Publications by authors named "Matthew Crawford"

72 Publications

Safety and Diagnostic Yield of Transthoracic Needle Aspiration of the Lung in Elderly Patients.

Lung 2021 Apr 12;199(2):171-176. Epub 2021 Mar 12.

Division of Pulmonary, Allergy, and Sleep Medicine, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Background: Pulmonary nodules in elderly patients are commonly encountered in clinical practice. Tissue sampling with image guided transthoracic needle aspiration is often performed but may be complicated by pneumothorax or bleeding. To understand the outcomes of transthoracic needle aspiration in the elderly, we retrospectively reviewed outcomes of patients age 75 or greater in a single tertiary center.

Methods: Four-hundred eleven patients age 75 or greater with a pulmonary nodule identified on computed tomography who underwent needle aspiration of the lung were studied. Diagnostic yield and procedural complications were assessed for each patient and subgroups analysis of those age 85 or greater was performed.

Results: Malignancy was confirmed in 70% of subjects and a benign diagnosis identified in 9%. Of the 411 patents, 203 (49.4%) experienced a complication; 150 patients (36.5%) developed a pneumothorax and 79 (19.2%) had bleeding. No patient required transfusion, experienced persistent air leak or massive hemoptysis, air embolism or death. Post procedural hospitalization was required in 36 patients (8.8%) with a median hospital stay of 2 days. No factors were identified to be associated with occurrence of a complication (all p ≥ 0.16) and complications were not increased in those 85 or greater.

Conclusion: Our results suggest that in an elderly population, image guided needle aspiration of a pulmonary nodule provides diagnostic findings in most patients. Procedural complications following are not uncommon but the severity and long-term impact are limited. The occurrence of complications is similar in those age 75-84 and age 85 and older.
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http://dx.doi.org/10.1007/s00408-021-00429-7DOI Listing
April 2021

Using greenspace and nature exposure as an adjunctive treatment for opioid and substance use disorders: Preliminary evidence and potential mechanisms.

Behav Processes 2021 Feb 2;186:104344. Epub 2021 Feb 2.

Department of Health Education and Behavior, University of Florida, Gainesville, FL, USA.

The demand for opioid medication to effectively treat pain has contributed to the surging opioid crisis, which is a major source of morbidity and mortality in the U.S. More than 100,000 people begin opioid maintenance treatment (OMT) annually, the standard pharmacotherapy for opioid use disorder (OUD). Although OMT is the standard care for OUD, patients often experience or develop a heightened sensitivity to pain (hyperalgesia) as a result of the opioid medication, and also have high rates of stress, affective, and anxiety-related conditions. These conditions are interactive with other behavioral and environmental correlates of opioid and other substance use disorders including impulsive decision-making (e.g., harmful opioid use associated with increased delay discounting), and a lack of alternative (i.e., substance-free) and social reinforcement. Collectively these complex and multifaceted factors constitute significant predictors of lack of adherence to OMT (and other pharmacotherapies) and relapse. There is an urgent need, therefore, to develop novel adjunctive treatments that preserve the benefits of OMT and various pharmacotherapies, and simultaneously diminish continued pain and hyperalgesia, reduce stress and anxiety-related conditions, target relevant behavioral mechanism such as impulsive choice, and also serve to enhance the value of alternative and substance free activities. Here, we discuss evidence that an environmental manipulation - access to greenspace and nature - could serve as a potential adjunctive treatment to standard pharmacotherapies by targeting multiple biological and behavioral mechanisms that standard pharmacotherapies do not address.
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http://dx.doi.org/10.1016/j.beproc.2021.104344DOI Listing
February 2021

To which world regions does the valence-dominance model of social perception apply?

Authors:
Benedict C Jones Lisa M DeBruine Jessica K Flake Marco Tullio Liuzza Jan Antfolk Nwadiogo C Arinze Izuchukwu L G Ndukaihe Nicholas G Bloxsom Savannah C Lewis Francesco Foroni Megan L Willis Carmelo P Cubillas Miguel A Vadillo Enrique Turiegano Michael Gilead Almog Simchon S Adil Saribay Nicholas C Owsley Chaning Jang Georgina Mburu Dustin P Calvillo Anna Wlodarczyk Yue Qi Kris Ariyabuddhiphongs Somboon Jarukasemthawee Harry Manley Panita Suavansri Nattasuda Taephant Ryan M Stolier Thomas R Evans Judson Bonick Jan W Lindemans Logan F Ashworth Amanda C Hahn Coralie Chevallier Aycan Kapucu Aslan Karaaslan Juan David Leongómez Oscar R Sánchez Eugenio Valderrama Milena Vásquez-Amézquita Nandor Hajdu Balazs Aczel Peter Szecsi Michael Andreychik Erica D Musser Carlota Batres Chuan-Peng Hu Qing-Lan Liu Nicole Legate Leigh Ann Vaughn Krystian Barzykowski Karolina Golik Irina Schmid Stefan Stieger Richard Artner Chiel Mues Wolf Vanpaemel Zhongqing Jiang Qi Wu Gabriela M Marcu Ian D Stephen Jackson G Lu Michael C Philipp Jack D Arnal Eric Hehman Sally Y Xie William J Chopik Martin Seehuus Soufian Azouaghe Abdelkarim Belhaj Jamal Elouafa John P Wilson Elliott Kruse Marietta Papadatou-Pastou Anabel De La Rosa-Gómez Alan E Barba-Sánchez Isaac González-Santoyo Tsuyueh Hsu Chun-Chia Kung Hsiao-Hsin Wang Jonathan B Freeman Dong Won Oh Vidar Schei Therese E Sverdrup Carmel A Levitan Corey L Cook Priyanka Chandel Pratibha Kujur Arti Parganiha Noorshama Parveen Atanu Kumar Pati Sraddha Pradhan Margaret M Singh Babita Pande Jozef Bavolar Pavol Kačmár Ilya Zakharov Sara Álvarez-Solas Ernest Baskin Martin Thirkettle Kathleen Schmidt Cody D Christopherson Trinity Leonis Jordan W Suchow Jonas K Olofsson Teodor Jernsäther Ai-Suan Lee Jennifer L Beaudry Taylor D Gogan Julian A Oldmeadow Benjamin Balas Laura M Stevens Melissa F Colloff Heather D Flowe Sami Gülgöz Mark J Brandt Karlijn Hoyer Bastian Jaeger Dongning Ren Willem W A Sleegers Joeri Wissink Gwenaël Kaminski Victoria A Floerke Heather L Urry Sau-Chin Chen Gerit Pfuhl Zahir Vally Dana M Basnight-Brown Hans I Jzerman Elisa Sarda Lison Neyroud Touhami Badidi Nicolas Van der Linden Chrystalle B Y Tan Vanja Kovic Waldir Sampaio Paulo Ferreira Diana Santos Debora I Burin Gwendolyn Gardiner John Protzko Christoph Schild Karolina A Ścigała Ingo Zettler Erin M O'Mara Kunz Daniel Storage Fieke M A Wagemans Blair Saunders Miroslav Sirota Guyan V Sloane Tiago J S Lima Kim Uittenhove Evie Vergauwe Katarzyna Jaworska Julia Stern Karl Ask Casper J J van Zyl Anita Körner Sophia C Weissgerber Jordane Boudesseul Fernando Ruiz-Dodobara Kay L Ritchie Nicholas M Michalak Khandis R Blake David White Alasdair R Gordon-Finlayson Michele Anne Steve M J Janssen Kean Mun Lee Tonje K Nielsen Christian K Tamnes Janis H Zickfeld Anna Dalla Rosa Michelangelo Vianello Ferenc Kocsor Luca Kozma Ádám Putz Patrizio Tressoldi Natalia Irrazabal Armand Chatard Samuel Lins Isabel R Pinto Johannes Lutz Matus Adamkovic Peter Babincak Gabriel Baník Ivan Ropovik Vinet Coetzee Barnaby J W Dixson Gianni Ribeiro Kim Peters Niklas K Steffens Kok Wei Tan Christopher A Thorstenson Ana Maria Fernandez Rafael M C S Hsu Jaroslava V Valentova Marco A C Varella Nadia S Corral-Frías Martha Frías-Armenta Javad Hatami Arash Monajem MohammadHasan Sharifian Brooke Frohlich Hause Lin Michael Inzlicht Ravin Alaei Nicholas O Rule Claus Lamm Ekaterina Pronizius Martin Voracek Jerome Olsen Erik Mac Giolla Aysegul Akgoz Asil A Özdoğru Matthew T Crawford Brooke Bennett-Day Monica A Koehn Ceylan Okan Tripat Gill Jeremy K Miller Yarrow Dunham Xin Yang Sinan Alper Martha Lucia Borras-Guevara Sun Jun Cai Dong Tiantian Alexander F Danvers David R Feinberg Marie M Armstrong Eva Gilboa-Schechtman Randy J McCarthy Jose Antonio Muñoz-Reyes Pablo Polo Victor K M Shiramazu Wen-Jing Yan Lilian Carvalho Patrick S Forscher Christopher R Chartier Nicholas A Coles

