Publications by authors named "Kevin Chow"

55 Publications

Basic Tests of Autonomic Function.

J Clin Neurophysiol 2021 Mar 30. Epub 2021 Mar 30.

Neurology Department, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.

Summary: Over the past 3 decades, tests of autonomic function have become increasingly standardized across most laboratories, particularly with commercially available equipment similar to other neurophysiologic tests. Most neurologically based laboratories perform four or five tests of autonomic function. Two of these, the sudomotor axon reflex response and the thermoregulatory sweat test (which some laboratories do not perform because it requires extensive equipment), examine sudomotor autonomic function. The remaining three, the cardiovascular response to a tilt table test, the cardiovascular response to the Valsalva maneuver, and the cardiac response to deep breathing examine cardiovascular autonomic function. Tests of sweating typically localize the lesion in the neuraxis, differentiating between central nervous system pathways, the spinal cord, or pre- or postganglionic roots or nerves. Tests of cardiovascular function delineate specific autonomic subsystem involvement, whether vagal parasympathetic as reflected in the deep breathing response and specific phases of the Valsalva maneuver or sympathetic adrenergic as reflected in the tilt table test and the other phases of the Valsalva. This review details the basic performance, analysis, and interpretation of these and a few other tests, with illustrative patient cases.
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http://dx.doi.org/10.1097/WNP.0000000000000789DOI Listing
March 2021

Does Auditory Environment Predict Speech Perception Outcomes in Elderly Cochlear Implant Patients?

Audiol Neurootol 2021 May 5:1-9. Epub 2021 May 5.

Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine, Ear Institute, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA.

Introduction: Cochlear implantation (CI) is a reliable and safe means by which sensorineural hearing loss can be ameliorated in the elderly population. However, a high degree of variation exists in postimplantation hearing outcomes for which some modifiable factors of the daily natural auditory environment may be contributory. In this study, we analyze the relationship between cochlear implant patient age, natural auditory environment, and postimplantation speech perception among older adults.

Methods: Data log from automatic environment classification enabled sound processors of postlingually deafened CI recipients ≥50 years old (n = 115) were obtained retrospectively and analyzed for time spent (hours per day) in listening environment and loudness (SPL dB). Speech perception testing was assessed in a subset of patients (n = 27) using open-set word recognition in quiet Consonant-Nucleus-Consonant in the short and intermediate postoperative period.

Results: The mean subject age was 70 years (range, 53-99 years). Average daily implant use was 10.8 h and was not significantly correlated with age (p = 0.23, Spearman's rho). Age was positively correlated with the percentage of hours spent at <40 and 40-50 dB and negatively correlated to proportional CI use at higher volume (60-70, 70-80, and >80 dB; rs = 0.21, 0.20, -0.20, -0.35, -0.43; p = 0.021, 0.036, 0.033, <0.001, <0.001, respectively). Age was positively correlated with CI use in the quiet scene (rs = 0.26, p = 0.006) and negatively correlated with scenes containing speech and noise (rs = -0.19, -0.25; p = 0.046, 0.007). Total hours of device use and time spent at <40, 40-50 dB, and quiet environments were significantly correlated with improved CNC word scores (rs = 0.48, 0.48, 0.51; p = 0.01, 0.01, <0.01, Spearman's rho). While all speech (speech in noise + speech) was not significantly correlated to improvements in speech perception, a medium effect size was observed (rs = 0.37, p = 0.057).

Discussion/conclusion: This study supports a relationship between auditory environment and age, with older CI recipients spending a greater proportion of time in quiet. Older CI users demonstrated greater improvements in speech perception with longer daily device use. Additional examination of the relationship between auditory environment and speech perception is necessary to conclusively guide future auditory rehabilitation efforts.
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http://dx.doi.org/10.1159/000513637DOI Listing
May 2021

Traumatic abdominal wall hernias: a single-center case series of surgical management.

Trauma Surg Acute Care Open 2020 1;5(1):e000495. Epub 2020 Dec 1.

Trauma Surgery and Critical Care, Memorial Hospital of Carbondale, Carbondale, Illinois, USA.

Background: Traumatic abdominal wall hernias (TAWHs) are a rare clinical entity that can be difficult to diagnose and manage. There is no consensus on management of TAWH due to its low incidence and complex concomitant injury patterns. We hereby present the largest single-center case series in the USA to characterize associated injury patterns, identify optimal strategies for hernia management, and determine outcomes.

