Positron emission tomography myocardial perfusion imaging (PET MPI) findings predictive of post-liver transplant major adverse cardiac events.

Positron emission tomography myocardial perfusion imaging (PET MPI) is a noninvasive diagnostic test capable of detecting coronary artery disease, structural heart disease, and myocardial flow reserve (MFR). We aimed to determine the prognostic utility of PET MPI to predict post-liver transplant (LT) major adverse cardiac events (MACE). Among the 215 LT candidates that completed PET MPI between 2015 and 2020, 84 underwent LT and had 4 biomarker variables of clinical interest on pre-LT PET MPI (summed stress and difference scores, resting left ventricular ejection fraction, global MFR). Post-LT MACE were defined as acute coronary syndrome, heart failure, sustained arrhythmia, or cardiac arrest within the first 12 months post-LT. Cox regression models were constructed to determine associations between PET MPI variable/s and post-LT MACE. The median LT recipient age was 58 years, 71% were male, 49% had NAFLD, 63% reported prior smoking, 51% had hypertension, and 38% had diabetes mellitus. A total of 20 MACE occurred in 16 patients (19%) at a median of 61.5 days post-LT. One-year survival of MACE patients was significantly lower than those without MACE (54% vs. 98%, p =0.001). On multivariate analysis, reduced global MFR ≤1.38 was associated with a higher risk of MACE [HR=3.42 (1.23-9.47), p =0.019], and every % reduction in left ventricular ejection fraction was associated with an 8.6% higher risk of MACE [HR=0.92 (0.86-0.98), p =0.012]. Nearly 20% of LT recipients experienced MACE within the first 12 months of LT. Reduced global MFR and reduced resting left ventricular ejection fraction on PET MPI among LT candidates were associated with increased risk of post-LT MACE. Awareness of these PET-MPI parameters may help improve cardiac risk stratification of LT candidates if confirmed in future studies.

Quantifying molecular- to cellular-level forces in living cells.

Mechanical cues have been suggested to play an important role in cell functions and cell fate determination, however, such physical quantities are challenging to directly measure in living cells with single molecule sensitivity and resolution. In this review, we focus on two main technologies that are promising in probing forces at the single molecule level. We review their theoretical fundamentals, recent technical advancements, and future directions, tailored specifically for interrogating mechanosensitive molecules in live cells.

Predictors of Adverse Alcohol Use Consequences Among Tertiary Students.

BACKGROUND: The alcohol consumption patterns of young adults are of concern. Critically, tertiary students consume greater quantities of alcohol, are at increased risk of injury/harm, and have higher rates of alcohol use disorders as compared to their nonuniversity enrolled peers. The Brief Young Adult Alcohol Consequences Questionnaire (BYAACQ) is one of several tools utilized to explore adverse alcohol-related outcomes among tertiary students. Alcohol intake behavior, assessed via retrospective summary measures, has been linked to BYAACQ score. It is unclear, however, how drinking assessed in real time, in conjunction with variables such as age of drinking onset, might predict severity of adverse alcohol consequences as captured by the BYAACQ. METHODS: The psychometric properties of the BYAACQ were explored using a large Australian sample of tertiary students (N = 893). A subsample (n = 504) provided alcohol intake information in real time (21 days; event and notification contingent) via a smartphone app (CNLab-A) plus details related to age of drinking onset, drug use, parental alcohol/drug use, and anxiety/depression symptomology. RESULTS: Average BYAACQ score was 7.53 (SD = 5.37). Classical and item response theory analyses revealed inconsistencies related to dimensionality, progressive item severity, and male/female differential item functioning. Current drinking-namely, frequency of intake and quantity per drinking occasion-plus age of drinking onset predicted BYAACQ score after controlling for age, other drug use, and depression symptomology. CONCLUSIONS: The BYAACQ is a sound tool for use with Australian samples. Information related to current drinking, age of drinking onset, and drug use is useful for predicting severity of alcohol use consequences. These markers might enable tertiary institutions to better target students who could benefit from prevention/intervention programs.

