bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of chimeric antigen receptor-T cells in the treatment of B cell lymphoma: a systematic review and meta-analysis
Authors: Zheng Xiao-Hong , Zhang Xi-You , Dong Qian-Qian , Chen Feng , Yang Shou-Bo , Li Wen-Bin
Published: December 2019

Background

Conventional treatment has limited efficacy in relapsed/refractory B-cell lymphoma. Since chimeric antigen receptor T-cell (CAR-T) technology has shown high safety and results in high remission rates, we investigated its efficacy and safety in B-cell lymphoma treatment and analyzed potential affecting factors to provide evidence for therapeutic strategies and applications.

Methods

We searched databases including PubMed, Embase, and Cochrane up to July 2019. Meta-analysis 1 was conducted to study the efficacy of CAR-T cell for treating B-cell lymphoma, measuring the response rate and complete remission rate as outcomes. Sub-group analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, and conditioning chemotherapy. Meta-analysis 2 was undertaken on the safety of the treatment with the incidence rate of toxicity (cytokine-releasing syndrome [CRS], neurotoxicity) as an outcome.

Results

Seventeen studies were included in the systematic review and meta-analysis. It was found that CAR-T cells had good therapeutic effects in the following cases: B-cell lymphoma (patients ≥65 years old); diffuse large B-cell lymphoma pathological type; patients with treatment target antigen other than CD19; patients treated with co-stimulatory molecules other than CD28, including 4-1BB+CD28 or 4-1BB; and patients treated with cyclophosphamide/fludarabine pre-treatment protocol conditioning chemotherapy. Although the CRS and neurotoxicity incidences were high, most were reversible with minimal risk of death.

Conclusion

CAR-T cell treatment is safe for clinical application; however, toxicity effects should be monitored.
Vasectomy: An Opportunity for Obstetricians and Gynecologists
Authors: PATEL JASMINE , NGUYEN BRIAN T.
Published: December 2019

Vasectomy is a safe, effective, and cost-effective contraceptive method, with a failure rate lower than that of female sterilization. Nevertheless, vasectomy is underutilized—only 6% of American women rely on vasectomy. Access to vasectomy may be limited by provider advocacy and availability. Obstetricians and gynecologists can increase both the acceptability of and access to this method if adequately trained to counsel about and provide the procedure. Although some concerns may persist surrounding obstetricians and gynecologists performing a vasectomy, increasing the availability and uptake of vasectomy avoids unnecessary surgical risks for female patients and promotes reproductive justice via shared contraceptive responsibility.
When Should Prophylactic Oophorectomy Be Recommended at the Time of Elective Hysterectomy?
Authors: HUBER-KEENER KATHRYN J. , PEARLMAN MARK D.
Published: December 2019

Gynecologists are frequently confronted with the decision of when to recommend oophorectomy at the time of an elective hysterectomy. When deciding if oophorectomy should be recommended, first a careful history and risk assessment must be performed to determine if a patient is a candidate for a risk-reducing oophorectomy. If the patient does not have a hereditary ovarian cancer risk, then it is recommended the surgeon carefully consider the implications of ovarian removal on the health of their patient. This review covers the potential benefits and risks of prophylactic oophorectomy and offers a decision aid for when to recommend this procedure.
FACTORS ASSOCIATED WITH THE USE OF 360-DEGREE LASER RETINOPEXY DURING PRIMARY VITRECTOMY WITH OR WITHOUT SCLERAL BUCKLE FOR RHEGMATOGENOUS RETINAL DETACHMENT AND IMPACT ON SURGICAL OUTCOMES (PRO STUDY REPORT NUMBER 4)
Authors: Wang Jay C. , Ryan Edwin H. , Ryan Claire , Kakulavarapu Srividya , Mardis Patrick J. , Rodriguez Marianeli , Stefater James A. , Forbes Nora J. , Gupta Omesh , Capone Antonio , Emerson Geoffrey G. , Joseph Daniel P. , Eliott Dean , Yonekawa Yoshihiro ,   For the Primary Retinal Detachment Outcomes (PRO) Study Group
Published: December 2019

Purpose:

To determine factors associated with 360-degree laser retinopexy (360LR) during primary pars plana vitrectomy ± scleral buckle for rhegmatogenous retinal detachment (RRD) and its impact on surgical outcomes.

Methods:

This is a multicenter, retrospective, interventional study. Patients undergoing primary pars plana vitrectomy or primary pars plana vitrectomy + scleral buckle for noncomplex primary RRD in 2015 were evaluated. Primary outcomes were single surgery anatomical success (SSAS) and final anatomical success. Secondary outcomes included final logarithm of the minimum angle of resolution visual acuity, epiretinal membrane formation, cystoid macular edema development, and number of subsequent vitrectomies. Multivariate regressions were performed.

Results:

Two thousand two hundred and forty-eight surgeries by 61 surgeons were included; of which, 516 underwent 360LR. Younger age (P = 0.01), more retinal breaks (P = 0.01), more extensive RRD (P < 0.001), and surgeon ID (P < 0.001) were significantly associated with 360LR. No significant associations between 360LR and single surgery anatomical success (P = 0.44), epiretinal membrane formation (P = 0.14), cystoid macular edema development (P = 0.28), or number of subsequent vitrectomies (P = 0.41) were found. Controlling for case complexity, 360LR was significantly associated with lower final anatomical success (P < 0.001) and worse final logarithm of the minimum angle of resolution visual acuity (P < 0.001).

