Therapeutic synthetic and natural materials for immunoengineering.

Immunoengineering is a rapidly evolving field that has been driving innovations in manipulating immune system for new treatment tools and methods. The need for materials for immunoengineering applications has gained significant attention in recent years due to the growing demand for effective therapies that can target and regulate the immune system. Biologics and biomaterials are emerging as promising tools for controlling immune responses, and a wide variety of materials, including proteins, polymers, nanoparticles, and hydrogels, are being developed for this purpose. In this review article, we explore the different types of materials used in immunoengineering applications, their properties and design principles, and highlight the latest therapeutic materials advancements. Recent works in adjuvants, vaccines, immune tolerance, immunotherapy, and tissue models for immunoengineering studies are discussed.

HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

CT Colonography Reporting and Data System (C-RADS): Version 2023 Update.

The CT Colonography Reporting and Data System (C-RADS) has withstood the test of time and proven to be a robust classification scheme for CT colonography (CTC) findings. C-RADS version 2023 represents an update on the scheme used for colorectal and extracolonic findings at CTC. The update provides useful insights gained since the implementation of the original system in 2005. Increased experience has demonstrated confusion on how to classify the mass-like appearance of the colon consisting of soft tissue attenuation that occurs in segments with acute or chronic diverticulitis. Therefore, the update introduces a new subcategory, C2b, specifically for mass-like diverticular strictures, which are likely benign. Additionally, the update simplifies extracolonic classification by combining E1 and E2 categories into an updated extracolonic category of E1/E2 since, irrespective of whether a finding is considered a normal variant (category E1) or an otherwise clinically unimportant finding (category E2), no additional follow-up is required. This simplifies and streamlines the classification into one category, which results in the same management recommendation.

Sociodemographic Factors and Screening CT Colonography Use Among Medicare Beneficiaries.

BACKGROUND. Approximately one-third of the eligible U.S. population have not undergone guideline-compliant colorectal cancer (CRC) screening. Guidelines recognize various screening strategies to increase adherence. CMS provides coverage for all recommended screening tests except CT colonography (CTC). OBJECTIVE. The purpose of this study was to compare CTC and other CRC screening tests in terms of associations of utilization with income, race and ethnicity, and urbanicity in Medicare fee-for-service beneficiaries. METHODS. This retrospective study used CMS Research Identifiable Files from January 1, 2011, through December 31, 2020. These files contain claims information for 5% of Medicare fee-for-service beneficiaries. Data were extracted for individuals 45-85 years old, and individuals with high CRC risk were excluded. Multivariable logistic regression models were constructed to determine the likelihood of undergoing CRC screening tests (as well as of undergoing diagnostic CTC, a CMS-covered test with similar physical access as screening CTC) as a function of income, race and ethnicity, and urbanicity while controlling for sex, age, Charlson comorbidity index, U.S. census region, screening year, and related conditions and procedures. RESULTS. For 12,273,363 beneficiary years (mean age, 70.5 ± 8.2 [SD] years; 2,436,849 unique beneficiaries: 6,774,837 female beneficiaries, 5,498,526 male beneficiaries), there were 785,103 CRC screenings events, including 645 for screening CTC. Compared with individuals living in communities with per capita income of less than US$25,000, individuals in communities with income of US$100,000 or more had OR for undergoing screening CTC of 5.73, optical colonoscopy (OC) of 1.36, sigmoidoscopy of 1.03, guaiac fecal occult blood test or fecal immunochemical test of 1.50, stool DNA of 1.43, and diagnostic CTC of 2.00. The OR for undergoing screening CTC was 1.00 for Hispanic individuals and 1.08 for non-Hispanic Black individuals compared with non-Hispanic White individuals. Compared with the OR for undergoing screening CTC for residents of metropolitan areas, the OR was 0.51 for residents of micropolitan areas and 0.65 for residents of small or rural areas. CONCLUSION. The association with income was substantially larger for screening CTC than for other CRC screening tests or for diagnostic CTC. CLINICAL IMPACT. Medicare's noncoverage for screening CTC may contribute to lower adherence with CRC screening guidelines for lower-income beneficiaries. Medicare coverage of CTC could reduce income-based disparities for individuals avoiding OC owing to invasiveness, need for anesthesia, or complication risk.