Acceptability of and Adherence to an Antiretroviral-Based Vaginal Microbicide among Pregnant Women in the United States.

The MTN-008 trial was the first multi-dose study conducted to evaluate the safety of a microbicide gel (2:1 randomized to tenofovir 1% or hydroxycellulose (HEC) placebo gel) during pregnancy. The study aim was to evaluate safety, tolerability and pharmacokinetics of the study products. Procedures included daily gel administration, with Day 0 and Day 6 in clinic, and Days 1-5 at home. Because pregnancy may pose unique challenges to consistent gel use and acceptability, evaluation of adherence and acceptability was a secondary objective of the trial. The study enrolled healthy, HIV-negative, pregnant women aged 18-40 in Pittsburgh, PA and Birmingham, AL, USA in 2 consecutive groups: cohort 1 was 37-39 weeks gestation, cohort 2 was 34-36 weeks. Ninety-one women completed the study (45 and 46 in each cohort, respectively) and were evaluable per protocol. Adherence was evaluated using self-reports: participants completed a web-based computer-assisted self-interview (CASI) at Days 0 and 6 about gel attitudes and behaviors. At Day 6 trained research staff conducted a short interviewer-administered questionnaire with both structured and open-ended questions. Frequencies of quantitative data were tabulated in SAS and descriptive statistics are presented; open-ended textual data were summarized by a behavioral scientist experienced in qualitative analysis. Participants reported generally neutral perceptions of gel characteristics. A small number of women (7-8%) reported pain (6/90), other physical discomfort (7/90), or mental discomfort (7/90) associated with the process of applicator insertion. About 5% reported the same for the gel itself. Two-thirds (61/90) thought the gel was runny, many complained of bothersome gel leakage and several cited this reason for not inserting a full dose. The majority were not worried the gel would cause problems for their pregnancy or babies. Ninety-seven percent (83/86) said they would use the gel in the future if they were pregnant, and 90% (81/90) when nonpregnant. Self-reported adherence was high with 88% (79/90) reporting daily gel use on both the computerized and interviewer-administered questionnaires. The majority (67/90) reported no difficulty with daily use. However, drug was undetectable (<0.31 ng/mL) among 45% (27/60; 95% CI 32-58%) of the women on active product prior to observed dosing at Day 6. The most common reason for reported nonuse (N = 6) was forgetting. Study gel was generally acceptable, but many complained of a runny consistency (61/90) and leakage (83/90). No frequent or strong concerns about the effects of the study gel on the pregnancy/fetus were reported. Self-reported adherence to study gel self-administered at home for 5 days was high, however plasma drug levels suggest actual use may have been considerably lower. Findings from this study can provide insights relevant to use of other antiretroviral-based, vaginally-inserted HIV prevention methods during pregnancy.

Transgene-free iPSCs generated from small volume peripheral blood nonmobilized CD34+ cells.

A variety of somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs), but CD34(+) hematopoietic stem cells (HSCs) present in nonmobilized peripheral blood (PB) would be a convenient target. We report a method for deriving iPSC from PB HSCs using immunobead purification and 2- to 4-day culture to enrich CD34(+) HSCs to 80% ± 9%, followed by reprogramming with loxP-flanked polycistronic (human Oct4, Klf4, Sox2, and c-Myc) STEMCCA-loxP lentivector, or with Sendai vectors. Colonies arising with STEMCCA-loxP were invariably TRA-1-60(+), yielding 5.3 ± 2.8 iPSC colonies per 20 mL PB (n = 17), where most colonies had single-copy STEMCCA-loxP easily excised by transient Cre expression. Colonies arising with Sendai were variably reprogrammed (10%-80% TRA-1-60(+)), with variable yield (6 to >500 TRA-1-60(+) iPSC colonies per 10 mL blood; n = 6). Resultant iPSC clones expressed pluripotent cell markers and generated teratomas. Genomic methylation patterns of STEMCCA-loxP-reprogrammed clones closely matched embryonic stem cells. Furthermore, we showed that iPSCs are derived from the nonmobilized CD34(+) HSCs enriched from PB rather than from any lymphocyte or monocyte contaminants because they lack somatic rearrangements typical of T or B lymphocytes and because purified CD14(+) monocytes do not yield iPSC colonies under these reprogramming conditions.