Methods: Patients who presented with a TAWH from blunt trauma requiring operative management were retrospectively identified over a 14-year period. Demographic data, Injury Severity Score (ISS), associated injuries, type of repair, durability of repair, and complications were collected, and descriptive statistics were calculated.

Results: Fifteen patients were identified. The average age was 31±11 years, ISS 15±9, and body mass index 33.4±7.1 kg/m. Mechanisms included falls (13%), motor vehicle collisions (60%), motorcycle accidents (20%), and pedestrian versus motor vehicle collisions (7%). The most commonly associated injuries included colonic injuries (53%), long bone fractures (47%), pelvic fractures (40%), and small bowel injuries (33%). Nineteen hernia repairs were performed: 6 underwent primary suture repair (32%) and 13 used mesh (68%). There were four recurrences. We could not find any significant relationship between contamination and mesh use or recurrence. There was one mortality related to sepsis.

Discussion: TAWHs have an associated injury pattern involving fractures and abdominopelvic visceral injuries where a tailored approach is advisable. Without hollow viscous injuries and gross contamination, these hernias can be repaired safely with mesh in the acute setting. However, in patients with gross contamination or hemodynamic instability, the risk of recurrence with primary repair must be weighed against the risk of infection and prolonged surgery with mesh repair. In those cases, a delayed reconstruction in the elective setting may be optimal.
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http://dx.doi.org/10.1136/tsaco-2020-000495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709513PMC
December 2020

A Case Report of Malignant Eccrine Porocarcinoma Involving the Palm Requiring Surgical Excision and Free Flap Reconstruction.

Am J Case Rep 2020 Nov 26;21:e925231. Epub 2020 Nov 26.

Department of General Surgery, University of Illinois at Chicago, Chicago, IL, USA.

BACKGROUND Eccrine porocarcinoma (EPC) was first described in 1963 as an epidermotropic eccrine carcinoma. Fifty years later, its etiology remains poorly understood. The infrequent nature of this disease merits further inquiry into its etiology, presentation, and standards of management. Furthermore, the propensity for metastasis, which may be as high as 31% on presentation, increases the importance of investigating this rare disease. CASE REPORT The patient was a 63-year-old mechanic who presented with the lesion as a chronic wound following a chemical exposure. The lesion involved the ulnar aspect of his right palm and had concern for extension to the underlying tendons. He underwent a wide excision extending from the wrist to the proximal interphalangeal joint, preserving the ulnar neurovascular bundle. The hand was reconstructed with an anterolateral thigh fascia perforator flap and a skin graft. He had an excellent functional and cosmetic recovery. Unfortunately, he developed metastases to the lymph nodes, necessitating an axillary lymphadenectomy followed by adjuvant chemoradiation using concurrent cisplatin and docetaxel with radiation for 6 weeks. Follow-up at 18 months found no recurrence. CONCLUSIONS Cases of EPC presenting in the fingers have been managed with amputation of the involved phalanges; however, in addition to obtaining complete excision with negative margins, surgeons who deal with tumors of the hand must also consider the goals of limb preservation, functional preservation, and functional reconstruction. Options for reconstruction following excision include primary closure, dermal regeneration templates, skin grafts, flaps, and free-tissue transfer, depending on what tissue types are needed.
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http://dx.doi.org/10.12659/AJCR.925231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703490PMC
November 2020

Teaching NeuroImages: Cytotoxic Lesion of the Corpus Callosum Secondary to Influenza A.

Neurology 2021 03 14;96(12):e1697-e1698. Epub 2020 Sep 14.

From the Department of Neurology, Medical College of Wisconsin, Milwaukee, WI.

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http://dx.doi.org/10.1212/WNL.0000000000010858DOI Listing
March 2021

Microdrill in endoscopic stapes surgery: Is it safe?

Am J Otolaryngol 2020 Nov - Dec;41(6):102666. Epub 2020 Aug 12.

Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose: To assess the safety of using a microdrill in endoscopic vs microscopic stapes surgery.

Materials And Methods: A retrospective review of 29 adult ears with otosclerosis who underwent either an endoscopic or microscopic approach to microdrill stapedotomy.

Primary Outcome: Determine if transcanal endoscopic stapes surgery with the microdrill is as safe as microscopic stapes surgery. Secondary outcome: Bone and air pure-tone averages, air-bone gap, speech discrimination, overall surgical cost, and operative time were measured and analyzed. Complications such as post-operative dysgeusia, vertigo, readmission, revision and hearing loss were noted.