Superficial retrocalcaneal bursae and nerves: From anatomy to ultrasound-guided procedures.

The pertinent literature widely describes ultrasound-guided procedures targeting the retrocalcaneal bursa and the tendon tissue to manage insertional Achilles tendinopathy. Synovial bursae and cutaneous nerves of the superficial retrocalcaneal pad are often overlooked pain generators and are poorly considered by clinicians and surgeons. A layer-by-layer dissection of the superficial soft tissues in the retrocalcaneal region of two fresh frozen cadavers was matched with historical anatomical tables of the textbook Traite d'Anatomie Topographique Avec Applications Médico-Chirurgicales (1909 by Testut and Jacob). An accurate and detailed description of the superficial retrocalcaneal pad with its synovial bursae and cutaneous nerves was provided. Cadaveric dissections confirmed the compartmentalized architecture of the superficial retrocalcaneal fat pad and its histological continuum with the superficial lamina of the crural fascia. Superficial synovial tissue islands have been demonstrated on the posterior aspect of the Achilles tendon in one cadaver and on the posterolateral surface of the tendon in the other one. Digitalization of the original anatomical tables of the textbook Traite d'Anatomie Topographique Avec Applications Médico-Chirurgicales (1909 by Testut and Jacob) showed five potential locations of the superficial calcaneal bursa and a superficial retrocalcaneal nerve plexus within the Achilles tendon-fat pad interface. In clinical practice, in addition to the previously described interventions regarding the retrocalcaneal bursa and the tendon tissue, ultrasound-guided procedures targeting the synovial and neural tissues of the superficial retrocalcaneal pad should be considered to optimize the management of insertional Achilles tendinopathy.

Ultrasound-guided injection of the ankle joint: cadaveric investigation of the anterolateral approach.

OBJECTIVE: Injection of the tibiotalar (TT) joint is commonly performed in clinical practice under ultrasound (US) guidance using an anteromedial approach. However, in some patients, this approach may be technically challenging due to post-traumatic and/or degenerative bony changes. Therefore, the aim of this cadaveric investigation was to demonstrate the feasibility of the ultrasound-guided (USG) injection of the ankle joint via the anterolateral sulcus (ALS) by confirming the dye placement/distribution inside the articular space. Likewise, the safety of the procedure has also been evaluated by measuring the distance between the needle and the intermediate dorsal cutaneous nerve of the foot. DESIGN: A descriptive laboratory study with eight embalmed cadaveric ankles using the Fix for Life (F4L) method was performed at the setting of an academic institution. The interventional technique and the related anatomical findings were illustrated. During the injection, the needle was advanced into the TT joint through the ALS under US guidance, i.e., in-plane anterior-to-posterior approach. With the objective to confirm its correct placement, the needle was kept in situ and-to demonstrate the location of the dye inside the articular space-all eight ankles were injected with 3 mL of green color dye. Thereafter, a layer-by-layer anatomical dissection was performed on all four cadavers. RESULTS: The position of the needle's tip within the ALS was confirmed in all specimens. Accurate placement of the dye inside the articular space of the ankle was confirmed in seven of the eight cadaveric ankles, with 87.5% of accuracy. Herewith, unintentional spilling of the dye within the superficial soft tissues was reported in two of the eight ankles (25.0%). The mean distance between the needle and the intermediate dorsal cutaneous nerve of the foot, measured in all eight procedures, was 3 cm. CONCLUSION: USG injection of the ALS using the in-plane, anterior-to-posterior approach can accurately place the injectate inside the articular space. CLINICAL RELEVANCE: This cadaveric investigation described the accuracy and potential pitfalls of USG injection of the ankle via the anterolateral approach which represents an alternative technique in patients with reduced accessibility of the anteromedial recess due to degenerative and/or post-traumatic bony changes.

