Publications by authors named "William W Hope"

192 Publications

Prospective, multicenter study of P4HB (Phasix™) mesh for hernia repair in cohort at risk for complications: 3-Year follow-up.

Ann Med Surg (Lond) 2021 Jan 15;61:1-7. Epub 2020 Dec 15.

Department of Surgery, The University of Tennessee Health Science Center, Memphis, TN, USA.

Background: This study represents a prospective, multicenter, open-label study to assess the safety, performance, and outcomes of poly-4-hydroxybutyrate (P4HB, Phasix™) mesh for primary ventral, primary incisional, or multiply-recurrent hernia in subjects at risk for complications. This study reports 3-year clinical outcomes.

Materials And Methods: P4HB mesh was implanted in 121 patients via retrorectus or onlay technique. Physical exam and/or quality of life surveys were completed at 1, 3, 6,12, 18, 24, and 36 months, with 5-year (60-month) follow-up ongoing.

Results: A total of n = 121 patients were implanted with P4HB mesh (n = 75 (62%) female) with a mean age of 54.7 ± 12.0 years and mean BMI of 32.2 ± 4.5 kg/m (±standard deviation). Comorbidities included: obesity (78.5%), active smokers (23.1%), COPD (28.1%), diabetes mellitus (33.1%), immunosuppression (8.3%), coronary artery disease (21.5%), chronic corticosteroid use (5.0%), hypo-albuminemia (2.5%), advanced age (5.0%), and renal insufficiency (0.8%). Hernias were repaired via retrorectus (n = 45, 37.2% with myofascial release (MR) or n = 43, 35.5% without MR), onlay (n = 8, 6.6% with MR or n = 24, 19.8% without MR), or not reported (n = 1, 0.8%). 82 patients (67.8%) completed 36-month follow-up. 17 patients (17.9% ± 0.4%) experienced hernia recurrence at 3 years, with n = 9 in the retrorectus group and n = 8 in the onlay group. SSI (n = 11) occurred in 9.3% ± 0.03% of patients.

Conclusions: Long-term outcomes following ventral hernia repair with P4HB mesh demonstrate low recurrence rates at 3-year (36-month) postoperative time frame with no patients developing late mesh complications or requiring mesh removal. 5-year (60-month) follow-up is ongoing.
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http://dx.doi.org/10.1016/j.amsu.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750179PMC
January 2021

Closed Loop Bowel Obstruction From a Loose Staple After Laparoscopic Appendectomy.

Am Surg 2020 Dec 22:3134820972978. Epub 2020 Dec 22.

Department of Surgery, 24520New Hanover Regional Medical Center, Wilmington, NC, USA.

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http://dx.doi.org/10.1177/0003134820972978DOI Listing
December 2020

The Effect of Tack Fixation Methods on Outcomes in Laparoscopic Ventral Hernia Repair.

J Laparoendosc Adv Surg Tech A 2020 Nov 4. Epub 2020 Nov 4.

Department of Surgery, New Hanover Regional Medical Center, Wilmington, North Carolina, USA.

There are weak data comparing the safety and efficacy of absorbable and permanent tacks in laparoscopic ventral hernia repair with tack-only mesh fixation. In this study, we compared recurrence and complications rates following hernia repair using either only absorbable or only permanent tacks. Data from the Americas Hernia Society Quality Collaborative database were retrospectively reviewed as accessed on June 30, 2017. The query included patients 18 years of age or older, who had undergone laparoscopic ventral hernia repair with mesh using tack-only fixation. Study groups were divided into patients who had only absorbable tacks used and those with only permanent tacks. Propensity score matching was applied to strengthen the groups. There were no significant differences in demographics, comorbidities, or hernia characteristics between the groups. There were no significant differences in length of stay, hernia recurrence rate, or surgical site infection. The permanent tack group had a significantly higher rate of surgical site occurrences (SSOs), as evidenced by a higher rate of seroma formation. When comparing the rates of complications and recurrences between absorbable and permanent tacks in the setting of laparoscopic ventral hernia repair with tack-only mesh fixation, the only significant difference found was that the permanent group had a higher rate of SSO due to seroma formation. Because this complication did not lead to an increased intervention rate, the clinical significance of this finding remains in question.
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http://dx.doi.org/10.1089/lap.2020.0661DOI Listing
November 2020

FDA Public Workshop Summary: Advancing Animal Models for Antibacterial Drug Development.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

Office of Infectious Diseases, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.