Results: 29 patients with otosclerosis were retrospectively reviewed, in total 14 endoscopic and 15 microscopic approaches were included, all performed over one-year period. None of the endoscopic surgeries require conversion to the microscope. No statistically significant audiometric differences between the endoscopic vs microscopic approaches in air pure-tone averages and air-bone gap. There were 82.8% air-bone gap closure to <15 dB with no significant difference in the percent of such closures between the endoscopic (85.7%) and microscopic groups (80%, P = .68). Three prostheses were used: 4.25 mm (17.2%), 4.5 mm (58.6%) and the 4.75 mm (24.1%) smart/eclipse. Endoscopic median operative time was 51 min vs 42 min for microscopic approach (P =.004).

Conclusions: The endoscopic with microdrill approach is criticized to lack depth perception, especially when using a microdrill to perform in stapedotomies. Our study showcases that using the microdrill use produces minimal differences in outcomes, cost, and is a safe modality to stapes surgery in both approaches.
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http://dx.doi.org/10.1016/j.amjoto.2020.102666DOI Listing
December 2020

Use of IL-5 Inhibitor Benralizumab as a Novel Therapy for Eosinophilic Otitis Media: Clinical Capsule and Review of Literature.

Otol Neurotol 2020 02;41(2):e238-e240

Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York.

Objective: We report a case of recurrent eosinophilic otitis media (EOM) successfully treated with the novel monoclonal IL-5 inhibitor benralizumab. We also review literature relevant to EOM diagnosis and potential for biologic treatment.

Patient: A 24-year-old woman with bilateral otitis media with effusion unresponsive to standard treatment.

Intervention(s): Multidisciplinary treatment using subcutaneous benralizumab after diagnosis of EOM.

Main Outcome Measure(s): Behavioral audiometry, peripheral serology, otomicroscopy, and eosinophilic otitis media symptom severity.

Results: Recalcitrant otitis media with effusion (OME) in the setting of nasal polyposis and asthma prompted clinical suspicion for EOM, which was confirmed by pathologic examination of middle ear effusion and soft tissue biopsy. Treatment with benralizumab was initiated by pulmonology and well-tolerated. Within 2 months of treatment onset there was a cessation of EOM symptoms, a reduction of peripheral eosinophil levels, and an improvement in conductive hearing loss.

Conclusions: Monoclonal antibodies such as benralizumab may be an effective treatment option for EOM. A high level of clinical suspicion in patients with bronchial asthma, nasal polyposis, and recalcitrant OME may allow early diagnosis of EOM. Awareness of emerging biologic treatment options is important in the management of this challenging entity and may prevent long-term sequelae.
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http://dx.doi.org/10.1097/MAO.0000000000002493DOI Listing
February 2020

Outcomes in patients with gunshot wounds to the brain.

Trauma Surg Acute Care Open 2019 17;4(1):e000351. Epub 2019 Nov 17.

Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Introduction: Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR.

Methods: We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation.

Results: 825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation.

Conclusion: We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition.

Level Of Evidence: Level II.
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http://dx.doi.org/10.1136/tsaco-2019-000351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861103PMC
November 2019

Amyloidosis Presenting as a Mass Abutting the Tympanic Membrane.

Ear Nose Throat J 2019 Sep 30:145561319868453. Epub 2019 Sep 30.

Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1177/0145561319868453DOI Listing
September 2019

ANCA: Alignment-Based Network Construction Algorithm.

IEEE/ACM Trans Comput Biol Bioinform 2021 Mar-Apr;18(2):512-524. Epub 2021 Apr 8.

Dynamic biological networks model changes in the network topology over time. However, often the topologies of these networks are not available at specific time points. Existing algorithms for studying dynamic networks often ignore this problem and focus only on the time points at which experimental data is available. In this paper, we develop a novel alignment based network construction algorithm, ANCA, that constructs the dynamic networks at the missing time points by exploiting the information from a reference dynamic network. Our experiments on synthetic and real networks demonstrate that ANCA predicts the missing target networks accurately, and scales to large-scale biological networks in practical time. Our analysis of an E. coli protein-protein interaction network shows that ANCA successfully identifies key temporal changes in the biological networks. Our analysis also suggests that by focusing on the topological differences in the network, our method can be used to find important genes and temporal functional changes in the biological networks.
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http://dx.doi.org/10.1109/TCBB.2019.2923620DOI Listing
April 2021

Facial Nerve Paralysis Occurring 4 Days following Stereotactic Radiosurgery for a Vestibular Schwannoma.