Adhesive Capsulitis Following Improper Tetanus-Diphtheria (Td) Booster Administration.

Adhesive capsulitis following vaccination is a rare complication secondary to improper intramuscular (IM) deltoid vaccine administration. It is considered a subset of the broad category known as shoulder injury related to vaccine administration (SIRVA). SIRVA typically results from improper shoulder anatomic localization prior to injection, leading to erroneous placement of the needle into the glenohumeral joint capsule or subacromial space. This can trigger a wide array of pathologies, including adhesive capsulitis. We present the first known case of adhesive capsulitis following improper tetanus-diphtheria (Td) vaccine administration. The patient, a previously healthy middle-aged female, began experiencing significant anterior left shoulder pain the day following a Td booster vaccination. She remarked receiving the injection "higher up" in the shoulder than normal. Over the next two weeks, she began noting significant shoulder stiffness, which was followed by a progressive loss of shoulder range of motion. Her symptoms persisted for four months without definitive diagnosis or treatment. After four months of symptoms, the patient visited an outpatient sports medicine clinic where the diagnosis of adhesive capsulitis was made. Although the patient was referred for physical therapy, focusing on gentle range of motion (ROM) and stretches, followed by a planned isometric strengthening program once ROM improved, she was eventually lost to follow-up, and her recovery is unclear. Given the rarity of the diagnosis, it is unclear if adhesive capsulitis, secondary to improper IM vaccination, follows the same temporal course as "classic" adhesive capsulitis or results in a different timeframe of recovery. Further studies are needed on this subject.

Performance Differences in Elite National Basketball Association and Women's National Basketball Association Players Based Upon Whether the Dominant or Non-dominant Achilles Tendon Was Ruptured.

Background National Basketball Association (NBA) and Women's National Basketball Association (WNBA) players with Achilles tendon ruptures have previously been noted to have a significant decline in performance post-injury. There has been recent anecdotal evidence that elite players with dominant Achilles tendon ruptures may be able to return at a higher level of play post-rupture. Objective This study aimed to evaluate for any differences in performance in higher-performing NBA and WNBA players with dominant versus non-dominant Achilles tendon ruptures pre- and post-injury. Methods This study was conducted at the University of Pennsylvania, Department of Physical Medicine and Rehabilitation. NBA and WNBA players with an Achilles tendon rupture from 1990 to 2020 were identified. Only elite players, indicated by an average player efficiency rating (PER) of >15 in either of the three seasons pre/post-injury, were included. The average PER, offensive rating, defensive rating, and usage percentage were compared in the three seasons pre- and post-injury. Results Eighteen players met the inclusion criteria, and nine each were classified as dominant and non-dominant Achilles tendon ruptures based on their primary shooting hand. There was no significant difference between the dominant and non-dominant rupture groups in any outcomes pre-injury, including age. The non-dominant cohort had a significant decline in PER (20.04 vs. 14.16; p < 0.001) and offensive rating (110.33 vs. 101.56; p = 0.004) post-injury. There was no significant difference observed post-injury in defensive rating or usage percentage. The dominant cohort had no significant difference in any outcomes post-injury, returning to the same level of play as pre-injury. Despite no difference existing between the groups at baseline, the dominant group performed significantly better post-rupture with regard to PER (19.56 vs. 14.16; p < 0.001) and offensive rating (114.00 vs. 101.56; p < 0.001) versus the non-dominant group. Conclusion Elite NBA and WNBA players with dominant Achilles tendon ruptures had no change in performance post-injury, returning to the same level of production as pre-injury. Post-rupture, they demonstrated notably superior outcomes versus the non-dominant group with regard to PER and offensive rating. The non-dominant rupture group experienced the same decline in PER and offensive rating post-injury observed in previous studies. The data indicate that elite NBA and WNBA players with a dominant Achilles tendon rupture have a much more favorable recovery post-injury and are able to return to the same level of performance.