Ultrasound-guided injection of the achilles paratenon: A cadaveric investigation.

BACKGROUND: Injections around the Achilles tendon (AT) are commonly performed in clinical practice to manage non-insertional Achilles tendinopathy, but the presence/distribution of the injectate with relation to its sheath has not been assessed specifically. Accordingly, the aim of this cadaveric investigation was to demonstrate the feasibility of Achilles paratenon injection under ultrasound guidance - by confirming the exact needle positioning as well as the dye distribution inside the paratenon lumen. METHODS: A descriptive laboratory study with three human cadaveric specimens (one fresh cadaver and two cadavers embalmed using the Fix for Life (F4L) method) was performed in a tertiary-care academic institution. The interventional technique and the related anatomical findings were illustrated. During the injection, the needle was advanced inside the Achilles paratenon under ultrasound guidance i.e. in-plane medial-to-lateral approach. With the objective to confirm its correct placement, the needle was kept in situ on the right AT of the fresh cadaver. Likewise, to demonstrate the location of the dye inside the lumen of Achilles paratenon, the other five ATs - four on the embalmed cadavers and one on the fresh cadaver - were injected with 5 mL of green color dye. After removal of the needle, a layer-by-layer anatomical dissection was performed on all three cadavers. RESULTS: On the right AT of the fresh cadaver, the position of the needle's tip within the Achilles paratenon was confirmed. Accurate placement of the dye inside the paratenon lumen was confirmed in four (80%) ATs, one of the fresh and three of the embalmed cadavers. No spread inside the crural fascia compartment or between the AT and the Kager's fat pad was observed. Herewith, unintentional spilling of the dye within the superficial soft tissues of the posterior leg was reported in the left AT of one of the two embalmed cadavers (20%). CONCLUSIONS: Ultrasound-guided injection using the in-plane, medial-to-lateral approach can accurately target the lumen of Achilles paratenon.

PSA density does not improve predictive accuracy of the UCSF-CAPRA score.

INTRODUCTION: The University of California, San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score is a validated tool using factors at diagnosis to predict prostate cancer outcomes after radical prostatectomy (RP). This study evaluates whether substitution of prostate-specific antigen (PSA) density for serum PSA improves predictive performance of the clinical CAPRA model. METHODS: Participants were diagnosed in 2000-2019 with stage T1/T2 cancer, underwent RP, with at least a 6-month follow-up. We computed standard CAPRA score using diagnostic age, Gleason grade, percent positive cores, clinical T stage, and serum PSA, and an alternate score using similar variables but substituting PSA density for PSA. We reported CAPRA categories as low (0-2), intermediate (3-5), and high (6-10) risk. Recurrence was defined as two consecutive PSA ≥ 0.2 ng/mL or receipt of salvage treatment. Life table and Kaplan-Meier analysis evaluated recurrence-free survival after prostatectomy. Cox proportional hazards regression models tested associations of standard or alternate CAPRA variables with recurrence risk. Additional models tested associations between standard or alternate CAPRA score with recurrence risk. Cox log-likelihood ratio test (-2 LOG L) assessed model accuracy. RESULTS: A total of 2880 patients had median age 62 years, GG1 30% and GG2 31%, median PSA 6.5, and median PSA density 0.19. Median postoperative follow-up was 45 months. Alternate CAPRA model was associated with shifts in risk scores, with 16% of patients increasing and 7% decreasing (p < 0.01). Recurrence-free survival after RP was 75% at 5 years and 62% at 10 years. Both CAPRA component models were associated with recurrence risk after RP on Cox regression. Covariate fit statistics showed better fit for standard CAPRA model versus alternate (p < 0.01). Standard (hazard ratio [HR]: 1.55; 95% confidence interval [CI]: 1.50-1.61) and alternate (HR: 1.50; 95% CI: 1.44-1.55) CAPRA scores were associated with recurrence risk, with better fit for standard model (p < 0.01). CONCLUSIONS: In a 2880 patient cohort followed for median 45 months after RP, alternate CAPRA model using PSA density was associated with higher biochemical recurrence (BCR) risk, but performed inferior to standard CAPRA at predicting BCR. While PSA density is an established prognostic variable in prediagnostic settings and sub-stratifying low-risk disease, it does not improve BCR model predictive accuracy when applied across a range of cancer risk.

