Light-induced Extracellular Vesicle Adsorption.

The role of extracellular vesicles (EVs) in human health and disease has garnered considerable attention over the past two decades. However, while several types of EVs are known to interact dynamically with the extracellular matrix and there is great potential value in producing high-fidelity EV micropatterns, there are currently no label-free, high-resolution, and tunable platform technologies with this capability. We introduce Light-induced Extracellular Vesicle Adsorption (LEVA) as a powerful solution to rapidly advance the study of matrix- and surface-bound EVs and other particles. The versatility of LEVA is demonstrated using commercial GFP-EV standards, EVs from glioblastoma bioreactors, and E. coli outer membrane vesicles (OMVs), with the resulting patterns used for single EV characterization, single cell migration on migrasome-mimetic trails, and OMV-mediated neutrophil swarming. LEVA will enable rapid advancements in the study of matrix- and surface-bound EVs and other particles, and should encourage researchers from many disciplines to create novel diagnostic, biomimetic, immunoengineering, and therapeutic screening assays.

Systematic Review of Intralesional Therapies for Cutaneous Warts.

Intralesional therapies are used for recalcitrant warts, but no Food and Drug Administration-approved treatment exists nor is there consensus regarding the most efficacious therapy. Therefore, this systematic review aims to summarize efficacy and adverse events reported in 62 randomized controlled trials (RCTs) of intralesional therapies for cutaneous warts. The most studied intralesional therapies included measles, mumps, rubella (MMR) vaccine (n = 24 studies), purified protein derivative (PPD) (n = 19 studies), vitamin D3 (n = 15 studies), and Candida antigen (n = 14 studies). Most studies included adult and pediatric patients or adults alone, with only 4 studies on pediatric patients alone. MMR vaccine was the most studied treatment (n = 853 patients). MMR had a complete response rate of 27-90%. The next most common treatment, PPD, had a complete response rate of 45-87%. Other treatments included Candida antigen and vitamin D3, with complete response rates of 25-84% and 40-96%, respectively. The most frequent side effects were injection-site reactions and flu-like symptoms. This systematic review represents a useful summary of intralesional therapy RCTs for clinician reference. This study also highlights the lack of large multi-institutional RCTs, despite many patients being treated for this widespread problem.

Impact of an Area Agency on Aging pharmacist-led Community Care Transition Initiative.

BACKGROUND: Rural older adults are at risk of readmissions and medication-related problems after hospital discharge. OBJECTIVES: This study aimed to compare 30-day hospital readmissions between participants and nonparticipants and describe medication therapy problems (MTPs) and barriers to care, self-management, and social needs among participants. PRACTICE DESCRIPTION: The Michigan Region VII Area Agency on Aging (AAA) Community Care Transition Initiative (CCTI) for rural older adults after hospitalization. PRACTICE INNOVATION: Eligible AAA CCTI participants were identified by an AAA community health worker (CHW) trained as a pharmacy technician. Eligibility criteria were Medicare insurance; diagnoses at risk of readmission; length of stay, acuity of admission, comorbidities, and emergency department visits score more than 4; and discharge to home from January 2018 to December 2019. The AAA CCTI included a CHW home visit, telehealth pharmacist comprehensive medication review (CMR), and follow-up for up to 1 year. EVALUATION METHODS: A retrospective cohort study examined the primary outcomes of 30-day hospital readmissions and MTPs, categorized by the Pharmacy Quality Alliance MTP Framework. Primary care provider (PCP) visit completion, barriers to self-management, health, and social needs were collected. Descriptive statistics, Mann-Whitney U, and chi-square analyses were used. RESULTS: Of 825 eligible discharges, 477 (57.8%) enrolled in the AAA CCTI; differences in 30-day readmissions between participants and nonparticipants were not statistically significant (11.5% vs. 16.1%, P = 0.07). More than one-third of participants (34.6%) completed their PCP visit within 7 days. MTPs were identified in 76.1% of the pharmacist visits (mean MTP 2.1 [SD 1.4]). Adherence (38.2%) and safety-related (32.0%) MTPs were common. Physical health and financial issues were barriers to self-management. CONCLUSION: AAA CCTI participants did not have lower hospital readmission rates. The AAA CCTI identified and addressed barriers to self-management and MTPs in participants after the care transition home. Community-based, patient-centered strategies to improve medication use and meet rural adults' health and social needs after care transitions are warranted.