Oxidase-deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease-mediated safe harbor targeting.

We have developed induced pluripotent stem cells (iPSCs) from a patient with X-linked chronic granulomatous disease (X-CGD), a defect of neutrophil microbicidal reactive oxygen species (ROS) generation resulting from gp91(phox) deficiency. We demonstrated that mature neutrophils differentiated from X-CGD iPSCs lack ROS production, reproducing the pathognomonic CGD cellular phenotype. Targeted gene transfer into iPSCs, with subsequent selection and full characterization to ensure no off-target changes, holds promise for correction of monogenic diseases without the insertional mutagenesis caused by multisite integration of viral or plasmid vectors. Zinc finger nuclease-mediated gene targeting of a single-copy gp91(phox) therapeutic minigene into one allele of the "safe harbor" AAVS1 locus in X-CGD iPSCs without off-target inserts resulted in sustained expression of gp91(phox) and substantially restored neutrophil ROS production. Our findings demonstrate how precise gene targeting may be applied to correction of X-CGD using zinc finger nuclease and patient iPSCs.

Evaluation of Low-Intensity Pulsed Ultrasound on Stress Fractures to Reduce the Time to Return to Sport or Activity in the Physically Active Population: A Systematic Review.

Stress fractures are a common and significant source of pain and burden that can require long periods of rest from physical activity to allow adequate healing. Specifically in athletes or those with physically demanding occupations, the prolonged period of rest and the potential for requiring surgical intervention in the case of poor or delayed healing can have devastating impacts on these individuals' careers and socioeconomic well-being. In this population, successful healing, in addition to a quicker healing time and a sooner return to activity, are important outcomes when faced with treating stress fractures. The use of low-intensity pulsed ultrasound (LIPUS) to accelerate bone healing has been a topic of investigation, though little research has explored the use of LIPUS specifically in the physically active population. The purpose of this study was to review the existing literature on the use of LIPUS for stress fracture healing in the physically active population with the outcome of a quicker return to sport or physical duties. The PubMed and Embase databases were screened for relevant articles using defined Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Two independent researchers screened articles using PICOS criteria for inclusion in the review. Data were independently extracted regarding study and population characteristics as well as outcome measures, including time to healing of fractures and time to return to sport or physical activity. Five studies were ultimately included in the systematic review. One study investigated the use of LIPUS in pediatric athletes with spondylolysis, while four studies investigated lower extremity stress fractures in adult populations. All reported the outcomes of either rate or time to healing and ability to return to sport or activity. One study found a statistically significant improvement in the rate of bone union in the intervention group undergoing LIPUS compared to the control. Two studies found a statistically significant decrease in the time to resolution of symptoms, allowing an earlier return to sport or physical duties. Two studies found no difference in the time to healing or success rate of healing between the LIPUS group and the control group. This review of the literature suggests that the use of LIPUS for the treatment of stress fractures in the athletic or physically active population has the potential to expedite the resolution of symptoms and return to activity. Due to the heterogeneity of the existing studies, more research is needed to definitively determine the most appropriate clinical application of LIPUS and its most effective ultrasound settings. Further research should be directed toward more controlled studies specifically investigating the athletic and physically active population.

CON: Should patients with nonalcoholic steatohepatitis fibrosis undergo bariatric surgery as a primary treatment?

Content available: Author Interview and Audio Recording.

Xanthogranulomatous cholangitis mimicking cholangiocarcinoma: Case report and review of literature.