Conclusion:

Multiple factors influenced whether 360LR was performed during primary pars plana vitrectomy ± scleral buckle for RRD. However, 360LR was not associated with improved surgical outcomes, and in fact, it may be associated with poorer outcomes.
Extracorporeal support to achieve lung-protective and diaphragm-protective ventilation
Authors: Spinelli Elena , Carlesso Eleonora , Mauri Tommaso
Published: December 2019

Purpose of review

Extracorporeal support allows ultraprotective controlled and assisted ventilation, which can prevent lung and diaphragm injury. We focused on most recent findings in the application of extracorporeal support to achieve lung protection and diaphragm- protection, as well as on relevant monitoring.

Recent findings

A recent randomized trial comparing the efficacy of extracorporeal support as a rescue therapy to conventional protective mechanical ventilation was stopped for futility but post hoc analyses suggested that extracorporeal support is beneficial for patients with very severe acute respiratory distress syndrome. However, the optimal ventilation settings during extracorporeal support are still debated. It is conceivable that they should enable the highest amount of CO2 removal with lowest mechanical power.

Extracorporeal CO2 removal can minimize acidosis and enable the use of ultra-protective lung ventilation strategies when hypoxemia is not a major issue. Moreover, it can protect lung and diaphragm function during assisted ventilation through control of the respiratory effort.

Lung mechanics, gas exchange, diaphragm electrical activity, ultrasound, electrical impedance tomography could be integrated into clinical management to define lung and diaphragm protection and guide personalized ventilation settings.

Technological improvement and the latest evidence indicate that extracorporeal support may be an effective tool for lung and diaphragm protection.
Effects of 2 Forms of Practice Facilitation on Cardiovascular Prevention in Primary Care
Authors: Persell Stephen D. , Liss David T. , Walunas Theresa L. , Ciolino Jody D. , Ahmad Faraz S. , Brown Tiffany , French Dustin D. , Hountz Randy , Iversen Karen , Lindau Stacy T. , Lipiszko Dawid , Makelarski Jennifer A. , Mazurek Kathryn , Murakami Linda , Peprah Yaw , Potempa Jennifer , Rasmussen Luke V. , Wang Andrew , Wang Jesi , Yeh Chen , Kho Abel N.
Published: December 2019

Background:

Effective quality improvement (QI) strategies are needed for small practices.

Objective:

The objective of this study was to compare practice facilitation implementing point-of-care (POC) QI strategies alone versus facilitation implementing point-of-care plus population management (POC+PM) strategies on preventive cardiovascular care.

Design:

Two arm, practice-randomized, comparative effectiveness study.

Participants:

Small and mid-sized primary care practices.

Interventions:

Practices worked with facilitators on QI for 12 months to implement POC or POC+PM strategies.

Measures:

Proportion of eligible patients in a practice meeting “ABCS” measures: (Aspirin) Aspirin/antiplatelet therapy for ischemic vascular disease, (Blood pressure) Controlling High Blood Pressure, (Cholesterol) Statin Therapy for the Prevention and Treatment of Cardiovascular Disease, and (Smoking) Tobacco Use: Screening and Cessation Intervention, and the Change Process Capability Questionnaire. Measurements were performed at baseline, 12, and 18 months.

Results:

A total of 226 practices were randomized, 179 contributed follow-up data. The mean proportion of patients meeting each performance measure was greater at 12 months compared with baseline: Aspirin 0.04 (95% confidence interval: 0.02–0.06), Blood pressure 0.04 (0.02–0.06), Cholesterol 0.05 (0.03–0.07), Smoking 0.05 (0.02–0.07); P<0.001 for each. Improvements were sustained at 18 months. At 12 months, baseline-adjusted difference-in-differences in proportions for the POC+PM arm versus POC was: Aspirin 0.02 (−0.02 to 0.05), Blood pressure −0.01 (−0.04 to 0.03), Cholesterol 0.03 (0.00–0.07), and Smoking 0.02 (−0.02 to 0.06); P>0.05 for all. Change Process Capability Questionnaire improved slightly, mean change 0.30 (0.09–0.51) but did not significantly differ across arms.

Conclusion:

Facilitator-led QI promoting population management approaches plus POC improvement strategies was not clearly superior to POC strategies alone.
Depression and Uptake of Oral Anticoagulation Therapy in Patients With Atrial Fibrillation
Authors: Fenger-Grøn Morten , Vestergaard Claus H. , Frost Lars , Davydow Dimitry S. , Parner Erik T. , Christensen Bo , Ribe Anette R.
Published: December 2019

Background:

Oral anticoagulation therapy (OAT) in patients with atrial fibrillation (AF) is a highly important preventive intervention, perhaps especially in those with comorbid depression, who have a worse prognosis. However, OAT may pose particular challenges in depressed patients.

Objectives:

To assess whether AF patients with depression have lower OAT uptake.

Methods:

This nationwide register-based 2005–2016 cohort study of all Danes with AF and OAT indication (CHA2DS2VASc stroke risk score ≥2) assessed OAT initiation within 90 days in those with incident AF (N=147,162) and OAT prevalence in those with prevalent AF (N=192,656). The associations of depression with both outcomes were estimated in regression analyses with successive adjustment for socioeconomic characteristics and somatic and psychiatric comorbidity.