Asian J Neurosurg 2019 Jan-Mar;14(1):262-265

Stanford Cancer Institute, Stanford University, California, USA.

Stereotactic radiosurgery (SRS) is commonly used for the treatment of vestibular schwannomas given its high rate of tumor control and low rate of complications. Facial nerve palsy has been reported several months after treatment as a rare late complication of SRS. Here, we report a case of facial weakness occurring only 4 days after treatment and discuss potential etiology and management considerations.
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http://dx.doi.org/10.4103/ajns.AJNS_53_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417297PMC
April 2019

Epidermal Growth Factor Receptor Mutation Status Confers Survival Benefit in Patients with Non-Small-Cell Lung Cancer Undergoing Surgical Resection of Brain Metastases: A Retrospective Cohort Study.

World Neurosurg 2019 05 31;125:e487-e496. Epub 2019 Jan 31.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA. Electronic address:

Background: Few prognostic markers are available for patients with non-small-cell lung cancer (NSCLC) undergoing neurosurgical resection of symptomatic brain metastases.

Objective: We investigated whether tumor mutation status (EGFR, KRAS, ALK, ROS1, and BRAF) and treatment history were associated with survival after neurosurgery.

Methods: We reviewed the electronic health records of 104 patients with NSCLC with genomic profiling who underwent neurosurgical resection for symptomatic brain metastases at an academic institution between January 2000 and January 2018. We used multivariate Cox proportional hazards regression models to evaluate the association between overall survival (OS) after neurosurgery and clinicopathologic factors, including mutation status.

Results: Mean age of patients in this study was 61 (±12) years, and 44% were men. The median OS after neurosurgery was 24 months (95% confidence interval, 18-34 months). Our multivariate analysis showed that the presence of an EGFR mutation in the tumor was significantly associated with improved OS (hazard ratio [HR], 0.214; P = 0.029), independent of tyrosine kinase inhibitor use. Presence of KRAS, ALK, ROS1, and BRAF alterations was not associated with survival (all P > 0.05). Conversely, older age (HR, 1.039; P = 0.029), a history of multiple brain irradiation procedures (HR, 9.197; P < 0.001), and presence of extracranial metastasis (HR, 2.556; P = 0.016) resulted in increased risk of mortality.

Conclusions: Patients requiring surgical resection of an epidermal growth factor receptor-mutated NSCLC brain metastasis had an associated improved survival compared with patients without this mutation, independent of tyrosine kinase inhibitor use. Decreased survival was associated with older age, multiple previous brain radiation therapies, and extracranial metastasis.
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http://dx.doi.org/10.1016/j.wneu.2019.01.112DOI Listing
May 2019

In Reply: Commentary: Peritumoral Edema/Tumor Volume Ratio: A Strong Survival Predictor for Posterior Fossa Metastases.

Neurosurgery 2019 03;84(3):E232

Department of Neurosurgery Stanford University Stanford, California.

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http://dx.doi.org/10.1093/neuros/nyy574DOI Listing
March 2019

Surgical treatment for a case of coronary steal from a traumatic coronary artery-cameral fistula after blunt cardiac injury.

Int J Surg Case Rep 2018 13;51:50-53. Epub 2018 Aug 13.

University of Illinois at Chicago, 1740 W Taylor St, Chicago, IL 60612, United States; Advocate Christ Medical Center, 4440 95th St, Oak Lawn, IL 60453, United States.

Introduction: Blunt cardiac trauma covers a spectrum of injuries from clinically insignificant myocardial contusions to lethal ruptures of cardiac valves and chambers. Traumatic coronary artery-cameral fistulas (TCAF) are a rare sequelae of blunt chest trauma.

Case Presentation: A 53-year-old male developed a TCAF after a motor vehicle collision. He was found on admission to be in cardiogenic shock with an elevated troponin and intermittent bifascicular block. An echocardiogram revealed hypokinesis of the mid-anteroseptal myocardium with an ejection fraction of 50%. Cardiac catheterization revealed a pseudoaneurysm of the left anterior descending artery (LAD) with a fistulous connection to the right ventricle, shown to be associated with reversible anterior wall ischemia from distal LAD coronary steal phenomenon on a nuclear perfusion scan. Given the ischemic burden, he was treated with operative revascularization via a single vessel coronary artery bypass graft (CABG) using the left internal mammary artery to LAD.