Stability of Prognostic Estimation Using the CAPRA Score Incorporating Imaging-based vs Physical Exam-based Staging.

PURPOSE: Although official T-staging criteria for prostate cancer are based on digital rectal examination findings, providers increasingly rely on transrectal US and MRI to define pragmatic clinical stage to guide management. We assessed the impact of incorporating imaging findings into T-staging on performance of a well-validated prognostic instrument. MATERIALS AND METHODS: Patients who underwent radical prostatectomy for prostate cancer diagnosed between 2000 and 2019 with stage ≤cT3a on both digital rectal examination and imaging (transrectal US/MRI) were included. The University of California, San Francisco CAPRA (Cancer of the Prostate Risk Assessment) score was computed 2 ways: (1) incorporating digital rectal examination-based T stage and (2) incorporating imaging-based T stage. We assessed for risk changes across the 2 methods and associations of CAPRA (by both methods) with biochemical recurrence, using unadjusted and adjusted Cox proportional hazards models. Model discrimination and net benefit were assessed with time-dependent area under the curve and decision curve analysis, respectively. RESULTS: Of 2,222 men included, 377 (17%) increased in CAPRA score with imaging-based staging (P < .01). Digital rectal examination-based (HR 1.54; 95% CI 1.48-1.61) and imaging-based (HR 1.52; 95% CI 1.46-1.58) CAPRA scores were comparably accurate for predicting recurrence with similar discrimination and decision curve analyses. On multivariable Cox regression, positive digital rectal examination at diagnosis (HR 1.29; 95% CI 1.09-1.53) and imaging-based clinical T3/4 disease (HR 1.72; 95% CI 1.43-2.07) were independently associated with biochemical recurrence. CONCLUSIONS: The CAPRA score remains accurate whether determined using imaging-based staging or digital rectal examination-based staging, with relatively minor discrepancies and similar associations with biochemical recurrence. Staging information from either modality can be used in the CAPRA score calculation and still reliably predict risk of biochemical recurrence.

Electrophoresis of a dielectric droplet with constant surface charge density.

Electrophoresis of a dielectric fluid droplet with constant surface charge density is investigated theoretically in this study. A pseudo-spectral method based on Chebyshev polynomials is adopted to solve the governing electrokinetic equations. It is found, among other things, that the larger the electrolyte strength in the ambient solution is, the slower the droplet moves in general. This is due to the strong screening effect of the large amount of indifferent counterions in the neighborhood of the droplet, with no reinforcement of potential-determining ions adsorbing to the droplet surface. The droplet comes to a complete halt eventually. Critical points are discovered for highly charged droplets, at which the droplet surface becomes immobile and the interior fluid stops recirculating. The droplet moves like a rigid particle with constant mobility regardless of its viscosity, a situation referred to as the "solidification phenomenon." The deadlock between the spinning motions on the charged droplet surface induced by the electric driving force and the hydrodynamic driving force respectively is responsible for this peculiar phenomenon. This is also observed for a dielectric droplet with constant surface electric potential. We demonstrate here that it occurs in the constant surface charge density situation as well.

The Impact of Race and Sex on the Clinical Outcomes of Homeless Patients With Alcoholic Liver Disease: Propensity Score Matched Analysis of US Hospitals.