Ambulatory Erector Spinae Plane Continuous Nerve Catheter for Acute Pain Management Following Rib Resection for Slipping Rib Syndrome in an Adolescent: A Case Report.

Continuous regional analgesia techniques for ambulatory management of postoperative thoracic and abdominal wall pain are limited. We report the placement of an erector spinae plane (ESP) catheter in a pediatric patient who underwent rib resection for slipping rib syndrome and was discharged on postoperative day 1 with an elastomeric pump for continued regional analgesia in the ambulatory setting. The patient required minimal opioids while the catheter was in place and experienced a functional level that surpassed her preoperative state. Ambulatory ESP peripheral nerve catheters are a feasible and potentially effective option for the treatment of acute postsurgical pain in children.

Infiltration Between Popliteal Artery and Capsule of the Knee Block to Augment Continuous Femoral Nerve Catheter for Adolescent Anterior Cruciate Ligament Reconstruction: A Case Series.

Infiltration between popliteal artery and capsule of the knee (IPACK) is a novel technique that can provide additional analgesic relief, although there are no studies to date in the adolescent population. In 3 adolescent patients undergoing anterior cruciate ligament surgery, IPACK block augmented continuous femoral nerve block by providing posterior knee analgesia with no or only minimal opioid needs in the post-anesthesia care unit and did not produce sciatic motor weakness.

Reproducibility of aortic valve calcification scoring with computed tomography - An interplatform analysis.

BACKGROUND: To investigate whether aortic valve calcification (AVC) scoring performed with different workstation platforms generates comparable and thus software-independent results. METHODS: In this IRB-approved retrospective study, we included 100 consecutive patients with symptomatic aortic stenosis undergoing CT prior to transcatheter aortic valve implantation. Two independent observers performed AVC scoring on non-enhanced images with commercially available software platforms of four vendors (GE, Philips, Siemens, 3mensio). Gender-specific Agatston score cut-off values were applied according to current recommendations to assign patients to different likelihood categories of aortic stenosis (unlikely to very likely). Comparative analysis of Agatston scores between the four platforms were performed by using Kruskal-Wallis analysis, Spearman rank correlation, linear regression analysis, and Bland-Altman analysis. Differences in category assignment were compared using Fisher's exact test and Cohen's kappa. RESULTS: For both observers, each workstation platform produced slightly different numeric AVC Agatston scores, however, without statistical significance (p = 0.96 and p = 0.98). Excellent correlation was found between platforms, with r = 0.991-0.996 (Spearman) and r2 = 0.981-0.992 (regression analysis) for both observers. Bland-Altman analyses revealed small mean differences with narrow limits of agreement between platforms (mean differences: 6 ±â€¯128 to 100 ±â€¯179), for inter-observer (mean differences: 1 ±â€¯43 to 12 ±â€¯70), and intra-observer variability (mean differences: 9 ±â€¯42 to 20 ±â€¯96). Observer 1 assigned 11 (kappa: 0.85-0.97) and observer 2 assigned 10 patients (kappa: 0.88-0.95) to different likelihood groups of severe aortic stenosis with at least one platform. Overall, there was no significant difference of likelihood assignment between platforms (p = 0.98 and p = 1.0, respectively). CONCLUSION: While absolute values differ slightly, common commercially available software platforms produce comparable results for AVC scoring, which indicates software-independence of the method.

Massive Hemorrhage From Suspected Iatrogenic Uterine Rupture.

BACKGROUND: Intrauterine balloon tamponade is recommended for refractory postpartum hemorrhage resulting from atony, but few studies have assessed complications associated with placement. CASE: A 39-year-old woman, gravida 4 para 1, with posterior placenta previa and suspected placenta accreta had a postpartum hemorrhage after a scheduled cesarean delivery. An intrauterine balloon tamponade device was easily placed transcervically; however, the patient required additional analgesia for constant severe stabbing pain worsened on examination. Three hours after placement, the balloon was expelled from the cervix, resulting in 1,500 mL of fresh blood and clot. Emergent exploratory laparotomy identified a uterine rupture inferior and lateral to the hysterotomy site. CONCLUSION: Intrauterine balloon tamponade may contribute to iatrogenic uterine rupture and should be considered in patients with refractory hemorrhage, hemodynamic instability, or severe pain despite analgesia.