Nat Hum Behav 2021 01 4;5(1):159-169. Epub 2021 Jan 4.

Harvard Kennedy School, Harvard University, Cambridge, MA, USA.

Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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http://dx.doi.org/10.1038/s41562-020-01007-2DOI Listing
January 2021

Microvascular Anatomy and Intrinsic Gene Expression of Menisci From Young Adults.

Am J Sports Med 2020 11 12;48(13):3147-3153. Epub 2020 Oct 12.

Twin Cities Orthopedics, Edina, Minnesota, USA.

Background: Meniscal vascular supply is an important determinant of its healing potential. It has been reported that only the peripheral 30% of the meniscus is vascularized in cadavers aged 53 to 94 years; however, the vascularity in young patients, in whom meniscal repair is more often performed, is unknown.

Purpose: The primary objective was to analyze and measure the microvascular anatomy of the meniscus in adult cadaveric specimens <35 years old. The secondary objective was to assess angiogenic potential by quantifying regional gene expression in a meniscal allograft cohort <45 years old.

Study Design: Descriptive laboratory study.

Methods: In part 1 of this study, 13 fresh-frozen cadaveric knees (age range, 22-34 years; mean, 28.5 years) underwent popliteal artery India ink injection and tissue clearing using a Spalteholz technique, followed by microvascular vascular measurement. In part 2, mRNA was isolated from 13 meniscal allografts (age range, 17-43 years; mean, 27.2 years), and expression of angiogenic genes, vascular endothelial growth factor (), and vascular endothelial growth factor receptor 1 () was quantified using real-time polymerase chain reaction.

Results: The maximal depth of vascular penetration into the periphery of the medial and lateral menisci ranged from 0% to 42% and 0% to 48%, respectively. There was variation in the degree of vascular penetration within the medial meniscus, with the posterior horn having a significantly smaller depth of penetration (median, 8.7%) than that of the anterior horn (median, 17.4%; < .0001) or midbody (median, 17.5%; = .0003). There were no differences in angiogenesis gene expression (/) based on circumferential or radial meniscal locations.

Conclusion: The vascular supply of the medial and lateral menisci in specimens from adults <35 years of age extended farther than what was reported in specimens from older individuals; however, median values remained consistent. Gene expression of the angiogenic marker was low throughout all regions of uninjured menisci from young adults, which is consistent with reports in older specimens.

Clinical Relevance: Improved understanding of meniscal vascular supply in young adults is critical to informing clinical treatment decisions.
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http://dx.doi.org/10.1177/0363546520961555DOI Listing
November 2020

Acetabular Labral Reconstruction with Iliotibial Band Autograft: Outcome and Survivorship at a Minimum 10-Year Follow-up.

J Bone Joint Surg Am 2020 Sep;102(18):1581-1587

The Steadman Clinic (M.J.P. and J.W.A.), Steadman Philippon Research Institute (M.J.P., J.W.A., and K.K.B.), Vail, Colorado.

Background: Labral reconstruction has been shown to result in improved patient-reported outcomes (PROs) at mid-term follow-up in patients with a deficient labrum. The purpose of this study was to determine survivorship and PROs at a minimum 10-year follow-up.

Methods: A retrospective evaluation of a prospectively collected single-surgeon database included 91 hips (89 patients) that underwent arthroscopic labral reconstruction with iliotibial band autograft between 2006 and 2008. The primary PRO was the Hip Outcome Score (HOS)-activities of daily living (ADL). The modified Harris hip score (mHHS), HOS-sports, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and patient satisfaction (on a scale of 1 to 10) were also collected at a 10-year minimum follow-up. Survivorship analysis curves were evaluated.