BACKGROUND: Among patients with alcoholic liver disease (ALD), homelessness poses significant medical and psychosocial risks; however, less is known about the effects of race and sex on the hospital outcomes of admitted homeless patients with ALD. METHODS: The National Inpatient Sample database from 2012 to 2017 was used to isolate homeless patients with ALD, and the cohort was further stratified by race and sex for comparisons. Propensity score matching was utilized to minimize covariate confounding. The primary endpoints of this study include mortality, hospital length of stay, and hospital costs; secondary endpoints included the incidence of liver complications. RESULTS: There were 3972 females/males postmatch, as well as 2224 Blacks/Whites and 4575 Hispanics/Whites postmatch. In multivariate, there were no significant differences observed in mortality rate, length of stay, and costs between sexes. Comparing liver outcomes, females had a higher incidence of hepatic encephalopathy [adjusted odds ratio (aOR) 1.02, 95% CI: 1.01-1.04, P<0.001]. In comparing Blacks versus Whites, Black patients had higher hospitalization costs (aOR 1.13, 95% CI: 1.03-1.24, P=0.01); however, there were no significant differences in mortality, length of stay, or liver complications. In comparing Hispanics versus Whites, Hispanic patients had longer length of hospital stay (aOR 1.12, 95% CI: 1.06-1.19, P<0.001), greater costs (aOR 1.15, 95% CI: 1.09-1.22, P<0.001), as well as higher prevalence of liver complications including varices (aOR 1.04, 95% CI: 1.02-1.06, P<0.001), hepatic encephalopathy (aOR 1.03, 95% CI: 1.02-1.04, P<0.001), and hepatorenal syndrome (aOR 1.01, 95% CI 1.00-1.01, P=0.03). However, there was no difference in mortality between White and Hispanic patients. CONCLUSIONS: Black and Hispanic ALD patients experiencing homelessness were found to incur higher hospital charges; furthermore, Hispanic patients also had greater length of stay and higher incidence of liver-related complications compared with White counterparts.

The cost-effectiveness of a real-time seizure detection application for people with epilepsy.

OBJECTIVES: Automated seizure detection modalities can increase safety among people with epilepsy (PWE) and reduce seizure-related anxiety. We evaluated the potential cost-effectiveness of a seizure detection mobile application for PWE in Singapore. METHODS: We used a Markov cohort model to estimate the expected changes to total costs and health outcomes from a decision to adopt the seizure detection application versus the current standard of care from the health provider perspective. The time horizon is ten years and cycle duration is one month. Parameter values were updated from national databases and published literature. As we do not know the application efficacy in reducing seizure-related injuries, a conservative estimate of 1% reduction was used. Probabilistic sensitivity analysis, scenario analyses, and value of information analysis were performed. RESULTS: At a willingness-to-pay of $45,000/ quality-adjusted life-years (QALY), the incremental cost-effectiveness ratio was $1,096/QALY, and the incremental net monetary benefit was $13,656. Probabilistic sensitivity analyses reported that the application had a 99.5% chance of being cost-effective. In a scenario analysis in which the reduction in risk of seizure-related injury was 20%, there was a 99.8% chance that the application was cost-effective. Value of information analysis revealed that health utilities was the most important parameter group contributing to model uncertainty. CONCLUSIONS: This early-stage modeling study reveals that the seizure detection application is likely to be cost-effective compared to current standard of care. Future prospective trials will be needed to demonstrate the real-world impact of the application. Changes in health-related quality of life should also be measured in future trials.

Empowering health geography research with location-based social media data: innovative food word expansion and energy density prediction via word embedding and machine learning.