Results:

Comorbid depression was significantly associated with lower frequency of OAT initiation in incident AF patients {adjusted proportion differences (aPDs): −6.6% [95% confidence interval (CI), −7.4 to −5.9]} and lower prevalence of OAT [aPD: −4.2% (95% CI, −4.7 to −3.8)] in prevalent AF patients. Yet, the OAT uptake increased substantially during the period, particularly in depressed patients [aPD for OAT prevalence in 2016: −0.8% (95% CI, −1.6 to −0.0)].

Conclusions:

Comorbid depression was associated with a significantly lower OAT uptake in patients with AF, which questions whether depressed patients receive sufficient support to manage this consequential cardiac condition. However, a substantial increase in the overall OAT uptake and a decrease of the depression-associated deficit in OAT were seen over the period during which OAT was developed through the introduction of new oral anticoagulation therapy.
Technology and precision therapy delivery in childhood cancer
Authors: Tydings Caitlin , Kim AeRang
Published: December 2019

Purpose of review

The purpose of this review is to describe current advances in pediatric precision therapy through innovations in technology and engineering. A multimodal approach of chemotherapy, surgery and/or radiation therapy has improved survival outcomes for pediatric cancer but with significant early and late toxicities. The pediatric population is particularly vulnerable given their age during treatment. Advances in precision interventions discussed include image guidance, ablation techniques, radiation therapy and novel drug delivery mechanisms that offer the potential for more targeted approach approaches with improved efficacy while limiting acute and late toxicities.

Recent findings

Image-guidance provides improved treatment planning, real time monitoring and targeting when combined with ablative techniques and radiation therapy. Advances in drug delivery including radioisotopes, nanoparticles and antibody drug conjugates have shown benefit in adult malignancies with increasing use in pediatrics. These therapies alone and combined may lead to augmented local antitumor effect while sparing systemic exposure and potentially limiting early and late toxicities.

Pediatric cancer medicine often requires a multimodal approach, each with early and late toxicities. Precision interventions and therapies offer promise for more targeted approaches in treating pediatric malignancies and require further investigation to determine long-term benefit.
Severe, Fatal Methotrexate-related Neurotoxicity in 2 Adolescent Patients With ALL
Authors: Dabagh Sarah , David Henry , Young Sarah , Doan Andrew , Bhojwani Deepa
Published: December 2019

Neurotoxicity is a well-documented adverse effect of methotrexate in the treatment of pediatric cancers. The spectrum of symptoms is broad, can include stroke-like episodes and seizures, and classically resolves within days. The majority of patients tolerate subsequent doses without recurrence of symptoms. The population of patients who experience persistent and irreversible neurologic symptoms is poorly described, with the existing literature suggestive of a relationship with radiation therapy. The authors present a case series of 2 patients with pre-B-cell acute lymphoblastic leukemia who developed severe and ultimately fatal methotrexate-related neurotoxicity in the absence of radiation.
A Novel Use of Long-Term Subcutaneous Hydration Therapy for a Pediatric Patient With Intestinal Failure and Chronic Dehydration
Authors: Wheaton Taylor , Schlichting Christine , Madhavarapu Swetha , Koncicki Monica L.
Published: December 2019

Long-term subcutaneous hydration has not been described in pediatrics. A case of a 4-year-old born prematurely with subsequent intestinal failure, large vessel thrombi, and repeated central line-associated bloodstream infections prompting catheter removal is discussed. Chronic dehydration ensued and was managed with long-term subcutaneous fluid infusions with no serious complications.
Analysis of Intestinal Metaplasia Without Dysplasia in the Urinary Bladder Reveal Only Rare Mutations Associated With Colorectal Adenocarcinoma
Authors: Amin Ali , Murati-Amador Belkiss , Lombardo Kara A. , Jackson Cynthia L. , Grada Zakaria , Palsgrove Doreen N. , Matoso Andres
Published: December 2019

Intestinal metaplasia (IM) is a rare finding in urinary bladder specimens. It is unclear whether IM without dysplasia is a precursor of malignancy in the urinary system. We retrospectively selected 9 cases of IM of bladder (1 case harboring high-grade dysplasia), and performed mutation analysis for genes frequently mutated in colon cancer including BRAF, APC, KRAS, MET, NRAS, PIK3CA, CTNNB1, FBXW7, and TP53 using validated clinical tests. Control groups included 7 colonic tubular adenomas, 10 high-grade papillary urothelial carcinomas. One IM case revealed an APC mutation and another showed an NRAS mutation. Among the tubular adenomas cases, 6 of 7 (85.7%) harbored KRAS mutations and 3 of 7 (42%) APC mutations. Among urothelial carcinomas cases, 1 revealed a KRAS mutation, 2 had PIK3CA mutations, and all cases were negative for APC mutations. Clinical follow-up for the IM patients was available with a median follow-up of 70 months. One patient—without any mutation in the genes investigated—developed invasive bladder adenocarcinoma with intestinal differentiation with metastasis to the liver and lung. Neither of the 2 patients harboring mutations developed any malignancy. In conclusion, a minority of cases with IM without dysplasia bear mutations in the genes commonly associated with colonic adenocarcinoma, suggesting a premalignant potential for such lesions possibly following the classic multistep chromosomal instability pathway of carcinogenesis. A larger cohort of patients with longer follow-up is needed to better establish whether close follow-up is warranted for mutation-harboring IM of the bladder.
Assessment of HPV Risk Type in H&E-stained Biopsy Specimens of the Cervix by Microscopy Image Analysis
Authors: Konstantinou Christos , Kostopoulos Spiros , Glotsos Dimitris , Kalatzis Ioannis , Asvestas Pantelis , Ravazoula Panagiota , Michail George , Cavouras Dionisis , Sakellaropoulos George
Published: December 2019

Objectives:

The objective of this study was (a) to identify, by computer processing of digitized images of hematoxylin and eosin (H&E)-stained biopsy material of the cervix, differences in the structure of nuclei between high-risk (HR) and low-risk (LR) human papillomavirus virus (HPV) types and (b) to assess the HPV risk type by designing a decision-support system (DSS).