Discussion: Early repair of TCAF can halt the progression of complications like left-to-right shunting, pulmonary hypertension, and heart failure. The two best described operative approaches to surgical closure of the fistula are either via external ligation or direct repair from within the recipient chamber, possibly with bypass grafting distal to the fistula site. Transcatheter closure and conservative management has been described for select patients with iatrogenic fistulas in recent literature.

Conclusion: High levels of clinical suspicion are necessary for the early detection and intervention of TCAF. Surgical or transcatheter interventions including fistula ligation and CABG can prevent later complications of heart failure.
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http://dx.doi.org/10.1016/j.ijscr.2018.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106710PMC
August 2018

A Traumatic Direct Inguinal Hernia from Pelvic Ring Disruption.

Case Rep Surg 2018 10;2018:5392430. Epub 2018 Jul 10.

Department of Surgery, Division of Trauma Critical Care, Advocate Christ Medical Center, 4440 W. 95th Street, Suite 183, South Oak Lawn, Chicago, IL 60453, USA.

Introduction: Pelvic fractures usually involve a high-energy traumatic mechanism and account for approximately 3% of all blunt traumatic skeletal injuries. Additional musculoskeletal injuries are found in over 80% of unstable pelvic fractures. Traumatic abdominal wall hernias (TAWHs) are a rare entity, and traumatic inguinal hernias (TIHs) associated with open-book pelvic fractures have not been described previously.

Case Presentation: We present the case of a 45-year-old male motorcyclist involved in a collision resulting in a traumatic direct inguinal hernia due to abdominal wall disruption from an open-book pelvic fracture. He underwent a combined operation with an open reduction and internal fixation (ORIF) of his pelvic fracture and an abdominal wall reconstruction with a modified Stoppa technique utilizing mesh for his hernia.

Discussion: This is a unique presentation of a TIH due to an open-book pelvic fracture after blunt abdominal trauma. The formation of TAWH is typically from a combination of local tangential shearing forces and a sudden rise in intraabdominal pressures damaging the muscle, fascia, and peritoneum while the skin remains intact. In patients without hollow viscous injuries and gross contamination, these hernias can be repaired safely with mesh in the acute setting simultaneously with pelvic reduction.
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http://dx.doi.org/10.1155/2018/5392430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079551PMC
July 2018

Commentary: Peritumoral Edema/Tumor Volume Ratio: A Strong Survival Predictor for Posterior Fossa Metastases.

Neurosurgery 2019 07;85(1):E18-E19

Department of Neurosurgery, Stanford University, Stanford, California.

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http://dx.doi.org/10.1093/neuros/nyy281DOI Listing
July 2019

A Randomized Controlled Trial on Intra-Abdominal Irrigation during Emergency Trauma Laparotomy; Time for Yet Another Paradigm Shift.

Bull Emerg Trauma 2018 Apr;6(2):100-107

University of Illinois, College of Medicine, Chicago, USA.

Objective: To determine the optimal volume of abdominal irrigation that will prevent surgical site infections (both deep and superficial), eviscerations and fistula formations; and improve 30-day mortality in trauma patients.

Methods: We conducted a three-arm parallel clinical superiority randomized controlled trial comparing different volumes of effluent (5, 10 and 20 liters) used in trauma patients (both blunt and penetrating) age 14 and above undergoing an emergency laparotomy between April 2002 and July 2004 in a busy urban Level 1 trauma center.

Results: After randomization, a total of 204 patients were analyzed. All patient groups were comparable with respect to age, gender distribution, admission injury severity score, and mechanism of injury, estimated blood loss and degree of contamination. The mortality rate overall was 1.96% (4/204).No differences were noted with respect to contamination, wound infection, fistula formation, and evisceration. The twenty liter group (Group III) showed a trend toward an increased incidence of deep surgical site infections when compared to the five liter (Group I) (=0.051) and ten liter (Group II) (=0.057) groups. This did not however reach statistical significance.

Conclusion: The old surgical adage "the solution to pollution is dilution" is not applicable to trauma patients. Our results suggest that using more irrigation, even when large amounts of contamination have occurred, does not reduce post-operative complications or affect mortality; and it may predispose patients to increased incidence of abscess formation. (Trial registration number: ISRCTN66454589).
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http://dx.doi.org/10.29252/beat-060203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928265PMC
April 2018

DNA methylation analysis for the treatment of meningiomas.

J Vis Surg 2017 5;3:178. Epub 2017 Dec 5.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.