INTRODUCTION: Xanthogranulomatous cholangitis is an extremely rare diagnosis and is believed to be an extension of xanthogranulomatous cholecystitis, a benign inflammatory process characterized by lipid-laden foamy macrophages (called "xanthoma cells") occurring in a background of chronic inflammation consisting of lymphocytes, plasma cells, and eosinophils. Here, we report a case of xanthogranulomatous cholangitis mimicking cholangiocarcinoma. CASE PRESENTATION: A 72 year old male with history of recurrent cholangitis had preoperative workup highly suggestive of intrahepatic cholangiocarcinoma. He underwent right hepatectomy and portal lymphadenectomy, with pathology showing xanthogranulomatous cholangitis, with no evidence of malignancy. Interestingly, the patient did not have xanthogranulomatous cholecystitis. DISCUSSION: We reviewed the current literature on xanthogranulomatous cholangitis, and identified only 14 previously reported cases. In our case series, there were six female and eight male patients. Among the 14 patients, 11 presented to the hospital with jaundice. Twelve patients had preoperative workup concerning for malignancy. The diagnosis of xanthogranulomatous cholangitis was confirmed through pathology in 13 patients, and through endoscopic ultrasound biopsy in one patient. In our review, seven patients had associated xanthogranulomatous cholecystitis, three patients had an isolated case of xanthogranulomatous cholangitis, and four patients had unknown status. Our patient is the fourth case of isolated xanthogranulomatous cholangitis without xanthogranulomatous cholecystitis. CONCLUSION: Xanthogranulomatous cholangitis is a very rare phenomenon that can lead to benign strictures of the bile ducts, especially in the setting of recurrent cholangitis. It can mimic malignancies, such as cholangiocarcinoma, and should be considered in the differential diagnosis.

Prevalence and risk factors of steatosis and advanced fibrosis using transient elastography in the United States' adolescent population.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children and adolescents. AIM: To determine the prevalence and risk factors of steatosis and advanced fibrosis using transient elastography (TE) in the United States' adolescent population. METHODS: Using the National Health and Nutrition Examination Survey 2017-2018, adolescent participants aged 13 to 17 years who underwent TE and controlled attenuation parameter (CAP) were included in this study. Forty-one factors associated with liver steatosis and fibrosis were collected. Univariate and multivariate linear regression analysis were used to identify statistically significant predictors. RESULTS: Seven hundred and forty participants met inclusion criteria. Steatosis (S1-S3), based on CAP, and advanced fibrosis (F3-F4), based on TE, were present in 27% and 2.84% of the study population, respectively. Independent predictors of steatosis grade included log of alanine aminotransferase, insulin resistance, waist-to-height ratio, and body mass index. Independent predictors of fibrosis grade included steatosis grade, non-Hispanic black race, smoking history, and systolic blood pressure. CONCLUSION: This study demonstrated a high prevalence of steatosis in the United States' adolescent population. Almost 3% of United States' adolescents had advanced fibrosis. These findings are concerning because a younger age of onset of NAFLD can lead to an earlier development of severe disease, including steatohepatitis, cirrhosis, and liver decompensation.

Fast Acoustic Steering Via Tilting Electromechanical Reflectors (FASTER): A Novel Method for High Volume Rate 3-D Ultrasound Imaging.