Materials and Methods:

Clinical material comprised H&E-stained biopsies from squamous intraepithelial lesions of 55 patients with polymerase chain reaction-verified HR-HPV (26 patients) or LR-HPV (29 patients) infection. From each patient’s biopsy specimen, we digitized 1 region of interest, guided by the expert physician. After the segmentation of nuclei, we quantified from each nucleus 77 textural and morphologic features. We represented each patient by a 77-feature vector, the feature means of all nuclei, and we created 2 classes for HR-HPV and LR-HPV types. We carried out (a) a statistical analysis to determine features with statistically significant differences between the 2 classes and (b) a discriminant analysis, by designing a DSS, to estimate the HPV risk type.

Results:

Statistical analysis revealed 40 features with between-classes statistically significant differences and discriminant analysis showed that the best DSS design achieved a high accuracy of about 93% in identifying the HPV risk type on data not used in the design of the DSS.

Conclusions:

Nuclei of HR-HPV types were of higher intensity, contained larger structures, had higher edges, were coarser, rougher, had higher contrast, were larger, and attained more irregular shapes. The proposed DSS indicates that discrimination of HPV risk type from images of H&E-stained biopsy material of the cervix is promising.
Flap Reconstruction of the Hand
Authors: Wink Jason D. , Gandhi Rikesh A. , Ashley Blair , Levin L. Scott
Published: December 2019

Learning Objectives:

After studying this article, the participant should: 1. Be familiar with local, regional, and free flaps for reconstruction of the hand. 2. Be able to identify potential sources of tissue for vascularized coverage using an algorithmic approach to provide stable and functional reconstruction of the hand. 3. Recognize the controversies and complications unique to flap reconstruction of the hand.

The goal of this continuing medical education module is to provide the practicing reconstructive surgeon with a framework in which to think about reconstruction of the hand. The hand has unique functional and aesthetic characteristics that must be considered when choosing the optimal methods for reconstruction. There are a number of reliable local and regional flaps that can be used to treat the hand requiring soft-tissue coverage and/or vascularized bone graft. The “reconstructive ladder,” originally described by Mathes and Nahai, is based on the principle of using the simplest approach that adequately restores form and ideally optimizes function. In cases where the simplest techniques prove to be inadequate, local and regional flaps and, ultimately, microsurgical tissue transfer should be considered.
Initial Opioid Prescriptions Predict Continued Narcotic Use: Analysis of 24,594 Reduction Mammaplasty Patients
Authors: Merola David , Calotta Nicholas A. , Lu Zhen A. , Lifchez Scott D. , Aliu Oluseyi , Coon Devin
Published: December 2019

Background:

The objective of this study was to establish whether a particular perioperative opioid regimen was associated with a higher risk of opioid refilling in the reduction mammaplasty patient population.

Methods:

A retrospective cohort study was conducted on subjects that underwent bilateral reduction mammaplasty with no history of opioid use in the year before surgery. Patients were followed for a period of 4 months after surgery. Multivariable logistic regression was used to establish factors associated with prescription refilling. Predictive probabilities of opioid refilling, given various perioperative opioid regimens, were explored.

Results:

A total of 24,594 subjects met all criteria for inclusion in the study, 13 percent of whom demonstrated continued opioid use following surgery. The probability of refill in patients receiving 15 to 59 daily morphine milligram equivalents perioperatively was significantly lower than in those receiving less than 15 daily morphine milligram equivalents (e.g., 15 mg of codeine every 4 hours) or more than 60 daily morphine milligram equivalents (e.g., 10 mg of oxycodone every 6 hours).

Conclusions:

The probability of refilling prescription opioids is increased by nonmodifiable risk factors, such as age. However, modifiable risk factors exist as well, most notably the amount of narcotic prescribed during the perioperative period. Overprescribing was found to be common in the reduction mammaplasty patient population. Limiting outpatient opioid exposure to a range of 15 to 59 daily morphine milligram equivalents (e.g., 5 mg of hydrocodone every 6 hours) during the perisurgical period may reduce the probability that the surgeon will need to prescribe further narcotics. Further studies are needed to validate our findings.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
An Evaluation of Race Disparities in Academic Plastic Surgery
Authors: Smith Brandon T. , Egro Francesco M. , Murphy Carolyn P. , Stavros Alexander G. , Nguyen Vu T.
Published: December 2019

Background:

Academic plastic surgery has a history of underrepresentation of ethnic and racial minority groups. Recent policy shifts by national medical groups and plastic surgery societies have focused on reversing these inequalities. This study seeks to measure ethnic and racial representation at academic and leadership positions following recent changes.

Methods:

A cross-sectional study was conducted in June of 2018, measuring ethnic and racial diversity of U.S. academic plastic surgery faculty. Among faculty, career qualifications, years of experience, faculty positions, and leadership ethnicity were compared.