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http://dx.doi.org/10.21037/jovs.2017.11.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730532PMC
December 2017

Invasive gastric mucormycosis: A case report of a deadly complication in an immunocompromised patient after penetrating trauma.

Int J Surg Case Rep 2017 15;40:90-93. Epub 2017 Sep 15.

University of Illinois at Chicago, 1740 W Taylor St, Chicago, IL 60612, United States; Advocate Christ Medical Center, 4440 95th St, Oak Lawn, IL 60453, United States.

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http://dx.doi.org/10.1016/j.ijscr.2017.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614730PMC
September 2017

Heterogeneity, functional specialization and differentiation of monocyte-derived dendritic cells.

Immunol Cell Biol 2017 03 17;95(3):244-251. Epub 2016 Oct 17.

Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Dendritic cells (DCs) are professional antigen-presenting cells that consist of functionally and phenotypically heterogeneous populations. Monocyte-derived DCs (moDCs) are a DC subset that have been attracting increasing interest owing to their potent influence on adaptive immune function and their rapid accumulation upon an inflammatory stimulus. Although early studies on moDCs mainly addressed infection, their emergence and function in other settings such as autoimmunity and allogeneic organ transplantation are now being increasingly appreciated. In this review, the relationship between murine monocyte subsets and the moDCs that arise from them is discussed. Their role in initiating and modulating innate and adaptive immune responses in various pathophysiological scenarios is also explored, including how they may separate their labour from conventional DCs. How these findings might relate to their human counterparts is also discussed. Overall, monocytes and moDCs exhibit complex and heterogeneous behaviours that are critical in responses against microbial invasion, autoimmunity and allograft rejection.
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http://dx.doi.org/10.1038/icb.2016.104DOI Listing
March 2017

Monocyte-Derived Dendritic Cells Impair Early Graft Function Following Allogeneic Islet Transplantation.

Cell Transplant 2017 02 13;26(2):319-326. Epub 2016 Oct 13.

Islet transplantation can cure type 1 diabetes but is limited by lack of donor organs and early graft dysfunction, such that many patients require multiple transplants to achieve insulin independence. Monocyte-derived dendritic cells (moDCs) arise during inflammation and allograft encounters where they can promote various innate and adaptive immune responses. To determine whether moDCs impair early graft function following allogeneic islet transplantation, we transplanted MHC-mismatched BALB/c (H-2d) islets into diabetic C57BL/6-CCR2.DTR recipients (H-2b) treated with either saline (control) or diphtheria toxin (DT) to deplete moDCs. Graft function was assessed by blood glucose (BG) measurement. DT treatment resulted in specific depletion of graft site moDCs posttransplant. Despite equivalent pretransplant BG levels [27.0 ± 1.3 vs. 29.6 ± 1.1 mM, not significant (ns)], DT recipients achieved lower posttransplant BG levels and better rates of normoglycemia than control recipients (11.0 ± 1.9 vs. 19.1 ± 1.4 mM, p = 0.004) at 1 day posttransplant in diabetic recipients. When a suboptimal donor dose of 200 islets was transplanted, DT-induced moDC depletion resulted in normoglycemia in 78% compared to 25% of control recipients (p = 0.03). As well as amelioration of graft dysfunction in the immediate peritransplant period, prolonged DT administration (15 days posttransplant) resulted in improved graft survival (21 vs. 11 days, p = 0.005). moDCs impair early graft function post-allogeneic islet transplantation. moDC depletion may allow for improved early graft function, permit transplantation with lower islet masses, and enhance graft survival.
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http://dx.doi.org/10.3727/096368916X693482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657768PMC
February 2017

Histological and Extended Clinical Outcomes After ABO-Incompatible Renal Transplantation Without Splenectomy or Rituximab.

Transplantation 2017 06;101(6):1433-1440

1 Department of Nephrology, Royal Melbourne Hospital, Victoria, Australia. 2 Department of Medical Biology, University of Melbourne, Victoria, Australia. 3 Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia. 4 Department Anatomical Pathology, Royal Melbourne Hospital, Victoria, Australia. 5 Department of Medicine, University of Melbourne, Victoria, Australia 6 Department of Nephrology, Western Hospital, Victoria, Australia.

Background: Excellent short-term results have been reported in ABO-incompatible (ABOi) renal transplant recipients managed solely with antibody removal and conventional immunosuppression. However, long-term clinical outcomes with this regimen and predictive information from protocol biopsies are lacking.

Methods: We compared outcome data in ABOi and ABO-compatible (ABOc) recipients receiving this regimen approximately 4 years posttransplant, and histology from biopsies approximately 12 months posttransplant.

