAS) for pain is one of the most commonly used measures for perioperative pain assessment. Currently, there is limited understanding of clinically significant improvement in VAS pain. PURPOSE: To define the substantial clinical benefit (SCB), patient acceptable symptomatic state (PASS), and minimal clinically important difference (MCID) for the VAS pain score in patients undergoing open subpectoral (OSPBT) or arthroscopic suprapectoral biceps tenodesis (ASPBT) at 1 year from surgery; and to identify preoperative predictors of achieving each outcome end point. METHODS: Data from consecutive patients who underwent isolated biceps tenodesis between January 2014 and March 2017 were collected and analyzed. Baseline data and postoperative patient-reported outcome (PRO) scores were recorded at 1 year postoperatively. In order to quantify the clinical significance of outcome achievement for the VAS pain score, the MCID, PASS, and SCB were calculated. RESULTS: A total of 165 patients were included in the final analysis. The VAS pain score threshold for achieving MCID was defined as a decrease of 12.9 (0-100). PASS was defined as achieving a 2-year postoperative score of 27.4 points (0-100), and SCB was defined as a decrease of 25.1 (0-100) at 1-year follow-up. The rates of achieving MCID, PASS, and SCB were 73.3%, 52.8%, and 45.9%, respectively. Multivariate regression analysis demonstrated that ASPBT (P = .01) and a lower preoperative Constant-Murley score were predictive of achieving the MCID (P = .01). In contrast, a lower preoperative score on the SF-12 Physical Component Summary (P = .01) and a higher score on the preoperative American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (P < .001) were predictive of achieving the SCB and PASS, respectively. Preoperative duration of symptoms >6 months was predictive of a reduced likelihood to achieve PASS. CONCLUSION: This study identified scores for VAS pain that can be used to define clinically significant outcome after biceps tenodesis. Specifically, a decrease in pain score of 12.9 was a clinically important improvement in VAS pain, whereas a decrease of 25.1 represented the upper threshold of VAS pain improvement. Additionally, there were both modifiable and nonmodifiable factors that predicted achieving clinically significant levels of postoperative pain improvement.

Nano-analysis Reveals High Fraction of Serotonin Release during Exocytosis from a Gut Epithelium Model Cell.

Electrochemical methods were used to explore the exocytotic nature of serotonin (5-HT) release in human carcinoid BON cells, an in vitro human enterochromaffin cell model, to understand the mechanisms operating the release of gut-derived 5-HT in the intestinal mucosal epithelium. We show that the fractional vesicular 5-HT release in BON cells is 80 % compared to previous work in pancreatic beta cells (34 %). The fractional release increased from 80 % in control BON cells to 87 % with 5-HT preincubation and nearly 100 % with the combination of 5-HT and the 5-HT4 autoreceptor agonist, cisapride. Thus, partial release is the primary mechanism of exocytosis in BON cells, resulting in a variable amount of the vesicular content being released. Factors that control secretion of 5-HT from enterochromaffin cells or BON cells are important as partial release provides a mechanism for development of effective therapeutic strategies to treat gastrointestinal diseases.