Results:

A total of 930 academic plastic surgeons were included in the study. Classified collectively as nonwhite, this group graduated more recently than other academic plastic surgeons (2006 versus 2001; p < 0.0001) and had greater rates of clinical fellowship attainment (OR, 1.62; 95 percent CI, 1.16 to 2.26). Nonwhite individuals were less likely to be employed in the full professor position compared with their white colleagues (OR, 0.6; 95 percent CI, 0.42 to 0.88; p = 0.0077). However, after adjustment for differences in years of postresidency experience, this disparity was no longer significant (OR, 1.06; 95 percent CI, 0.62 to 1.83; p = 0.82), indicating the importance of current cohort experience differences. Assessment of program leadership found that nonwhite chairs employed significantly more nonwhite faculty (42.5 percent versus 20.9 percent; p < 0.0001).

Conclusions:

Academic plastic surgery continues to face disparities in representation of both ethnic and racial minorities. Current inequalities are most severe at senior academic positions and may be linked to cohort experience differences along with leadership and promotion biases.
Population-Based Health Utility Assessment of Migraine Headache Symptoms before and after Surgical Intervention
Authors: Torabi Radbeh , Bourn Lynn , Veith Jacob , Wisecarver Ian , Briley Kenneth , Bartow Matthew , Austen William G. , Tessler Oren
Published: December 2019

Background:

Approximately 30 million Americans suffer from migraine headaches. The primary goals of this study are to (1) use Migraine-Specific Symptoms and Disability criteria and Migraine Headache Index to describe the symptomatic improvement following decompressive surgery for refractory migraines, and (2) use the average Migraine Headache Index preoperatively and postoperatively for health utility assessment from a healthy patient’s perspective.

Methods:

The Migraine-Specific Symptoms and Disability criteria and the Migraine Headache Index were used to characterize migraine symptoms in the authors’ patient population before and after decompressive surgery. Healthy individuals were randomized to a scenario in which they assumed either the preoperative or postoperative average patient symptom profile described by the authors’ migraine patients. Health utility assessments were used to quantify the evaluation of health states the authors’ patients experienced before and after surgical migraine therapy.

Results:

Twenty-five patients underwent surgery for migraine headaches. The Migraine-Specific Symptoms and Disability questionnaire showed a significant decrease in both frequency of headaches per month (p < 0.0001) and overall pain score (p = 0.007). The Migraine Headache Index demonstrated a statistically significant improvement (p = 0.03). Healthy individuals in the preoperative group had significantly lower utility scores compared with the postoperative group in all of the health utility assessments completed for migraine symptoms.

Conclusion:

This is the first study to use health utility assessments to attest the efficacy of decompressive therapy by demonstrating the population perspective, which perceived a significant improvement in quality of life following the surgical treatment of migraines in the authors’ patients.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Evaluation of Hydrocodone/Acetaminophen for Pediatric Laceration Repair: A Randomized Trial
Authors: Chumpitazi Corrie E. , Caviness A. Chantal , Grawe Glenda H. , Camp Elizabeth A. , Shah Manish I.
Published: December 2019

Background:

Laceration repair is a common procedure, and causes pain and distress in children. The purpose of this study was to measure the effect of hydrocodone/acetaminophen elixir in reducing both pain and anxiety in children undergoing sutured laceration repair in the emergency department.

Methods:

The authors conducted a randomized, double-blinded, placebo-controlled trial in children aged 2 to 17 years, stratified by age younger than 8 years, with topical lidocaine-treated lacerations requiring sutured repair in the emergency department. The primary outcome was pain score at 5 minutes of laceration repair. Secondary outcomes included progression to procedural sedation and anxiety scores in older children.

Results:

Eighty-five children were randomized, 43 to the hydrocodone/acetaminophen group and 42 to the placebo group. Median 5-minute pain scores in children aged 2 to 7 years were significantly lower in the medication group (5.0; interquartile range, 4.0 to 6.50) compared with the placebo group (7.0; interquartile range, 5.25 to 10.0; p = 0.01). Three patients (12 percent) in the placebo group proceeded to procedural sedation. For children aged 8 to 17 years, there was no significant difference in pain scores between the treatment (0.5; interquartile range, 0.0 to 0.1; p = 0.81) and placebo groups (0.1; interquartile range, 0.01 to 0.4) or in anxiety scores using the State-Trait Anxiety Inventory for Children.

Conclusion:

Adjuvant oral hydrocodone/acetaminophen is more effective than placebo in reducing pain in children younger than 8 years undergoing topical lidocaine–treated laceration repair, but it does not decrease pain or anxiety in older children.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Snapshot Multispectral Imaging Is Not Inferior to SPY Laser Fluorescence Imaging When Predicting Murine Flap Necrosis
Authors: Jones Glyn E. , Yoo Aran , King Victor A. , Sowa Michael , Pinson David M.
Published: December 2019

Background:

Objective assessment of tissue viability is critical to improve outcomes of cosmetic and reconstructive procedures. A widely used method to predict tissue viability is indocyanine green angiography. The authors present an alternative method that determines the relative proportions of oxyhemoglobin to deoxyhemoglobin through multispectral reflectance imaging. This affordable, hand-held device is noninvasive and may be used in clinic settings. The authors hypothesize that multispectral reflectance imaging is not inferior to indocyanine green angiography in predicting flap necrosis in the murine model.