Results: Patient and graft survivals among 54 ABOi recipients were 98.1% and 90.7%, respectively, at 4 years. Graft function was similar between ABOi (creatinine, 140.3 μmol/L) and ABOc recipients (creatinine, 140.2 μmol/L) (P = 0.99), with no significant change over the study period in either group (Δcreatinine, -0.83 vs 6.6 μmol/L) (P = 0.59). There was no transplant glomerulopathy in biopsies from either group. Interstitial fibrosis (IF) and tubular atrophy (TA) was present in 7 (28%) of 25 ABOi compared with 7 (20.6%) of 34 ABOc (P = 0.52). Progression of IF/TA from implantation was noted in 6 (24%) of 25 ABOi and 6 (17.6%) of 34 ABOc, respectively. C4d staining without antibody-mediated rejection was present in 13 (52%) 25 early posttransplant biopsies from ABOi recipients by immunohistochemistry, but in only 4 (16%) of 25 at 12 months.

Conclusions: ABO-incompatible renal transplant performed with antibody removal and conventional immunosuppression continues to provide excellent patient and graft survival, and stable renal function over 4 years. Coupled with absent transplant glomerulopathy and low rates of progressive IF/TA on earlier biopsies, this suggests that ABOi with conventional immunosuppression and antibody removal, without rituximab or splenectomy, can achieve long-term outcomes comparable to ABO-compatible transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001415DOI Listing
June 2017

Innate Allorecognition Results in Rapid Accumulation of Monocyte-Derived Dendritic Cells.

J Immunol 2016 09 29;197(5):2000-8. Epub 2016 Jul 29.

Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia

Although the mechanisms governing the innate recognition of pathogen-associated molecular patterns have been well defined, how allogeneic cellular stimuli evoke innate responses remains less so. In this article, we report that upon i.v. transfer (to avoid major iatrogenic interference), allogeneic but not syngeneic leukocytes could induce a rapid (after 1 d) accumulation of host monocyte-derived dendritic cells (moDCs) without any increase in conventional DCs. This occurred in various donor-host strain combinations, did not require MHC mismatch, and could be induced by various donor cell types including B cells, T cells, or NK cells. Using RAG(-/-)γc(-/-) and scid γc(-/-)mice with different MHC, we found that the presence of either donor or host lymphoid cells was required. Alloinduced moDC accumulation was significantly reduced when splenocytes from mice deficient in NK cells by genetic ablation were used as donors. A major component of this moDC accumulation appears to be recruitment. Our findings provide new insights into how the innate and adaptive immune system may interact during allogeneic encounters and thus transplant rejection.
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http://dx.doi.org/10.4049/jimmunol.1600181DOI Listing
September 2016

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.

J Clin Invest 2016 08 18;126(8):3036-52. Epub 2016 Jul 18.

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
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http://dx.doi.org/10.1172/JCI83416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966331PMC
August 2016

Plasmacytoid dendritic cells are short-lived: reappraising the influence of migration, genetic factors and activation on estimation of lifespan.

Sci Rep 2016 04 26;6:25060. Epub 2016 Apr 26.

The Walter &Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.

Plasmacytoid dendritic cells (pDCs) play an important role in immunity to certain pathogens and immunopathology in some autoimmune diseases. They are thought to have a longer lifespan than conventional DCs (cDCs), largely based on a slower rate of BrdU labeling by splenic pDCs. Here we demonstrated that pDC expansion and therefore BrdU labeling by pDCs occurs in bone marrow (BM). The rate of labeling was similar between BM pDCs and spleen cDCs. Therefore, slower BrdU labeling of spleen pDCs likely reflects the "migration time" (∼2 days) for BrdU labeled pDCs to traffic to the spleen, not necessarily reflecting longer life span. Tracking the decay of differentiated DCs showed that splenic pDCs and cDCs decayed at a similar rate. We suggest that spleen pDCs have a shorter in vivo lifespan than estimated utilizing some of the previous approaches. Nevertheless, pDC lifespan varies between mouse strains. pDCs from lupus-prone NZB mice survived longer than C57BL/6 pDCs. We also demonstrated that activation either positively or negatively impacted on the survival of pDCs via different cell-death mechanisms. Thus, pDCs are also short-lived. However, the pDC lifespan is regulated by genetic and environmental factors that may have pathological consequence.
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http://dx.doi.org/10.1038/srep25060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844974PMC
April 2016

PGE2 released by primary sensory neurons modulates Toll-like receptor 4 activities through an EP4 receptor-dependent process.