The 3-D ultrasound imaging is essential for a wide range of clinical applications in diagnostic and interventional cardiology, radiology, and obstetrics for prenatal imaging. 3-D ultrasound imaging is also pivotal for advancing technical developments of emerging imaging technologies, such as elastography, blood flow imaging, functional ultrasound (fUS), and super-resolution microvessel imaging. At present, however, existing 3-D ultrasound imaging methods suffer from low imaging volume rate, suboptimal imaging quality, and high costs associated with 2-D ultrasound transducers. Here, we report a novel 3-D ultrasound imaging technique, fast acoustic steering via tilting electromechanical reflectors (FASTER), which provides both high imaging quality and fast imaging speed while at low cost. Capitalizing upon unique water immersible and fast-tilting microfabricated mirror to scan ultrafast plane waves in the elevational direction, FASTER is capable of high volume rate, large field-of-view (FOV) 3-D imaging with conventional 1-D transducers. In this article, we introduce the fundamental concepts of FASTER and present a series of calibration and validation studies for FASTER 3-D imaging. In a wire phantom and tissue-mimicking phantom study, we demonstrated that FASTER was capable of providing spatially accurate 3-D images with a 500-Hz imaging volume rate and an imaging FOV with a range of 48° (20 mm at 25-mm depth) in the elevational direction. We also showed that FASTER had comparable imaging quality with conventional mechanical translation-based 3-D imaging. The principles and results presented in this study establish the technical foundation for the new paradigm of high volume rate 3-D ultrasound imaging based on ultrafast plane waves and fast-tilting, water-immersible microfabricated mirrors.

Doxycycline-Induced Autoimmune Hepatitis.

Doxycycline and minocycline are tetracyclines with the potential to cause hepatoxicity. Although autoimmune-like hepatitis from minocycline is well-described, doxycycline-induced autoimmune hepatitis (DIAH) has only been described once. We report a rare case of DIAH with elevated liver enzymes over 5 times the normal upper limit, elevated immunoglobulin G, and high titers of antismooth muscle antibody and antinuclear antibody. By stopping doxycycline, our patient's liver enzymes normalized and immunoglobulin G and autoantibody titers rapidly downtrended. As long-term doxycycline therapy becomes more prevalent to treat acne vulgaris and other skin conditions, DIAH may become more prevalent and recognized.

A Smartphone App to Assess Alcohol Consumption Behavior: Development, Compliance, and Reactivity.

BACKGROUND: There are disadvantages-largely related to cost, participant burden, and missing data-associated with traditional electronic methods of assessing drinking behavior in real time. This potentially diminishes some of the advantages-namely, enhanced sample size and diversity-typically attributed to these methods. Download of smartphone apps to participants' own phones might preserve these advantages. However, to date, few researchers have detailed the process involved in developing custom-built apps for use in the experimental arena or explored methodological concerns regarding compliance and reactivity. OBJECTIVE: The aim of this study was to describe the process used to guide the development of a custom-built smartphone app designed to capture alcohol intake behavior in the healthy population. Methodological issues related to compliance with and reactivity to app study protocols were examined. Specifically, we sought to investigate whether hazard and nonhazard drinkers would be equally compliant. We also explored whether reactivity in the form of a decrease in drinking or reduced responding ("yes") to drinking behavior would emerge as a function of hazard or nonhazard group status. METHODS: An iterative development process that included elements typical of agile software design guided the creation of the CNLab-A app. Healthy individuals used the app to record alcohol consumption behavior each day for 21 days. Submissions were either event- or notification-contingent. We considered the size and diversity of the sample, and assessed the data for evidence of app protocol compliance and reactivity as a function of hazard and nonhazard drinker status. RESULTS: CNLab-A yielded a large and diverse sample (N=671, mean age 23.12). On average, participants submitted data on 20.27 (SD 1.88) out of 21 days (96.5%, 20.27/21). Both hazard and nonhazard drinkers were highly compliant with app protocols. There were no differences between groups in terms of number of days of app use (P=.49) or average number of app responses (P=.54). Linear growth analyses revealed hazardous drinkers decreased their alcohol intake by 0.80 standard drinks over the 21-day experimental period. There was no change to the drinking of nonhazard individuals. Both hazard and nonhazard drinkers showed a slight decrease in responding ("yes") to drinking behavior over the same period. CONCLUSIONS: Smartphone apps participants download to their own phones are effective and methodologically sound means of obtaining alcohol consumption information for research purposes. Although further investigation is required, such apps might, in future, allow for a more thorough examination of the antecedents and consequences of drinking behavior.