Methods:

Reverse McFarlane skin flaps measuring 10 × 3 cm were raised on 300- to 400-g male Sprague-Dawley rats. Indocyanine green angiography and multispectral reflectance imaging was performed before surgery, immediately after surgery, and 30 minutes after surgery. Clinical outcome images acquired 72 hours after surgery were evaluated by three independent plastic surgeons. Objective data obtained immediately after surgery were compared to postsurgical clinical outcomes to determine which method more accurately predicted flap necrosis.

Results:

Nine reverse McFarlane skin flaps were evaluated 72 hours after flap elevation. Data analysis demonstrated that the 95 percent confidence intervals for the sensitivity of postoperative multispectral reflectance imaging and indocyanine green angiography imaging to predict 72-hour tissue viability at a fixed specificity of 90 percent for predicting tissue necrosis were 86.3 to 91.0 and 79.1 to 86.9, respectively.

Conclusions:

In this experimental animal model, multispectral reflectance imaging does not appear to be inferior to indocyanine green angiography in detecting compromised tissue viability. With the advantages of noninvasiveness, portability, affordability, and lack of disposables, multispectral reflectance imaging has an exciting potential for widespread use in cosmetic and reconstructive procedures.
Quality and Safety in Healthcare, Part LXII
Authors: Harolds Jay A.
Published: December 2019

Multiple national organizations promote resident wellness. The Accreditation Council for Graduate Medical Education limits work hours and sleep deprivation for residents. The Accreditation Council for Graduate Medical Education requires that residency programs take into consideration the intensity of the work, how residents are scheduled, and that residents be given reasonable time off to go to medical and dental care appointments. The Action Collaborative on Clinician Well-Being and Resilience, the National Wellness Institute, the American Medical Association, and the American College of Radiology are some of the other national organizations fighting burnout and promoting wellness.
Quantification of Perinodular Emphysema in High-risk Patients Offers No Benefit in Lung Nodule Risk-Stratification of Malignancy Potential
Authors: Amundson William H. , Swanson Eric J. , Petersen Ashley , Bell Brian J. , Hatt Charles , Wendt Chris H.
Published: December 2019

Purpose:

Pulmonary nodules, found either incidentally or on lung cancer screening, are common. Evaluating the benign or malignant nature of these nodules is costly in terms of patient risk and expense. The presence of both global and regional emphysema has been linked to increased lung cancer risk. We sought to determine whether the measurement of emphysema directly adjacent to a lung nodule could inform the likelihood of a nodule being malignant.

Materials and Methods:

Within a population of Veterans at high risk for lung cancer, 58 subjects with malignant nodules found on computerized tomographic chest scans were matched by lobe and nodule size to 58 controls. Lung densitometry was measured via determination of the low attenuation area percentage at −950 Hounsfield units (LAA950) and the Hounsfield unit (HU) value at which 15% of lung voxels have a lower lung density (Perc15), at predefined lung volumes that encompassed the nodule to evaluate both perinodular and regional lung fields. The association between measured lung density and malignancy was investigated using conditional logistic regression models, with densitometry measurements used as the primary predictor, adjusting for age alone, or age and computerized tomographic scan characteristics.

Results:

No significant differences in emphysema measurements between malignant and benign nodules were identified at lung volumes encompassing both perinodular and regional emphysema. Furthermore, emphysema quantification remained stable across lung volumes within individuals.

Conclusions:

In this study, quantifying the degree of perinodular or regional emphysema did not offer any benefit in the risk stratification of lung nodules.
Association of Perioperative Variables and the Acute Respiratory Distress Syndrome in Liver Transplant Recipients
Authors: Ripoll Juan G. , Wanta Brendan T. , Wetzel David R. , Frank Ryan D. , Findlay James Y. , Vogt Matthew N.P.
Published: December 2019

Background.

The assessment of perioperative risk factors for the development of acute respiratory distress syndrome (ARDS) has been described in various surgical populations. However, there are only limited data among patients undergoing liver transplantation (LT), particularly regarding the influence of intraoperative ventilation parameters. We sought to identify the perioperative risk factors associated with the development of ARDS in LT recipients.

Methods.

This is a single-center, retrospective cohort study of adult patients who underwent LT at a tertiary academic medical center between January 1, 2006, and January 31, 2016. Postoperative ARDS was identified using the Berlin definition. Multivariable logistic regression analysis was used to identify perioperative risk factors for ARDS.

Results.

Of 817 eligible patients who underwent an LT during the study period, 20 (2.45%) developed postoperative ARDS. In the preoperative model, ongoing dialysis (odds ratio, 6.41; P < 0.01) was identified as an independent risk factor of ARDS post-LT. A higher mean peak inspiratory pressure per increase of 1 cm H2O (odds ratio, 1.31; P < 0.01) was the only independent risk factor in the intraoperative model. Patients who developed ARDS postoperatively had significantly greater intensive care unit and hospital stay compared to non-ARDS patients (P < 0.001). There were no significant differences in the 30-day (P = 0.16) and 1-year (P = 0.51) mortality between the groups.

Conclusions.