Results: Eighty-two hips were evaluated at a 10-year minimum follow-up. Overall survivorship, with revision hip arthroscopy or total hip arthroplasty (THA) as the end point, was 70% at 5 years and 61% at 10 years, and the mean survival time was 9 years (95% confidence interval = 7.6 to 10 years). For the patients who did not undergo subsequent surgery, on average the mHHS increased from 60 preoperatively to 82 at the 10-year follow-up (p = 0.001), the HOS-ADL improved from 69 to 90 (p = 0.004), the HOS-sports improved from 43 to 76 (p = 0.001), and the median patient satisfaction was 10 of 10. Eighty percent of the patients achieved the minimal clinically important difference (MCID) in the HOS-ADL, and 87% obtained a patient acceptable symptom state (PASS).

Conclusions: Following arthroscopic labral reconstruction with iliotibial band autograft, 9% of the hips underwent revision arthroscopy and 27% underwent THA. At 10 years, the survival rate, with revision hip arthroscopy or THA as the end point, was 61%; however, for those with >2 mm of joint space, the current indication for labral reconstruction, the 10-year survival rate was 90%. Excellent PROs and patient satisfaction were reported by those who did not require revision or THA. With appropriate patient selection and prevention of postoperative adhesions, labral reconstruction results in excellent outcomes and high patient satisfaction that is sustained at a minimum 10-year follow-up.

Level Of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.19.01499DOI Listing
September 2020

Empiricism in Microsampling: Utilizing a Novel Lateral Flow Device and Intrinsic Normalization to Provide Accurate and Precise Clinical Analysis from a Finger Stick.

Clin Chem 2020 06;66(6):821-831

Center for Esoteric Testing, Laboratory Corporation of America Holdings, Burlington, NC.

Background: Phlebotomy plays a key role in clinical laboratory medicine but poses certain challenges for the patient and the laboratory. Dried blood spots simplify collection and stabilize specimens effectively, but clinical reference intervals are based primarily on serum or plasma. We evaluated use of dried separated blood plasma specimens to simplify plasma sample collection via finger stick; however, this sampling technique posed substantial analytical challenges. We discuss herein our efforts to overcome these challenges and provide accurate and precise clinical measurements.

Methods: Microsamples of whole blood were collected via finger stick using a collection device employing laminar-flow separation of cellular blood and plasma fractions with subsequent desiccation. Samples were analyzed on modern autoanalyzers with FDA-approved reagent and calibration systems, as well as commercially available reagents with laboratory-developed assay parameters. Measured analyte concentrations from extracted dried plasma samples were normalized to a coextracted endogenous analyte, chloride.

Results: Chloride normalization reduced variability incurred through extraction and undefined plasma volume. Excellent correlation of normalized measurements from dried finger-stick samples (whole blood and plasma) versus matched venous samples facilitated developing mathematical transformations to provide concordance between specimen types. Independent end-to-end performance verification yielded mean biases <3% for the 5 analytes evaluated relative to venous drawn samples analyzed on FDA-approved measurement systems.

Conclusion: Challenges inherent with this microsampling technique and alternate sample matrix were obviated through capabilities of modern autoanalyzers and implementation of chloride normalization. These results demonstrate that self-collected microsamples from a finger stick can give results concordant with those of venous samples.
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http://dx.doi.org/10.1093/clinchem/hvaa082DOI Listing
June 2020

Draft Genome Sequences of Two Extensively Drug-Resistant Strains of Acinetobacter baumannii Isolated from Clinical Samples in Pakistan.

Microbiol Resour Announc 2020 May 14;9(20). Epub 2020 May 14.

Division of Microbiology, Office of Regulatory Science, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland, USA.

Infections in immunocompromised patients that are caused by extensively drug-resistant (XDR) strains have been increasingly reported worldwide. In particular, carbapenem-resistant strains are a prominent cause of health care-associated infections. Here, we report draft genome assemblies for two clinical XDR isolates obtained from hospitalized patients in Pakistan.
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http://dx.doi.org/10.1128/MRA.00026-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225525PMC
May 2020

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

Clinical Presentation and Outcomes Associated With Fabellectomy in the Setting of Fabella Syndrome.

Orthop J Sports Med 2020 Feb 25;8(2):2325967120903722. Epub 2020 Feb 25.

The Steadman Clinic, Vail, Colorado, USA.

Background: Clinical outcomes pertaining to isolated lateral fabellectomy in the setting of fabella syndrome are limited to small case reports at this time.

Purpose: To assess the most common presenting symptoms, clinical outcomes, and satisfaction after fabella excision in the setting of fabella syndrome.

Study Design: Case series; Level of evidence, 4.

Methods: Consecutive patients with a minimum of 21-month follow-up after isolated fabellectomy for fabella syndrome were reviewed retrospectively. Clinical outcome scores of the following domains were collected: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and Lysholm knee survey, along with a simple numeric patient satisfaction score (range, 1-10; 10 = "very satisfied"). Statistical analysis was performed using paired tests for all clinical outcome data.

Results: A total of 11 isolated fabella excisions were included in 10 patients with isolated lateral-sided knee pain in the setting of fabella syndrome (8 males, 2 females), with a mean age of 36.9 years (range, 23-58 years) and a mean follow-up of 2.4 years (range, 21-47 months). A total of 8 patients (80%) were able to return to full desired activities, including sports. Only 5 of 11 (45%) excisions had concomitant lateral femoral condyle cartilage pathology. There were significant improvements across multiple WOMAC domains, and the WOMAC total score improved from 28.5 ± 17.6 preoperatively to 11.6 ± 10.2 postoperatively ( < .05). Lysholm scores significantly improved from 66.6 ± 23.1 preoperatively to 80.2 ± 13.9 postoperatively ( = .044). Overall patient-reported satisfaction was 8.8 ± 1.6.

Conclusion: Fabella excision in the setting of fabella syndrome demonstrated improvements in clinical outcome scores, high rate of returning to preinjury level of activities, and low risk of complications or need for additional surgical procedures.
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http://dx.doi.org/10.1177/2325967120903722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042559PMC
February 2020

Incidence of Displaced Posterolateral Tibial Plateau and Lateral Femoral Condyle Impaction Fractures in the Setting of Primary Anterior Cruciate Ligament Tear.

Am J Sports Med 2020 03 9;48(3):545-553. Epub 2020 Jan 9.

Twin Cities Orthopedics, Edina, Minnesota, USA.

Background: Bone bruising of the posterolateral tibial plateau and the lateral femoral condyle sulcus terminalis has a well-established association with anterior cruciate ligament (ACL) tears. Impaction fractures of the femur and tibia may occur in these locations; however, there is a paucity of literature describing these fractures.