J Neuroimmunol 2016 Apr 10;293:8-16. Epub 2016 Feb 10.

School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.

Exogenous prostaglandin E2 (PGE2) displays mixed regulatory properties with regard to inflammatory gene expression in dorsal root ganglion (DRG) cells. We show here that endogenously-produced nanomolar concentrations of PGE2, such as that generated in response to Toll-like receptor 4 (TLR4) stimulation, inhibits both cyclooxygenase-2 (COX-2) and tumour necrosis factor alpha (TNFα) mRNA expression in DRG cells in an EP4 receptor-dependent manner. DRG neurons appear to be the major source of PGE2 in the DRG and likely serve as both an autocrine and paracrine system for limiting over-activation of both DRG neurons and glial cells in response to TLR4 stimulation.
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http://dx.doi.org/10.1016/j.jneuroim.2016.02.005DOI Listing
April 2016

Abducens Nerve Avulsion and Facial Nerve Palsy After Temporal Bone Fracture: A Rare Concomitance of Injuries.

World Neurosurg 2016 Apr 23;88:689.e5-689.e8. Epub 2015 Dec 23.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.

Background: Avulsion of the abducens nerve in the setting of geniculate ganglion injury after temporal bone fracture is unreported previously. We discuss clinical assessment and management of a patient with traumatic avulsion of cranial nerve (CN) VI in the setting of an ipsilateral CN VII injury after temporal bone fracture and call attention to this unusual injury.

Case Description: A 26-year-old man suffered a temporal bone fracture after a motor vehicle accident and developed diplopia and right-sided facial droop. Six weeks after the accident, the patient was readmitted with worsening diplopia and ipsilateral facial weakness. He demonstrated absent lateral gaze on the right suggestive of either restrictive movement or right.

Cn Vi Deficit: In addition, he had right-sided facial palsy graded as 6/6 House-Brackmann. High-resolution computed tomography demonstrated a right-sided longitudinal otic capsule-sparing temporal bone fracture that propagated into the facial nerve canal and geniculate fossa. Magnetic resonance imaging revealed discontinuity of the right CN VI between the pons and the Dorello canal, as well as injury to the ipsilateral geniculate ganglion. CN VII was intact proximally, from the pons through the internal auditory canal. Consensus was reached to proceed with conservative management. At 13 months after injury, the patient reported 1/6 House-Brackmann with no improvement in CN VI function.

Conclusions: This case illustrates 2 subtle findings on imaging with potential therapeutic implications, notably the role of surgical intervention for facial nerve palsy.
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http://dx.doi.org/10.1016/j.wneu.2015.11.076DOI Listing
April 2016

Monocyte-Derived Dendritic Cells Promote Th Polarization, whereas Conventional Dendritic Cells Promote Th Proliferation.

J Immunol 2016 Jan 9;196(2):624-36. Epub 2015 Dec 9.

Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia;

Monocyte-derived dendritic cells (moDCs) dramatically increase in numbers upon infection and inflammation; accordingly, we found that this also occurs during allogeneic responses. Despite their prominence, how emergent moDCs and resident conventional DCs (cDCs) divide their labor as APCs remain undefined. Hence, we compared both direct and indirect presentation by murine moDCs versus cDCs. We found that, despite having equivalent MHC class II expression and in vitro survival, moDCs were 20-fold less efficient than cDCs at inducing CD4(+) T cell proliferation through both direct and indirect Ag presentation. Despite this, moDCs were more potent at inducing Th1 and Th17 differentiation (e.g., 8-fold higher IFN-γ and 2-fold higher IL-17A in T cell cocultures), whereas cDCs induced 10-fold higher IL-2 production. Intriguingly, moDCs potently reduced the ability of cDCs to stimulate T cell proliferation in vitro and in vivo, partially through NO production. We surmise that such division of labor between moDCs and cDCs has implications for their respective roles in the immune response.
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http://dx.doi.org/10.4049/jimmunol.1501202DOI Listing
January 2016

Endoscopic repair of duodenocutaneous fistula with an enterocutaneous fistula plug.

Gastrointest Endosc 2016 Jan 28;83(1):258-9. Epub 2015 Aug 28.

Loyola University Stritch School of Medicine, Maywood, Illinois, USA.

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http://dx.doi.org/10.1016/j.gie.2015.07.017DOI Listing
January 2016