Off the shelf T cell therapies for hematologic malignancies.

Adoptive transfer of autologous CAR-T cells can induce durable remissions in patients with relapsed/refractory hematologic malignancies. However, multiple challenges exist for manufacturing CAR-T cells from patients with advanced disease including inability to manufacture a product, disease progression or death while waiting for the CAR-T product to be available, and heterogeneity among autologous CAR-T products that contributes to unpredictable and variable clinical activity. Healthy donor T cells can provide a source for production of universal CAR-T cells when combined with gene editing to prevent expression of endogenous TCRs and avoid generation of GvHD in HLA mismatched recipients. Additional gene edits can be included to impart resistance to immunosuppression or improve trafficking to tumor sites. Recent advances in cell manufacturing and analytics technology can provide for consistent batch to batch manufacturing of gene edited allogeneic CAR-T cells in sufficient quantity to treat thousands of patients when needed as off the shelf products.

Evaluation of CSF and plasma biomarkers of brain melanocortin activity in response to caloric restriction in humans.

The melanocortin neuronal system, which consists of hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, is a leptin target that regulates energy balance and metabolism, but studies in humans are limited by a lack of reliable biomarkers to assess brain melanocortin activity. The objective of this study was to measure the POMC prohormone and its processed peptide, ß-endorphin (ß-EP), in cerebrospinal fluid (CSF) and AgRP in CSF and plasma after calorie restriction to validate their utility as biomarkers of brain melanocortin activity. CSF and plasma were obtained from 10 lean and obese subjects after fasting (40 h) and refeeding (24 h), and from 8 obese subjects before and after 6 wk of dieting (800 kcal/day) to assess changes in neuropeptide and hormone levels. After fasting, plasma leptin decreased to 35%, and AgRP increased to 153% of baseline. During refeeding, AgRP declined as leptin increased; CSF ß-EP increased, but POMC did not change. Relative changes in plasma and CSF leptin were blunted in obese subjects. After dieting, plasma and CSF leptin decreased to 46% and 70% of baseline, CSF POMC and ß-EP decreased, and plasma AgRP increased. At baseline, AgRP correlated negatively with insulin and homeostasis model assessment (HOMA-IR), and positively with the Matsuda index. Thus, following chronic calorie restriction, POMC and ß-EP declined in CSF, whereas acutely, only ß-EP changed. Plasma AgRP, however, increased after both acute and chronic calorie restriction. These results support the use of CSF POMC and plasma AgRP as biomarkers of hypothalamic melanocortin activity and provide evidence linking AgRP to insulin sensitivity.

Pseudoangiomatous Stromal Hyperplasia on Core Needle Biopsy Does Not Require Surgical Excision.

Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon, benign localized fibrotic lesion. Historically, PASH has been difficult to differentiate from angiosarcoma. This difficulty has led to recommendations of surgical excision. We sought to identify the incidence of upgraded pathology to atypia or malignancy on surgical excisional biopsy after identification of PASH on core needle biopsy (CNB). A 5-year retrospective review at a single institution was conducted including all cases of PASH confirmed on CNB. The data set was divided into patients who underwent excisional biopsy and those followed only by imaging. Primary end points included the incidence of subsequent malignancy or high-risk pathology on histologic analysis or the presentation of suspicious imaging. Thirty-seven patients were reviewed, 19 (51.4%) underwent surgical excision and 18 (48.6%) were followed with imaging alone. A palpable mass was noted in 36.8 per cent of patients in the excisional group versus 5.6 per cent in the imaging group (P = 0.02). The median follow-up for the excisional and imaging groups were 43 and 35 months, respectively (P = 0.85). The 95 per cent confidence interval for the presence of malignancy was 0 to 9.4 per cent. Although further characterization of PASH is needed, our data support using CNB with follow-up imaging as a safe alternative to excisional biopsy in the absence of symptoms or other clinical factors. However, further research in this area is needed.

Evaluation of pulmonary nodules and infection on chest CT with radiation dose equivalent to chest radiography: Prospective intra-individual comparison study to standard dose CT.