Purpose: The primary objective was to quantify the incidence, size, and location of impaction fractures of the posterolateral tibial plateau and lateral femoral condyle in patients with primary ACL tears. The secondary objective was to investigate the association between impaction fractures and concomitant meniscal and ligamentous injuries.

Study Design: Case series; Level of evidence 4.

Methods: Patients with available magnetic resonance imaging (MRI) scans who were treated for primary ACL tear by a single surgeon were identified. MRI scans were reviewed with denotation of posterolateral tibial and femoral condylar contusions and displaced impaction fractures. Measurements of the lateral tibial plateau were taken in all patients with displaced lateral tibial plateau fractures and in a subset of control patients without tibial plateau fracture present to characterize the size and location of the bony lesion. Associations of impaction fractures with concomitant meniscal or ligamentous injuries were evaluated through use of chi-square testing.

Results: There were 825 knees identified with available MRI scans. Lateral tibial plateau bone bruising was present in 634 knees (76.8%), and lateral femoral condyle bone bruising was present in 407 knees (49.3%). Posterolateral tibial plateau impaction fractures were present in 407 knees (49.3%), and lateral femoral condylar impaction fractures were present in 214 knees (25.9%). Patients with posterolateral tibial plateau impaction fractures were older than patients without these fractures (42.6 vs 32.7 years; < .001), whereas patients with lateral femoral condylar impaction fractures were younger (23.8 vs 32.7 years; < .001). There were 71 knees (8.6%) with a posterolateral tibial plateau impaction fracture with greater than 10% loss of lateral tibial plateau depth, and this group had an increased incidence of lateral meniscus posterior root tears (22.1% vs 12.0%; = .02).

Conclusion: Posterolateral tibial plateau impaction fractures occurred with a high incidence (49.3%) in patients with primary ACL tears and demonstrated an increased association with lateral meniscus posterior horn root tears as their size increased. Lateral femoral condylar impaction fractures occurred in 25.9% of patients with primary ACL tears and entailed an increased incidence of lateral meniscal tears and medial meniscal ramp lesions.
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http://dx.doi.org/10.1177/0363546519895239DOI Listing
March 2020

Morphologic Variants of Posterolateral Tibial Plateau Impaction Fractures in the Setting of Primary Anterior Cruciate Ligament Tear.

Am J Sports Med 2020 02 3;48(2):318-325. Epub 2020 Jan 3.

Twin Cities Orthopedics, Edina, Minnesota, USA.

Background: Impaction fractures of the posterolateral tibial plateau commonly occur in the setting of anterior cruciate ligament (ACL) tears, with considerable variability found in fracture size and morphologic features.

Purpose: The primary objective was to characterize different morphologic variants of posterolateral tibial plateau impaction fractures. The secondary objective was to investigate the association between these impaction fracture variants and concomitant meniscal and ligamentous injuries.

Study Design: Cross-sectional study; Level of evidence 3.

Methods: Patients treated for primary ACL tears and having magnetic resonance imaging available were included in this study, and magnetic resonance images were reviewed with denotation of displaced posterolateral tibial impaction fractures. A classification system was created based on morphologic variants of impaction fractures; associations were evaluated through use of independent chi-square testing.

Results: There were 825 knees meeting the inclusion criteria, with displaced posterolateral tibial plateau impaction fractures present in 407 knees (49.3%). We observed 3 distinct morphologic variants of lateral tibial plateau impaction fractures: (I) posterior cortical buckle not involving the articular surface; (II) posterior impaction fracture involving the articular surface, with subtypes based on (A) tibial plateau depth bone loss <10% and (B) bone loss >10%; and (III) displaced osteochondral fragment, with subtypes for (A) shear or (B) depressed fragment. Type IIIA impaction fractures were associated with an increased incidence of lateral meniscus posterior root tears (33.3% vs 12.4%; = .009) and an increased incidence of lateral meniscal tears (83.3% vs 56.7%; = .024) compared with all knees without type IIIA impaction fracture. An increased incidence of medial collateral ligament (MCL) tears was noted in patients with type IIIA impaction fractures compared with those who had no fracture or had another fracture type (61.1% vs 20.1%; < .001). Type IIIB impaction fractures were associated with an increased incidence of lateral meniscal tears (80.0% vs 56.2%; = .005).

Conclusion: A high prevalence of displaced posterolateral tibial plateau impaction fractures occur in the setting of ACL tears, and they can be classified into distinct morphologic subtypes. Posterolateral tibial plateau impaction fractures with displaced depressed or shear fragments were both associated with an increased incidence of lateral meniscal tears, whereas impaction fractures with a shear fragment were associated with an increased incidence of lateral meniscus posterior root tears and MCL tears.
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http://dx.doi.org/10.1177/0363546519893709DOI Listing
February 2020

Combined Posterior Cruciate Ligament and Superficial Medial Collateral Ligament Knee Reconstruction: Avoiding Tunnel Convergence.

Arthrosc Tech 2019 Aug 30;8(8):e929-e933. Epub 2019 Jul 30.

Steadman Clinic, Vail, Colorado, U.S.A.

Combined posterior cruciate ligament (PCL) and medial collateral ligament (MCL) injuries represent a complex pathology that requires a thorough clinical and radiographic examination to diagnose and identify all injured structures. Anatomic reconstruction of the injured ligaments is recommended, including double-bundle PCL reconstruction and superficial MCL augmentation. In the setting of this complex reconstruction, several technical aspects require consideration and preoperative planning, including the risk of femoral tunnel convergence on the medial aspect of the femoral condyle. This article details our technique for combined anatomic double-bundle PCL reconstruction and superficial MCL augmentation to avoid tunnel convergence. Level I (knee); level II (PCL).
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http://dx.doi.org/10.1016/j.eats.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823869PMC
August 2019

Combined Anterior Cruciate Ligament Reconstruction and Lateral Extra-Articular Tenodesis.

Arthrosc Tech 2019 Aug 19;8(8):e855-e859. Epub 2019 Jul 19.

Steadman Clinic, Vail, Colorado, U.S.A.

Anterolateral rotational instability may persist after anterior cruciate ligament (ACL) reconstruction for a variety of reasons including damage to lateral or posterolateral structures, injury to the meniscus, disruption of anterolateral soft tissue structures, or increased tibial slope. In the setting of revision or primary ACL reconstruction with persistent anterolateral laxity, despite repair or reconstruction of other injured structures or in the setting of increased tibial slope, a lateral extra-articular tenodesis procedure can be used to augment an ACL reconstruction to aid in restoring anterolateral rotational stability and to upload the ACL reconstruction graft. This article details our technique for performing a modified Lemaire lateral extra-articular tenodesis using iliotibial band autograft as an adjunct to ACL reconstruction.
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http://dx.doi.org/10.1016/j.eats.2019.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823830PMC
August 2019

Draft Genome Sequences of Antimicrobial-Resistant Clinical Isolates from Pakistan.