Dialysis at the time of transplant and elevated intraoperative mean peak inspiratory pressure were associated with the development of ARDS. ARDS post LT was associated with increased intensive care unit and hospital length of stay, but not increased mortality.
Cell type prioritization in single-cell data
Authors: Skinnider Michael A. , Squair Jordan W. , Kathe Claudia , Anderson Mark A. , Gautier Matthieu , Matson Kaya J.E. , Milano Marco , Hutson Thomas H. , Barraud Quentin , Phillips Aaron A. , Foster Leonard J. , La Manno Gioele , Levine Ariel J. , Courtine Grégoire
Published: December 2019

We present a machine-learning method to prioritize the cell types most responsive to biological perturbations within high-dimensional single-cell data. We validate our method, Augur (https://github.com/neurorestore/Augur), on a compendium of single-cell RNA-seq, chromatin accessibility, and imaging transcriptomics datasets. We apply Augur to expose the neural circuits that enable walking after paralysis in response to spinal cord neurostimulation.
Neutrophil: Airway Epithelial Interactions Result in Increased Epithelial Damage and Viral Clearance during RSV Infection
Authors: Deng Yu , Herbert Jenny A. , Robinson Elisabeth , Ren Luo , Smyth Rosalind L. , Smith Claire M.
Published: December 2019

Respiratory syncytial virus (RSV) is a major cause of paediatric respiratory disease. Large numbers of neutrophils are recruited into the airways of children with severe RSV disease. It is not clear whether or how neutrophils enhance recovery from disease or contribute to its pathology.

Using anin vitromodel of the differentiated airway epithelium, we found that addition of physiological concentrations of neutrophils to RSV infected nasal cultures was associated with greater epithelial damage with lower ciliary activity, cilia loss, less tight junction expression (ZO-1) and more detachment of epithelial cells than seen with RSV infection alone. This was also associated with a decrease in infectious virus and fewer RSV positive cells in cultures after neutrophil exposure compared to pre-exposure. Epithelial damage in response to RSV infection was associated with neutrophil activation (within 1h), and neutrophil degranulation with significantly greater cellular expression of CD11b, MPO and higher neutrophil elastase and myeloperoxidase activity in apical surface medias compared to that from mock-infected AECs. We also recovered more apoptotic neutrophils from RSV infected cultures (>40%), compared to <5% in mock infected cultures after 4h.

The results of this study could provide important insights into the role of neutrophils in host response in the airway.
Optogenetic Stimulation of Pancreatic Function via Vagal Cholinergic Axons
Authors: Fontaine Arjun K. , Ramirez David G. , Littich Samuel F. , Piscopio Robert A. , Kravets Vira , Caldwell John H. , Weir Richard F. , Benninger Richard K.P.
Published: December 2019

Previous studies have demonstrated stimulation of endocrine pancreas function by vagal nerve electrical stimulation. While this increases insulin secretion; concomitant reductions in circulating glucose do not occur. A complicating factor is the non-specific nature of electrical nerve stimulation. Optogenetic tools enable high specificity in neural stimulation using cell-type specific targeting of opsins and/or spatially shaped excitation light. Here, we demonstrate light-activated stimulation of the endocrine pancreas by targeting vagal parasympathetic axons. In a mouse model expressing ChannelRhodopsin2 (ChR2) in cholinergic cells, serum insulin and glucose were measured in response to both ultrasound image-guided optical stimulation of axon terminals in the pancreas and optical stimulation of axons of the cervical vagus nerve, together with ultrasound-based measures of pancreas blood flow. Measurements were made in basal-glucose and glucose-stimulated conditions. Significant increases in plasma insulin occurred relative to controls under both pancreas and vagal stimulation, accompanying rapid reductions in glycemic levels. Additionally, a significant increase in pancreatic blood flow was measured following optical stimulation. Together, these results demonstrate the utility of in-vivo optogenetics for studying the neural regulation of endocrine pancreas function and suggest therapeutic potential for the control of insulin secretion and glucose homeostasis.
Long reads from Nanopore sequencing as a tool for animal microbiome studies
Authors: Delgado Beatriz , Serrano Magdalena , González Carmen , Bach Alex , González-Recio Oscar
Published: December 2019

In the era of bioinformatics and metagenomics, the study of the ruminal microbiome has gained considerable relevance in the field of animal breeding, since the composition of the rumen microbiota significantly impacts production and the environment. Illumina sequencing is considered the gold standard for the analysis of microbiomes, but it is limited by obtaining only short DNA sequences to analyze. As an alternative, Oxford Nanopore Technologies (ONT) has developed a new sequencing technique based on nanopores that can be carried out in the MinION, a portable device with a low initial cost which long DNA readings can be obtained with. The aim of this study was to compare the performance of both types of sequencing applied to samples of ruminal content using a similar pipeline. The ONT sequencing provided similar results to the Illumina sequencing, although it was able to classify a greater number of readings at the species level, possibly due to the increase in the read size. The results also suggest that, due to the size of the reads, it would be possible to obtain the same amount of information in a smaller number of hours. However, detection of archaeal and eukaryotic species is still difficult to accomplish due to their low abundance in the rumen compared to bacteria, suggesting different pipelines and strategies are needed to obtain a whole representation of the less abundant species in the rumen microbiota.
A novel G protein-biased and subtype selective agonist for a G protein-coupled receptor discovered from screening herbal extracts
Authors: Zhang Bingjie , Zhao Simeng , Yang Dehua , Wu Yiran , Xin Ye , Cao Haijie , Huang Xi-Ping , Cai Xiaoqing , Sun Wen , Ye Na , Xu Yueming , Peng Yao , Zhao Suwen , Liu Zhi-Jie , Zhong Guisheng , Wang Ming-Wei , Shui Wenqing
Published: December 2019