PURPOSE: To compare prospectively, in patients undergoing chest computed tomography (CT) for pulmonary-nodules or infection, image-quality and accuracy of standard dose (SD) and reduced dose (RD) CT with tin-filtration. MATERIAL AND METHODS: This IRB-approved study included 100 consecutive patients (36 female;median age 56 years) referred for follow-up of pulmonary-nodules (n=43) or suspicion of infection (n=57) undergoing single-energy CT with SD and RD using tin-filtration at 100 kVp (CTDIvol 2.47 mGy and 0.07 mGy, respectively). Images were reconstructed with advanced modeled iterative reconstruction (ADMIRE) at strength 3 and 5. Image-noise was measured. Two independent readers evaluated nodules and pulmonary-infection. SD CT served as reference standard. RESULTS: No significant difference was found in noise between RD with ADMIRE5 and SD with ADMIRE3 (118HU ± 14 vs. 120HU ± 17; p=0.08). Sensitivity for detection of atelectasis and interstitial lung changes was higher in images reconstructed with ADMIRE5 (93% and 88%; respectively) than in those reconstructed with ADIMRE3 (77% and 78%; respectively). Sensitivity for detection of consolidations was 90% for ADMIRE3 and 89% for ADMIRE5. Sensitivity for nodule detection was 71% for ADMIRE3 and 81% for ADMIRE5. Specificity for detection of atelectasis and interstitial lung changes was 99% and 96% with ADMIRE5 and 99% and 96% with ADMIRE3. Specificity for detection of consolidations was 99% for ADMIRE3 and 5. Specificity for detection of nodules was 87% for both ADMIRE3 and 5. CONCLUSION: Chest CT with a radiation dose equivalent to conventional radiography is feasible and allows for detection of pulmonary infection with high sensitivity, whereas the accuracy for detecting nodules is only moderate.

Preserved Insulin Secretory Capacity and Weight Loss Are the Predominant Predictors of Glycemic Control in Patients With Type 2 Diabetes Randomized to Roux-en-Y Gastric Bypass.

Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA1c at 1 year after RYGB. ß-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA1c in both groups, independent of weight loss. Weight loss and preserved ß-cell function both predominantly determine the greatest glycemic benefit after RYGB.

The sum of many parts: potential mechanisms for improvement in glucose homeostasis after bariatric surgery.

Bariatric surgery has emerged as the most durably effective treatment of type 2 diabetes (DM). However, the mechanisms governing improvement in glucose homeostasis have yet to be fully elucidated. In this review we discuss the various types of surgical interventions and the multitude of factors that potentially mediate the effects on glycemia, such as altered delivery of nutrients to the distal ileum, duodenal exclusion, gut hormone changes, bile acid reabsorption, and amino acid metabolism. Accumulating evidence that some of these changes seem to be independent of weight loss questions the rationale of using body mass index as the major indication for surgery in diabetic patients. Understanding the complex mechanisms and interactions underlying improved glycemic control could lead to novel therapeutic targets and would also allow for greater individualization of therapy and optimization of surgical outcomes.

Age-based difference in activation markers of coagulation and fibrinolysis in extracorporeal membrane oxygenation.