Microbiol Resour Announc 2019 Jul 25;8(30). Epub 2019 Jul 25.

Division of Microbiology, Office of Regulatory Science, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland, USA.

spp. are the most common cause of dysentery in developing countries and the second leading cause of diarrheal deaths worldwide. Multidrug-resistant (MDR) spp. are a serious threat to global health. Herein, we report draft genome sequences for three MDR isolates from Pakistan, two isolates and one isolate.
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http://dx.doi.org/10.1128/MRA.00500-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658682PMC
July 2019

Injury Surveillance in Major League Soccer: A 4-Year Comparison of Injury on Natural Grass Versus Artificial Turf Field.

Am J Sports Med 2019 08 15;47(10):2279-2286. Epub 2019 Jul 15.

Investigation performed at Kerlan Jobe Institute, Santa Monica, California, USA.

Background: Artificial playing surfaces are becoming more common due to decreased cost of maintenance and increased field usability across different environmental conditions. The Fédération Internationale de Football Association (FIFA) has approved newer generation artificial turf for soccer competition at the elite level, but many elite-level athletes prefer to play on natural grass surfaces due to a perceived increase in injury rate, discomfort, and fatigability on artificial turf.

Hypothesis: Injury rates and rates of individually categorized types of injury experienced on artificial turf are noninferior to rates of injury on the standard comparator, natural grass, in elite-level Major League Soccer athletes.

Study Design: Cohort study; Level of evidence, 2.

Methods: Over the course of 4 Major League Soccer seasons (2013-2016), athlete injury data were recorded electronically. Injury data recorded in matches between 2 Major League Soccer teams were then analyzed. Playing surface was known for each venue, and all artificial turf surfaces were rated as 2-star according to FIFA criteria. Incidence rate ratios (Artificial Turf ÷ Natural Grass) were calculated with a 95% CI (α = .05) for both overall injury incidence and individual injury subgroups. A noninferiority margin (δ) of 0.15 was used to determine noninferiority of injury incidence rates.

Results: A total of 2174 in-game injuries were recorded during the study period, with 1.54 injuries per game on artificial turf and 1.49 injuries per game on natural grass (incidence rate ratio, 1.033; 95% CI, 0.937-1.139). Within injury subgroups, overall ankle injury, Achilles injury, and ankle fracture were found to have a statistically higher incidence on artificial turf. Artificial turf was found to be noninferior to natural grass for overall foot injury and forefoot injury. No statistically significant differences were found in knee injuries between the 2 surfaces.

Conclusion: The overall rate of injury on artificial turf was noninferior to that on natural grass. Within individual injury categories, a higher rate of ankle injury was found on artificial turf. No other injury subgroup demonstrated statistically significant differences between surfaces.

Clinical Relevance: FIFA 2-star rated artificial turf is a viable alternative to natural grass in elite-level soccer competition. Innovative research methods for comparing artificial turf versus natural grass may elucidate relative advantages with respect to player safety.
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http://dx.doi.org/10.1177/0363546519860522DOI Listing
August 2019

Large-volume injection gas chromatography-vacuum ultraviolet spectroscopy for the qualitative and quantitative analysis of fatty acids in blood plasma.

Anal Chim Acta 2019 Apr 15;1053:169-177. Epub 2018 Dec 15.

Department of Chemistry and Biochemistry, University of Texas Arlington, Arlington, TX, USA. Electronic address:

Qualitative and quantitative determination of fatty acids in plasma is of extreme importance as these are indicators of metabolic diseases. In this work, a sensitive and rugged method for detecting and quantifying fatty acids (as fatty acid methyl ester derivatives, FAMEs) in blood plasma was developed. The use of large-volume injection (LVI) gas chromatography-vacuum ultraviolet spectroscopy (GC-VUV) for analysis of fatty acids in blood plasma allowed the injection of higher sample volumes to accommodate sufficient analyte on-column for necessary detection ranges with a run time of 45 min. Calibration curves exhibited consistent linearity and reproducibility and were used along with internal standards for the quantification of 11 saturated and 21 unsaturated fatty acids. Intra-day and inter-day (n = 6) CVs had an average of 5 and 6%, respectively, and recoveries an average of 105%. The concentrations of EPA, DHA, and AA, as well as the omega-3 index and omega-6/omega-3 ratio, were calculated and compared with clinically actionable measurement ranges. Due to the use of LVI, the more volatile analyte (C8:0) was lost and therefore impossible to quantify. The volatility cutoff was determined to be the C10:0 analyte with a molecular weight of 186.295 g/mol.
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http://dx.doi.org/10.1016/j.aca.2018.12.007DOI Listing
April 2019

Thinking about negative life events as a mediator between depression and fading affect bias.

PLoS One 2019 25;14(1):e0211147. Epub 2019 Jan 25.

School of Psychology, Victoria University of Wellington, Wellington, New Zealand.

The current research examined the links between depressive symptomology and anxiety on the fading of affect associated with positive and negative autobiographical memories. Participants (N = 296) recalled and rated positive and negative events in terms of how pleasant or unpleasant they were at the time they occurred and at the time of event recollection. Multilevel mediation analyses identified evidence that higher levels of depressive symptoms were directly associated with lower affect fade for both negative and positive memories. Tests of indirect effects indicated that depressive symptoms were indirectly related to lower affect fade for negative (but not positive) autobiographical memories via the heightened tendency to think about negative (but not positive) memories. Anxiety was unrelated to affect fade both directly and indirectly. These results suggest that people higher in depressive symptoms retain more negative affect due to an increased likelihood of thinking about negative autobiographical events.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211147PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347156PMC
October 2019

DksA-DnaJ redox interactions provide a signal for the activation of bacterial RNA polymerase.

Proc Natl Acad Sci U S A 2018 12 14;115(50):E11780-E11789. Epub 2018 Nov 14.

Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO 80045;

RNA polymerase is the only known protein partner of the transcriptional regulator DksA. Herein, we demonstrate that the chaperone DnaJ establishes direct, redox-based interactions with oxidized DksA. Cysteine residues in the zinc finger of DksA become oxidized in exposed to low concentrations of hydrogen peroxide (HO). The resulting disulfide bonds unfold the globular domain of DksA, signaling high-affinity interaction of the C-terminal α-helix to DnaJ. Oxidoreductase and chaperone activities of DnaJ reduce the disulfide bonds of its client and promote productive interactions between DksA and RNA polymerase. Simultaneously, guanosine tetraphosphate (ppGpp), which is synthesized by RelA in response to low concentrations of HO, binds at site 2 formed at the interface of DksA and RNA polymerase and synergizes with the DksA/DnaJ redox couple, thus activating the transcription of genes involved in amino acid biosynthesis and transport. However, the high concentrations of ppGpp produced by experiencing oxidative stress oppose DksA/DnaJ-dependent transcription. Cumulatively, the interplay of DksA, DnaJ, and ppGpp on RNA polymerase protects from the antimicrobial activity of the NADPH phagocyte oxidase. Our research has identified redox-based signaling that activates the transcriptional activity of the RNA polymerase regulator DksA.
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http://dx.doi.org/10.1073/pnas.1813572115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294903PMC
December 2018

Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αβ Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis.

J Med Chem 2018 09 14;61(18):8417-8443. Epub 2018 Sep 14.

Department of Pure & Applied Chemistry , University of Strathclyde , 295 Cathedral Street , Glasgow G1 1XL , Scotland, U.K.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αβ, αβ, αβ, αβ, and αβ integrins. Numerous analogs with high affinity and selectivity for the αβ integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αβ integrin in a radioligand binding assay (p K = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00959DOI Listing
September 2018

Guanosine tetraphosphate relieves the negative regulation of Salmonella pathogenicity island-2 gene transcription exerted by the AT-rich ssrA discriminator region.

Sci Rep 2018 06 21;8(1):9465. Epub 2018 Jun 21.

Molecular Biology Program, University of Colorado School of Medicine, Aurora, CO, USA.

The repressive activity of ancestral histone-like proteins helps integrate transcription of foreign genes with discrepant AT content into existing regulatory networks. Our investigations indicate that the AT-rich discriminator region located between the -10 promoter element and the transcription start site of the regulatory gene ssrA plays a distinct role in the balanced expression of the Salmonella pathogenicity island-2 (SPI2) type III secretion system. The RNA polymerase-binding protein DksA activates the ssrAB regulon post-transcriptionally, whereas the alarmone guanosine tetraphosphate (ppGpp) relieves the negative regulation imposed by the AT-rich ssrA discriminator region. An increase in the GC-content of the ssrA discriminator region enhances ssrAB transcription and SsrB translation, thus activating the expression of downstream SPI2 genes. A Salmonella strain expressing a GC-rich ssrA discriminator region is attenuated in mice and grows poorly intracellularly. The combined actions of ppGpp and DksA on SPI2 expression enable Salmonella to grow intracellularly, and cause disease in a murine model of infection. Collectively, these findings indicate that (p)ppGpp relieves the negative regulation associated with the AT-rich discriminator region in the promoter of the horizontally-acquired ssrA gene, whereas DksA activates ssrB gene expression post-transcriptionally. The combined effects of (p)ppGpp and DksA on the ssrAB locus facilitate a balanced SPI2 virulence gene transcription that is essential for Salmonella pathogenesis.
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http://dx.doi.org/10.1038/s41598-018-27780-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013443PMC
June 2018

Resistome of carbapenem- and colistin-resistant Klebsiella pneumoniae clinical isolates.

PLoS One 2018 8;13(6):e0198526. Epub 2018 Jun 8.

Center for Food Safety and Applied Nutrition, U.S. Food & Drug Administration, College Park, Maryland, United States of America.

The emergence and dissemination of carbapenemases, bacterial enzymes able to inactivate most β-lactam antibiotics, in Enterobacteriaceae is of increasing concern. The concurrent spread of resistance against colistin, an antibiotic of last resort, further compounds this challenge further. Whole-genome sequencing (WGS) can play a significant role in the rapid and accurate detection/characterization of existing and emergent resistance determinants, an essential aspect of public health surveillance and response activities to combat the spread of antimicrobial resistant bacteria. In the current study, WGS data was used to characterize the genomic content of antimicrobial resistance genes, including those encoding carbapenemases, in 10 multidrug-resistant Klebsiella pneumoniae isolates from Pakistan. These clinical isolates represented five sequence types: ST11 (n = 3 isolates), ST14 (n = 3), ST15 (n = 1), ST101 (n = 2), and ST307 (n = 1). Resistance profiles against 25 clinically-relevant antimicrobials were determined by broth microdilution; resistant phenotypes were observed for at least 15 of the 25 antibiotics tested in all isolates except one. Specifically, 8/10 isolates were carbapenem-resistant and 7/10 isolates were colistin-resistant. The blaNDM-1 and blaOXA-48 carbapenemase genes were present in 7/10 and 5/10 isolates, respectively; including 2 isolates carrying both genes. No plasmid-mediated determinants for colistin resistance (e.g. mcr) were detected, but disruptions and mutations in chromosomal loci (i.e. mgrB and pmrB) previously reported to confer colistin resistance were observed. A blaOXA-48-carrying IncL/M-type plasmid was found in all blaOXA-48-positive isolates. The application of WGS to molecular epidemiology and surveillance studies, as exemplified here, will provide both a more complete understanding of the global distribution of MDR isolates and a robust surveillance tool useful for detecting emerging threats to public health.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993281PMC
December 2018

Mechanistic insights and therapeutic opportunities of antimicrobial chemokines.

Semin Cell Dev Biol 2019 04 21;88:119-128. Epub 2018 Feb 21.

Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia, Charlottesville, VA, 22908, USA. Electronic address:

Chemokines are a family of small proteins best known for their ability to orchestrate immune cell trafficking and recruitment to sites of infection. Their role in promoting host defense is multiplied by a number of additional receptor-dependent biological activities, and most, but not all, chemokines have been found to mediate direct antimicrobial effects against a broad range of microorganisms. The molecular mechanism(s) by which antimicrobial chemokines kill bacteria remains unknown; however, recent observations have expanded our fundamental understanding of chemokine-mediated bactericidal activity to reveal increasingly diverse and complex actions. In the current review, we present and consider mechanistic insights of chemokine-mediated antimicrobial activity against bacteria. We also discuss how contemporary advances are reshaping traditional paradigms and opening up new and innovative avenues of research with translational implications. Towards this end, we highlight a developing framework for leveraging chemokine-mediated bactericidal and immunomodulatory effects to advance pioneering therapeutic approaches for treating bacterial infections, including those caused by multidrug-resistant pathogens.
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http://dx.doi.org/10.1016/j.semcdb.2018.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613794PMC
April 2019

Ethnic Variation in Satisfaction and Appearance Concerns in Adolescents With Idiopathic Scoliosis Undergoing Posterior Spinal Fusion With Instrumentation.