BACKGROUND: The exponential growth of location-based social media (LBSM) data has ushered in novel prospects for investigating the urban food environment in health geography research. However, previous studies have primarily relied on word dictionaries with a limited number of food words and employed common-sense categorizations to determine the healthiness of those words. To enhance the analysis of the urban food environment using LBSM data, it is crucial to develop a more comprehensive list of food-related words. Within the context, this study delves into the exploration of expanding food-related words along with their associated energy densities. METHODS: This study addresses the aforementioned research gap by introducing a novel methodology for expanding the food-related word dictionary and predicting energy densities. Seed words are generated from official and crowdsourced food composition databases, and new food words are discovered by clustering food words within the word embedding space using the Gaussian mixture model. Machine learning models are employed to predict the energy density classifications of these food words based on their feature vectors. To ensure a thorough exploration of the prediction problem, ten widely used machine learning models are evaluated. RESULTS: The approach successfully expands the food-related word dictionary and accurately predicts food energy density (reaching 91.62%.). Through a comparison of the newly expanded dictionary with the initial seed words and an analysis of Yelp reviews in the city of Toronto, we observe significant improvements in identifying food words and gaining a deeper understanding of the food environment. CONCLUSIONS: This study proposes a novel method to expand food-related vocabulary and predict the food energy density based on machine learning and word embedding. This method makes a valuable contribution to building a more comprehensive list of food words that can be used in geography and public health studies by mining geotagged social media data.

Comparative Effectiveness of Corticosteroid Dosages for Ultrasound-Guided Glenohumeral Joint Hydrodilatation in Adhesive Capsulitis: A Randomized Controlled Trial.

OBJECTIVE: To investigate the efficacy of hydrodilatation with 40 mg triamcinolone acetonide (TA) compared with the same procedure with 10 mg TA in patients with adhesive capsulitis (AC) of the shoulders. DESIGN: Prospective, double-blind, randomized controlled trial with 12 weeks of follow-up. SETTING: Tertiary care rehabilitation center. PARTICIPANTS: Eighty-four patients diagnosed with AC (N=84). INTERVENTIONS: Ultrasound guidance using (A) hydrodilatation with 4 mL of TA (40 mg)+4 mL 2% lidocaine hydrochloride+12 mL normal saline or (B) hydrodilatation with 1 mL of TA (10 mg)+4 mL 2% lidocaine hydrochloride+15 mL normal saline through the posterior glenohumeral recess. MAIN OUTCOME MEASURES: Shoulder Pain and Disability Index (SPADI), visual analog scale (VAS) for pain, and range of motion (ROM) at baseline and at 6 and 12 weeks after injection. RESULTS: Both groups experienced improvements in the SPADI score, VAS scores for pain, and ROM throughout the study period. However, group-by-time interactions were not significant for any outcome measurement at any follow-up time point. No adverse events were reported in either group. CONCLUSION: Ultrasound-guided hydrodilatation with 40 and 10 mg TA yielded similar improvements in SPADI, VAS score, and ROM at the 12-week follow-up. Considering the potential detrimental effects of corticosteroids on the adjacent cartilage and tendons, a low dose of TA would be preferable for ultrasound-guided hydrodilatation for AC.

Subacromial Motion Metrics in Painful Shoulder Impingement: A Dynamic Quantitative Ultrasonography Analysis.

OBJECTIVES: To explore the subacromial motion metrics in patients with and without subacromial impingement syndrome (SIS) and to investigate whether the abnormality was associated with rotator cuff pathologies. DESIGN: This cross-sectional observational study used dynamic quantitative ultrasonography imaging for shoulder joint assessment. SETTING: Outpatient rehabilitation clinic. PARTICIPANTS: Individuals with SIS on at least 1 shoulder (n=32) and asymptomatic controls (n=32) (N=64). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Frame-by-frame, the humeral greater tuberosity against the lateral edge of the acromion was traced to obtain the minimal vertical acromiohumeral distance (AHD). The rotation angle and radius of the humerus were computed using the least-squares curve fitting method. RESULTS: Approximately two-thirds of the shoulders with SIS did not have any sonographically identifiable rotator cuff pathologies. There was a consistent trend of nonsignificantly increased humeral rotation angles in painful shoulders. The generalized estimating equation demonstrated that the decreased minimal vertical AHD was associated with painful subacromial impingement (ß coefficient: -0.123cm, 95% confidence interval [CI], -0.199 to -0.047). The area under the curve for the minimal vertical AHD to discriminate painful or impinged shoulders ranged from 0.624-0.676. The increased rotation angle (ß coefficient: 10.516°; 95% CI, 3.103-17.929) and decreased rotation radius (ß coefficient: -2.903cm; 95% CI, -5.693 to -0.111) were shown to be significantly related to the presence of supraspinatus tendinopathy. CONCLUSIONS: Shoulders with SIS were characterized by a decreased minimal vertical AHD during dynamic examination. Abnormal subacromial metrics can develop in patients with mild (or no) rotator cuff pathologies. More prospective cohort studies are warranted to investigate the changes in subacromial motion metrics in populations at risk for painful or impinged shoulders.