OBJECTIVE: Coagulation system activation in extracorporeal membrane oxygenation results in hemostatic derangements. Thrombin generation markers like prothrombin fragment 1+2 and thrombin-antithrombin complex are sensitive markers of hypercoagulability. Plasmin-antiplasmin complex is a sensitive marker for fibrinolysis. D-dimers reflect thrombin generation and fibrinolysis. The aim was to identify the extent of hemostasis activation during extracorporeal membrane oxygenation by measuring thrombin-antithrombin complex, prothrombin fragment 1+2, plasmin-antiplasmin complex, and D-dimer. DESIGN: Prospective cohort study. SETTING: Tertiary care academic center. PATIENTS: Children placed on extracorporeal membrane oxygenation from April 2011 to January 2013. INTERVENTIONS: Prothrombin fragment 1+2, thrombin-antithrombin complex, plasmin-antiplasmin complex, and D-dimer were measured on days 1 and 5 of extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Data presented as median (interquartile range); nonparametric tests were done using SPSS. Twenty-nine children (52% < 30 d old [neonates], median extracorporeal membrane oxygenation length 151 hr) were studied. Complications included thrombosis in 14%, bleeding in 45%, and thrombosis and bleeding together in 10%. Thrombin-antithrombin complex, prothrombin fragment 1+2, plasmin-antiplasmin complex, and D-dimer levels were high on day 1 and remained increased on extracorporeal membrane oxygenation. In neonates, all levels were higher on day 5 compared with day 1: thrombin-antithrombin complex (55.6 µg/L [30.7-76.0] vs 18.7 µg/L [10.9-34.6]; p = 0.03), prothrombin fragment 1+2 (2,038 pmol/L [1,093-4,018.5] vs 377.5 pmol/L [334.3-1,103.0]; p = 0.00), plasmin-antiplasmin complex (2,160 µg/L [786-3,090] vs 398 µg/L [296.8-990.8]; p = 0.00), and D-dimer (3.0 µg/mL [1.9-11.5] vs 1.5 µg/mL [0.6-2.9]; p = 0.01). Thrombin-antithrombin complex, prothrombin fragment 1+2, plasmin-antiplasmin complex, and D-dimer levels did not correlate with anti-Xa activity or heparin dose. In bleeders older than 30 days, plasmin-antiplasmin complex stayed elevated on day 5, but in patients with no bleeding complications, plasmin-antiplasmin level showed a declining trend. In neonates, plasmin-antiplasmin levels increased over the course of extracorporeal membrane oxygenation irrespective of bleeding. CONCLUSION: Despite our best efforts at adequate anticoagulation with unfractionated heparin, neonates showed persistent increase in coagulation activation on extracorporeal membrane oxygenation. Fibrinolysis activation may contribute to bleeding in patients older than 30 days. Different anticoagulation protocols should be individualized based on age.

Room-temperature chemoselective reduction of nitro groups using non-noble metal nanocatalysts in water.

Purely aqueous-phase chemoselective reduction of a wide range of aromatic and aliphatic nitro substrates has been performed in the presence of inexpensive Ni- and Co-based nanoparticle catalysts using hydrazine hydrate as a reducing agent at room temperature. Along with the observed high conversions and selectivities, the studied nanoparticle catalysts also exhibit a high tolerance to other highly reducible groups present in the nitro substrates. The development of these potential chemoselective reduction catalysts also provides a facile route for the synthesis of other industrially important fine chemicals or biologically important compounds, where other highly reducible groups are present in close proximity to the targeted nitro groups.

SLIPTA e-Tool improves laboratory audit process in Vietnam and Cambodia.

BACKGROUND: The Stepwise Laboratory Quality Improvement Process Towards Accreditation (SLIPTA) checklist is used worldwide to drive quality improvement in laboratories in developing countries and to assess the effectiveness of interventions such as the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme. However, the paper-based format of the checklist makes administration cumbersome and limits timely analysis and communication of results. DEVELOPMENT OF E-TOOL: In early 2012, the SLMTA team in Vietnam developed an electronic SLIPTA checklist tool. The e-Tool was pilot tested in Vietnam in mid-2012 and revised. It was used during SLMTA implementation in Vietnam and Cambodia in 2012 and 2013 and further revised based on auditors' feedback about usability. OUTCOMES: The SLIPTA e-Tool enabled rapid turn-around of audit results, reduced workload and language barriers and facilitated analysis of national results. Benefits of the e-Tool will be magnified with in-country scale-up of laboratory quality improvement efforts and potential expansion to other countries.

A novel CsrA titration mechanism regulates fimbrial gene expression in Salmonella typhimurium.

A hierarchical control of fimbrial gene expression limits laboratory grown cultures of Salmonella enterica serovar typhimurium (S. typhimurium) to the production of type I fimbriae encoded by the fimAICDHF operon. Here we show that an unlikely culprit, namely the 5'-untranslated region (5'-UTR) of a messenger (m)RNA, coordinated the regulation. Binding of CsrA to the 5'-UTR of the pefACDEF transcript was required for expression of plasmid-encoded fimbriae. The 5'-UTR of the fimAICDHF transcript cooperated with two small untranslated RNAs, termed CsrB and CsrC, in antagonizing the activity of the RNA binding protein CsrA. Through this post-transcriptional mechanism, the 5'-UTR of the fimAICDHF transcript prevented production of PefA, the major structural subunit of plasmid-encoded fimbriae. This regulatory mechanism limits the costly expression of plasmid-encoded fimbriae to host environments in a mouse model. Collectively, our data suggest that the 5'-UTR of an mRNA coordinates a hierarchical control of fimbrial gene expression in S. typhimurium.