Spine Deform 2018 Mar - Apr;6(2):148-155. Epub 2017 Oct 16.

Department of Orthopaedic Surgery, University of California-San Francisco (UCSF), San Francisco, CA, USA.

Study Design: Cohort analysis.

Objective: Document satisfaction with management and appearance concerns in children of different ethnicity who underwent spinal fusion/instrumentation for adolescent idiopathic scoliosis (AIS).

Summary Of Background Data: Scoliosis Research Society Questionnaire (SRS-30) outcomes in AIS indicate a link between appearance and satisfaction as well as ethnic variation in appearance domain. Exploration of these findings in the Scoliosis Appearance Questionnaire (SAQ) will allow better understanding of ethnic variation in appearance concerns.

Methods: Children with AIS who underwent posterior-only operations and completed the SAQ's question 31 were identified. Univariate logistic regression of SAQ questions 12-30 was used to assess relationships with ethnicity.

Results: 1,977 children [boys: 281, girls: 1,290, unspecified: 406; average age 15.1 ± 2.0 years preoperatively and 817 children (boys: 113, girls: 569, unspecified: 135; average age 15.1 ± 2.0 years) at 2 years' follow-up met inclusion criteria. The majority were Caucasian (57.3%). Few were Hispanic (3.4%). Preoperatively, the largest percentage of patients in each ethnic group answered "very true" to "wanting to be more even." Preoperatively, Asians were least likely to be concerned about evenness of shoulders, hips, waist, ribs, and chest in back (p < .05); however, they expressed greatest concern about height (p < .05). African Americans and Hispanics were more likely to be concerned about breast evenness and anterior chest and looking better in clothes (p < .05). African Americans were most concerned about overall evenness and evenness of shoulders, hips, waist, ribs, posterior chest, leg length, and looking more attractive (p < .05). Surgical scar was most important postoperatively for all ethnicities. African Americans and Hispanics were more self-conscious about scar (p < .05). African Americans were most likely to want to be more even and have more even shoulders, hips, waist, leg lengths, ribs, breasts, and chest postoperatively.

Conclusions: Ethnicity influenced appearance concerns in pre- and postoperative SAQ evaluation. Ethnic variation in appearance concerns should be taken into account and differentiated when counseling patients about AIS and surgical correction.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1016/j.jspd.2017.07.003DOI Listing
December 2018

Diabetes area patent participation analysis - part II: years 2011-2016.

Expert Opin Ther Pat 2018 02 29;28(2):111-122. Epub 2017 Nov 29.

a Department of Medicinal Sciences , Worldwide Research and Development, Pfizer, Inc. , Cambridge , MA , USA.

Introduction: Diabetes is a metabolic disease characterized by elevated levels of plasma glucose. When untreated, diabetes increases the risk of developing co-morbidities such as cardiovascular disease. Several drugs, often used as part of combination therapies, have been approved to treat the disease, but these drugs will eventually fail to effectively control blood glucose levels, at which point insulin replacement therapy is required. A medical need exists for new antidiabetic drugs that exhibit good efficacy with improved safety/toleration profiles and can be added on top of existing therapies, or that can provide additional benefits beyond glucose lowering such as pancreatic beta (β)-cell protection.

Areas Covered: This review analyzes drug targets and applicants of patents that published between 2011-2016 claiming novel small or large molecules for the treatment of diabetes, and compares the results to the 2008-2010 time period.

Expert Opinion: A majority of patent activity around the discovery of new antidiabetic drugs in 2011-2016 was directed against 15 targets, most of which were also the focus of drug discovery efforts in the 2008-2010 time period. The top targets by total patent counts were DPP4, GLP1R, INSR, GPR119, and SGLT2 (SLC5A2). With the exception of GPR119, these are the pharmacological targets of some of the best-selling antidiabetic drugs currently on the market. The top targets of patent families with the largest size counts, a metric useful in assessing patent value and applicant interest, were AMPK, CALCR, DPP4, and GLP1R. The patent analysis identified several emerging targets with greater patent activity in 2011-2016 compared to 2008-2010, including FFAR1, FFAR4, and FGFR1. Most of the patent activity in 2011-2016 was directed at established and precedented diabetes targets, the modulation of which may lead to improvements in glucose control and a delay in the progression of the disease. Few targets were identified that promote pancreatic β-cell regeneration and β-cell health, areas where future opportunities may exist for developing transformative drug therapies that may potentially lead to cures for diabetes.
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http://dx.doi.org/10.1080/13543776.2018.1406477DOI Listing
February 2018

CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens.

mBio 2017 11 14;8(6). Epub 2017 Nov 14.

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA

The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing and colistin-resistant members of the family that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens. As bacterial pathogens become resistant to multiple antibiotics, the infections they cause become increasingly difficult to treat. Carbapenem antibiotics provide an essential clinical barrier against multidrug-resistant bacteria; however, the dissemination of bacterial enzymes capable of inactivating carbapenems threatens the utility of these important antibiotics. Compounding this concern is the global spread of bacteria invulnerable to colistin, a polymyxin antibiotic considered to be a last line of defense against carbapenem-resistant pathogens. As the effectiveness of existing antibiotics erodes, it is critical to develop innovative antimicrobial therapies. To this end, we demonstrate that the chemokines CXCL9 and CXCL10 kill the most concerning carbapenem- and colistin-resistant pathogens. Our findings provide a unique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant "superbugs."
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http://dx.doi.org/10.1128/mBio.01549-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686536PMC
November 2017

Common Pediatric Pain Disorders and Their Clinical Associations.

Clin J Pain 2017 12;33(12):1131-1140

*Department of Anaesthesia and Pain Medicine, Sydney Children's Hospital, Randwick †Melbourne School of Population and Global Health, The University of Melbourne, Carlton ‡School of Women's and Children's Health, University of New South Wales, Kensington, NSW, Australia.

Background: Common childhood pain conditions (nonmigraine headache, migraine, recurrent abdominal pain, growing pains, low back pain) and persistent pains are often associated with each other and have significant implications in later life. Emerging evidence suggests additional associations between these pain conditions and restless legs syndrome, iron deficiency, anxiety, and depression. The aim of this cross-sectional study in pediatric twin individuals and their siblings was to investigate these associations.