Subtype selectivity and functional bias are vital in current drug discovery for G protein-coupled receptors (GPCRs) as selective and biased ligands are expected to yield drug leads with optimal on-target benefits and minimal side-effects. However, structure-based design and medicinal chemistry exploration remain challenging in part because of highly conserved binding pockets within subfamilies. Herein, we present an affinity mass spectrometry approach for screening herbal extracts to identify active ligands of a GPCR, the 5-HT2Creceptor. Using this method, we discovered a naturally occurring aporphine 1857 that displayed strong selectivity for activating 5-HT2Cwithout activating the 5-HT2Aor 5-HT2Breceptors. Remarkably, this novel ligand exhibited exclusive bias towards G protein signaling for which key residues were identified, and it showed comparablein vivoefficacy for food intake suppression and weight loss as the anti-obesity drug, lorcaserin. Our study establishes an efficient approach to discovering novel GPCR ligands by exploring the largely untapped chemical space of natural products.
TNF deficiency dysregulates inflammatory cytokine production leading to lung pathology and death during respiratory poxvirus infection
Authors: Kels Ma. Junaliah Tuazon , Ng Esther , Al Rumaih Zahrah , Pandey Pratikshya , Ruuls Sigrid R. , Korner Heinrich , Newsome Timothy P. , Chaudhri Geeta , Karupiah Gunasegaran
Published: December 2019

Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF-/-) also caused significant pathology during respiratory ectromelia virus (ECTV) infection, a surrogate mouse model for smallpox. TNF-/-mice succumbed to fulminant disease whereas wild-type mice, and those expressing only transmembrane TNF, recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines IL-6, IL-10, TGF-β, and IFN-γ. Blockade of these cytokines reduced lung pathology concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Short-term inhibition of STAT3 activation in ECTV-infected TNF-/-mice with an inhibitor reduced lung pathology. TNF is essential for regulating inflammation and its deficiency exacerbates ECTV infection as a consequence of significant lung pathology caused by dysregulation of inflammatory cytokine production, in part via overactivation of STAT3.
Cryo-EM Structures and Regulation of Arabinofuranosyltransferase AftD from Mycobacteria
Authors: Tan Yong Zi , Zhang Lei , Rodrigues José , Zheng Ruixiang Blake , Giacometti Sabrina I. , Rosário Ana L. , Kloss Brian , Dandey Venkata P. , Wei Hui , Brunton Richard , Raczkowski Ashleigh M. , Athayde Diogo , Catalão Maria João , Pimentel Madalena , Clarke Oliver B. , Lowary Todd L. , Archer Margarida , Niederweis Michael , Potter Clinton S. , Carragher Bridget , Mancia Filippo
Published: December 2019

Mycobacterium tuberculosiscauses tuberculosis, a disease that kills over one million people each year. Its cell envelope is a common antibiotic target and has a unique structure due, in part, to two lipidated polysaccharides – arabinogalactan and lipoarabinomannan. Arabinofuranosyltransferase D (AftD) is an essential enzyme involved in assembling these glycolipids. We present the 2.9 Å resolution structure ofM. abscessusAftD determined by single particle cryo-electron microscopy. AftD has a conserved GT-C glycosyltransferase fold and three carbohydrate binding modules. Glycan array analysis shows that AftD binds complex arabinose glycans. Additionally, AftD is non-covalently complexed with an acyl carrier protein (ACP). 3.4 and 3.5 Å structures of a mutant with impaired ACP binding reveal a conformational change that suggests the ACP may regulate AftD function. Using a conditional knock-out constructed inM. smegmatis, mutagenesis experiments confirm the essentiality of the putative active site and the ACP binding for AftD function.
Estimating allele-specific expression of SNVs from 10x Genomics Single-Cell RNA-Sequencing Data
Authors: Prashant N M , Liu Hongyu , Bousounis Pavlos , Spurr Liam , Alomran Nawaf , Ibeawuchi Helen , Sein Justin , Reece-Stremtan Dacian , Horvath Anelia
Published: December 2019

With the recent advances in single-cell RNA-sequencing (scRNA-seq) technologies, estimation of allele expression from single cells is becoming increasingly reliable. Allele expression is both quantitative and dynamic and is an essential component of the genomic interactome. Here, we systematically estimate allele expression from heterozygous single nucleotide variant (SNV) loci using scRNA-seq data generated on the 10x Genomics platform. We include in the analysis 26,640 human adipose-derived mesenchymal stem cells (from three healthy donors), with an average sequencing reads over 120K/cell (more than 4 billion scRNA-seq reads total). High quality SNV calls assessed in our study contained approximately 15% exonic and >50% intronic loci. To analyze the allele expression, we estimate the expressed Variant Allele Fraction (VAFRNA) from SNV-aware alignments and analyze its variance and distribution (mono- and bi-allelic) at different cutoffs for required minimal number of sequencing reads. Our analysis shows that when assessing SNV loci covered by a minimum of 3 unique sequencing reads, over 50% of the heterozygous SNVs show bi-allelic expression, while at minimum of 10 reads, nearly 90% of the SNVs are bi-allelic. Consistent with single cell studies on RNA velocity and models of transcriptional burst kinetics, we observe a substantially higher rate of monoallelic expression among intronic SNVs, signifying the usefulness of scVAFRNAto assess dynamic cellular processes. Our analysis demonstrates the feasibility of scVAFRNAestimation from current scRNA-seq datasets and shows that the 3’-based library generation protocol of 10x Genomics scRNA-seq data can be highly informative in SNV-based analyses.