Defining the optimal calcium repletion dosing in patients requiring activation of massive transfusion protocol.

PURPOSE: Massive transfusion protocols (MTP) commonly result in severe hypocalcemia due to the calcium-binding affinity of citrate in blood components. The purpose of this study is to determine the optimal grams (g) of citrate to repletion calcium (Ca) milliequivalents (mEq) (Citrate:Ca) ratio to reduce 30-day mortality. METHODS: This was a retrospective, single-centered, cohort study at a level 1 trauma center evaluating trauma and surgical patients in need of MTP activation from January 1, 2010-July 31, 2021. Patients with severe hypocalcemia at baseline, defined as ionized calcium (iCa) <0.9 mmol/L, were compared to patients without severe hypocalcemia. The primary endpoint was to determine the optimal ratio of grams of citrate to calcium mEq to reduce mortality in patients receiving a MTP. Secondary endpoints included mortality at 24 h and 30 days, blood components used in MTP, and type of calcium used. RESULTS: Overall, 501 patients were screened for inclusion. Of these patients, 193 were excluded, leaving 308 patients, of which 165 patients (53.6%) had an iCa <0.9 mmol/L within 24 h and 143 patients (46.4%) had iCa ≥0.9 mmol/L within 24 h. The ratio of Citrate:Ca for each patient was not significantly associated with mortality at 24 h (P = 0.79) or 30 days (P = 0.91) at a repletion Citrate:Ca ratio of median 1.97 (IQR 1.14-2.91). The rate of mortality was lowest at a Citrate:Ca of 2 in both <24-h mortality and 30-day mortality. CONCLUSIONS: There were no differences in 24 h or 30 day mortality based on repletion ratios seen in this study. A Citrate:Ca ratio between 2 and 3 in patients undergoing MTP was sufficient to obtain a normalized iCa within 24 h of MTP activation regardless of baseline iCa level. Further prospective studies will be needed to determine the optimal Citrate:Ca ratio.

Diffusiophoresis of a Weakly Charged Liquid Metal Droplet.

Diffusiophoresis of a weakly charged liquid metal droplet (LMD) is investigated theoretically, motivated by its potential application in drug delivery. A general analytical formula valid for weakly charged condition is adopted to explore the droplet phoretic behavior. We determined that a liquid metal droplet, which is a special category of the conducting droplet in general, always moves up along the chemical gradient in sole chemiphoresis, contrary to a dielectric droplet where the droplet tends to move down the chemical gradient most of the time. This suggests a therapeutic nanomedicine such as a gallium LMD is inherently superior to a corresponding dielectric liposome droplet in drug delivery in terms of self-guiding to its desired destination. The droplet moving direction can still be manipulated via the polarity dependence; however, there should be an induced diffusion potential present in the electrolyte solution under consideration, which spontaneously generates an extra electrophoresis component. Moreover, the smaller the conducting liquid metal droplet is, the faster it moves in general, which means a smaller LMD nanomedicine is preferred. These findings demonstrate the superior features of an LMD nanomedicine in drug delivery.

ATAC-Seq Reveals an Isl1 Enhancer That Regulates Sinoatrial Node Development and Function.