Materials And Methods: Surveys were sent to Australian twin families via the Australian Twin Registry, yielding responses from 2530 pediatric individuals. The lifetime prevalence of the common pain disorders of childhood and of other persistent pains, restless legs syndrome and iron deficiency, and anxious/depressed score were determined by questionnaires. Random-effects logistic regression modeling was used to investigate univariate and multivariate associations between conditions.

Results: Univariate associations were found between each of the pain conditions and persistent pain, and between the pain conditions with restless legs syndrome, iron deficiency, and anxious/depressed score. Derivative multivariate analyses retained statistically significant associations between each of the pain disorders included in the respective models (odds ratios [OR], 1.69-7.04) with the exception of growing pains with persistent pain. Of the nonpain conditions included in the multivariate analyses, restless legs syndrome remained associated with growing pains (OR, 8.50) and persistent pain (OR, 2.01). Iron deficiency remained significantly associated with migraine (OR, 2.38), persistent pain (OR, 3.70), and restless legs syndrome (OR, 5.10).

Conclusions: In light of their extensive associations, the common pain conditions, persistent pain, restless legs syndrome, iron deficiency, anxiety and depression, are likely to involve common etiological mechanisms that warrant further investigation.
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http://dx.doi.org/10.1097/AJP.0000000000000496DOI Listing
December 2017

Genome Sequences of Multidrug-Resistant, Colistin-Susceptible and -Resistant Klebsiella pneumoniae Clinical Isolates from Pakistan.

Genome Announc 2016 Dec 15;4(6). Epub 2016 Dec 15.

Division of Infectious Diseases & International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA

The emergence and spread of colistin resistance among multidrug-resistant (MDR) Klebsiella pneumoniae represent a critical threat to global health. Here, we report the complete genome sequences of 10 MDR, colistin-susceptible and -resistant K. pneumoniae clinical isolates obtained in Pakistan between 2010 and 2013.
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http://dx.doi.org/10.1128/genomeA.01419-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159589PMC
December 2016

Surgical Management and Treatment of the Anterior Cruciate Ligament-Deficient Knee with Malalignment.

Clin Sports Med 2017 Jan 15;36(1):119-133. Epub 2016 Oct 15.

Department of Orthopaedic Surgery, Duke University Medical Center, Duke University, Box 3000, Durham, NC 27710, USA.

Varus malalignment and an increased tibial slope can result in instability in an anterior cruciate ligament (ACL)-deficient knee. Malalignment can also be a cause of recurrent instability following ACL reconstruction. Varus malalignment can contribute to loosening or failure of primary ACL reconstruction and contribute to progressive medial compartment arthritis. High tibial osteotomies performed in conjunction with ACL reconstruction can improve alignment, restore anterior knee stability, and help reduce the advancement of arthritis.
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http://dx.doi.org/10.1016/j.csm.2016.08.006DOI Listing
January 2017

Massive gas gangrene secondary to occult colon carcinoma.

Radiol Case Rep 2016 Jun 5;11(2):67-9. Epub 2016 Mar 5.

Department of Radiology, Duke University Medical Center, DUMC Box 3808, Durham, NC 27710, USA.

Gas gangrene is a rare but often fatal soft-tissue infection. Because it is uncommon and the classic symptom of crepitus does not appear until the infection is advanced, prompt diagnosis requires a high index of suspicion. We present a case report of a middle-aged man who presented with acute onset lower-extremity pain that was initially thought to be due to deep vein thrombosis. After undergoing workup for pulmonary embolism, he was found to have massive gas gangrene of the lower extremity secondary to an occult colon adenocarcinoma and died within hours of presentation from multisystem organ failure.
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http://dx.doi.org/10.1016/j.radcr.2016.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878939PMC
June 2016

Redox-Active Sensing by Bacterial DksA Transcription Factors Is Determined by Cysteine and Zinc Content.

mBio 2016 Apr 19;7(2):e02161-15. Epub 2016 Apr 19.

Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA Molecular Biology Program, University of Colorado School of Medicine, Aurora, Colorado, USA Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, USA

Unlabelled: The four-cysteine zinc finger motif of the bacterial RNA polymerase regulator DksA is essential for protein structure, canonical control of the stringent response to nutritional limitation, and thiol-based sensing of oxidative and nitrosative stress. This interdependent relationship has limited our understanding of DksA-mediated functions in bacterial pathogenesis. Here, we have addressed this challenge by complementing ΔdksA Salmonella with Pseudomonas aeruginosa dksA paralogues that encode proteins differing in cysteine and zinc content. We find that four-cysteine, zinc-bound (C4) and two-cysteine, zinc-free (C2) DksA proteins are able to mediate appropriate stringent control in Salmonella and that thiol-based sensing of reactive species is conserved among C2 and C4 orthologues. However, variations in cysteine and zinc content determine the threshold at which individual DksA proteins sense and respond to reactive species. In particular, zinc acts as an antioxidant, dampening cysteine reactivity and raising the threshold of posttranslational thiol modification with reactive species. Consequently, C2 DksA triggers transcriptional responses in Salmonella at levels of oxidative or nitrosative stress normally tolerated by Salmonella expressing C4 orthologues. Inappropriate transcriptional regulation by C2 DksA increases the susceptibility of Salmonella to the antimicrobial effects of hydrogen peroxide and nitric oxide, and attenuates virulence in macrophages and mice. Our findings suggest that the redox-active sensory function of DksA proteins is finely tuned to optimize bacterial fitness according to the levels of oxidative and nitrosative stress encountered by bacterial species in their natural and host environments.

Importance: In order to cause disease, pathogenic bacteria must rapidly sense and respond to antimicrobial pressures encountered within the host. Prominent among these stresses, and of particular relevance to intracellular pathogens such as Salmonella, are nutritional restriction and the enzymatic generation of reactive oxygen and nitrogen species. The conserved transcriptional regulator DksA controls adaptive responses to nutritional limitation, as well as to oxidative and nitrosative stress. Here, we demonstrate that each of these functions contributes to bacterial pathogenesis. Our observations highlight the importance of metabolic adaptation in bacterial pathogenesis and show the mechanism by which DksA orthologues are optimized to sense the levels of oxidative and nitrosative stress encountered in their natural habitats. An improved understanding of the conserved processes used by bacteria to sense, respond to, and limit host defense will inform the development of novel strategies to treat infections caused by pathogenic, potentially multidrug-resistant bacteria.
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http://dx.doi.org/10.1128/mBio.02161-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850274PMC
April 2016