RATIONALE: Cardiac pacemaker cells (PCs) in the sinoatrial node (SAN) have a distinct gene expression program that allows them to fire automatically and initiate the heartbeat. Although critical SAN transcription factors, including Isl1 (Islet-1), Tbx3 (T-box transcription factor 3), and Shox2 (short-stature homeobox protein 2), have been identified, the cis-regulatory architecture that governs PC-specific gene expression is not understood, and discrete enhancers required for gene regulation in the SAN have not been identified. OBJECTIVE: To define the epigenetic profile of PCs using comparative ATAC-seq (assay for transposase-accessible chromatin with sequencing) and to identify novel enhancers involved in SAN gene regulation, development, and function. METHODS AND RESULTS: We used ATAC-seq on sorted neonatal mouse SAN to compare regions of accessible chromatin in PCs and right atrial cardiomyocytes. PC-enriched assay for transposase-accessible chromatin peaks, representing candidate SAN regulatory elements, were located near established SAN genes and were enriched for distinct sets of TF (transcription factor) binding sites. Among several novel SAN enhancers that were experimentally validated using transgenic mice, we identified a 2.9-kb regulatory element at the Isl1 locus that was active specifically in the cardiac inflow at embryonic day 8.5 and throughout later SAN development and maturation. Deletion of this enhancer from the genome of mice resulted in SAN hypoplasia and sinus arrhythmias. The mouse SAN enhancer also directed reporter activity to the inflow tract in developing zebrafish hearts, demonstrating deep conservation of its upstream regulatory network. Finally, single nucleotide polymorphisms in the human genome that occur near the region syntenic to the mouse enhancer exhibit significant associations with resting heart rate in human populations. CONCLUSIONS: (1) PCs have distinct regions of accessible chromatin that correlate with their gene expression profile and contain novel SAN enhancers, (2) cis-regulation of Isl1 specifically in the SAN depends upon a conserved SAN enhancer that regulates PC development and SAN function, and (3) a corresponding human ISL1 enhancer may regulate human SAN function.

Pericardial Manifestations of Thyroid Diseases.

PURPOSE OF REVIEW: Thyroid disorders, especially hypothyroidism, are known to be associated with pericardial diseases. The aim of this paper is to review the current knowledge of the pericardial manifestations of hypothyroidism and hyperthyroidism. RECENT FINDINGS: Many reports have described associations between dysthyroidism, which encompasses hypothyroidism and hyperthyroidism, and several pericardial diseases, including acute pericarditis, constrictive pericarditis, pericardial effusion, and tamponade. The diagnosis of dysthyroidism-induced pericardial diseases consists of a combination of thyroid blood levels that fall outside of the normal range and the exclusion of other causes. Treatment of the thyroid disorder is key, along with treatment of the pericardial disease as recommended by the guidelines. Early recognition of the thyroid disorder is key in patients with pericardial diseases, since treating the underlying cause should assist resolution of the pericardial issues and ideally prevent recurrence and possible future complications of suboptimally treated pericarditis or pericardial effusions.

Ultrasound of Small Nerves.

Nerve ultrasound has become an integral part of the diagnostic workup of peripheral neuropathies. Especially in the examination of small nerves, ultrasound provides superior image quality by using high frequency transducers. For a selection of small nerves, this article summarizes the local anatomy and common pathologies and offers simple instructions for determining their location with ultrasound including some cases with pathologies. This selection of nerves comprises the great auricular nerve, the supraclavicular nerves, the suprascapular nerve, the medial antebrachial cutaneous nerve, the lateral antebrachial cutaneous nerve, the palmar cutaneous branch of the median nerve, the long thoracic nerve, the intercostobrachial nerve, the posterior cutaneous nerve, the infrapatellar branch of the saphenous nerve, the medial calcaneal nerve, and the deep peroneal nerve at the ankle. Following our recommendations, these nerves can be swiftly located and tracked along their course to the site of the pathology.