The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled "Advancing Animal Models for Antibacterial Drug Development" on 5 March 2020. The workshop mainly focused on models of pneumonia caused by and The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.
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http://dx.doi.org/10.1128/AAC.01983-20DOI Listing
December 2020

Laparotomy Closure: A Review of Available Education Training Models.

Surg Technol Int 2020 Nov;37:121-125

University of North Carolina - Chapel Hill, Department of Surgery, New Hanover Regional Medical Center, Wilmington, North Carolina.

Introduction: As studies continue to provide advanced knowledge concerning abdominal wall closure after laparotomy, there have been many improvements in surgical techniques and recommended closure materials. However, there continues to be a high rate of incisional hernias following exploratory laparotomies. The goal of this review is to provide a comprehensive assessment of available educational models for laparotomy closure.

Material And Methods: A comprehensive literature review was made using PubMed, Cochrane, and NCBI MeSH databases to find the most relevant articles associated with various abdominal closure models using specific keywords.

Results: Human cadaver, animal, synthetic, and virtual reality models were reviewed. Strengths and limitations of each model were described.

Conclusion: Each model has practical benefits in its ability to mimic in vitro anatomy and the experiential similarities to actual laparotomy closure. However, there are also limitations and potential cost-prohibitive factors for individual models. Overall, while there have been some advances in synthetic and virtual models, human cadaver and porcine models remain the most similar to human abdominal wall closures.
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November 2020

An Evaluation of Tension Measurements During Myofascial Release for Hernia Repair.

Am Surg 2020 Sep 27;86(9):1159-1162. Epub 2020 Aug 27.

Department of Surgery, New Hanover Regional Medical Center, Wilmington, NC, USA.

Tension-free repairs have revolutionized the way we repair hernias. To help reduce undue tension when performing ventral hernia repair, multiple different techniques of myofascial releases have been described. The purpose of this project is to evaluate tension measurements for commonly performed myofascial releases in abdominal wall hernia repair. Patients undergoing myofascial release techniques for their ventral hernias were enrolled in a prospective Institutional Review Board-approved protocol to measure abdominal wall tension from June 1, 2011 to August 1, 2019. Abdominal wall tensions were measured using tensiometers before and after myofascial release techniques. Descriptive statistics were performed and data were analyzed. Thirty patients had tension measurements (5 anterior myofascial separation, 25 posterior myofascial separation with transversus abdominis release [TAR]). Average age was 60.1 years (range 29-81), 83% Caucasian, 53% female, and 42% recurrent hernias. The average hernia defect in patients undergoing anterior myofascial release was 117.3 cm, and the average mesh size was 650 cm. The reduction in tension after anterior release was 4.7 lbs (2.7 lbs vs 7.4 lbs). The average hernia defect in patients undergoing posterior myofascial release (TAR) was 183 cm, and the average mesh size was 761.36 cm. The reduction in tension after bilateral posterior rectus sheath incision was 2.55 lbs (5.01 lbs vs 7.56 lbs) with 0.66 lbs further reduction in tension after TAR (4.35 lbs vs 5.01). In this evaluation, abdominal wall tension measurements are shown to be a feasible adjunct during open hernia repair. Preliminary data show tension reductions associated with the different myofascial release techniques and, with further study, may be a useful intraoperative adjunct for decision making in hernia repair.
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http://dx.doi.org/10.1177/0003134820945243DOI Listing
September 2020

Metallo-β-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline.

Antimicrob Agents Chemother 2020 09 21;64(10). Epub 2020 Sep 21.

Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.

Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-β-lactamase (MBL) enzymes are a particular concern and are increasingly disseminated worldwide, though particularly in Asia. Many MBL producers have multiple further drug resistances, leaving few obvious treatment options. Nonetheless, and more encouragingly, MBLs may be less effective agents of carbapenem resistance , under zinc limitation, than Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed β-lactam-β-lactamase inhibitor combinations, although several stable agents and inhibitor combinations are at various stages in the development pipeline. These potential therapies, along with the epidemiology of producers and current treatment options, are the focus of this review.
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http://dx.doi.org/10.1128/AAC.00397-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508574PMC
September 2020

Population Pharmacokinetics of Praziquantel in Pregnant and Lactating Filipino Women Infected with Schistosoma japonicum.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom.

An estimated 40 million women of reproductive age are infected with one of three species of the waterborne parasite spp. Treatment with praziquantel (PZQ) via mass drug administration (MDA) campaigns is the mainstay of schistosomiasis control for populations living in areas of endemicity. The World Health Organization recommends that pregnant and lactating women be included in schistosomiasis MDA programs, and several recent studies have evaluated the safety and efficacy of PZQ use during pregnancy. To date, there are no data describing PZQ pharmacokinetics (PK) during pregnancy or among lactating postpartum women. As part of a randomized controlled trial investigating the safety and efficacy of PZQ during human pregnancy, we examined the PK of this therapeutic drug among three distinct cohorts of women infected with in Leyte, Philippines. Specifically, we studied the PK properties of PZQ among early- and late-gestation pregnant women ( = 15 each) and lactating postpartum women ( = 15) with schistosomiasis. We found that women in early pregnancy had increased apparent clearance and lower area-under-the-curve (AUC) values that may be related to physiological changes in drug clearance and/or changes in oral bioavailability. There was no relationship between body weight and apparent clearance. The mean ± standard deviation partition ratio of plasma to breast milk was 0.36. ± 0.13. The estimated median infant PZQ daily dose would be 0.037 mg/kg of body weight ingested from breast milk, which is significantly lower than the dosage required for antischistosomal activity and not known to be harmful to the infant. Our PK data do not support the suggestion to delay breastfeeding 72 h after taking PZQ. Results can help inform future drug efficacy studies in pregnant and lactating women with schistosomiasis.
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http://dx.doi.org/10.1128/AAC.00566-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449211PMC
August 2020

The Effect of Fixation Methods on Outcomes in Laparoscopic Ventral Hernia Repair.

Surg Technol Int 2020 May;36:112-118

Department of Surgery, New Hanover Regional Medical Center, Wilmington, North Carolina.

Introduction: The ideal fixation methods in laparoscopic ventral hernia repair continue to be debated. Early series touted the importance of suture and tack fixation; however, due to the perceived concern for increased pain, newer tack-only fixation methods have emerged. The purpose of this study was to compare fixation methods in laparoscopic ventral hernia repairs using a large hernia database.

Materials And Methods: We retrospectively reviewed data from the Americas Hernia Society Quality Collaborative (AHSQC) database comparing two groups of fixation (all tacks vs. all sutures and tacks and sutures and permanent tacks vs. sutures and absorbable tacks). The primary outcome measures were hernia recurrence, hospital length of stay, surgical site infection, surgical site occurrence, pain intensity scores, and quality-of-life scores evaluated at 30 days, six months, one year, and two years, Propensity score matching was used to strengthen the retrospective nature of the study.

Results: Eight hundred and fifty-two patients were included for analysis; 426 patients with tack-only fixation and 426 with tack and suture fixation. Eight hundred and four total patients were included for analysis; 402 patients with sutures with permanent tacks and 402 patients with sutures and absorbable tacks. For both comparisons, there was no significant difference in hospital length of stay, hernia recurrence rate, surgical site infection rate, surgical site occurrence rate, or surgical site occurrence requiring procedural intervention (p>0.05). There was also no significant difference in pain scores and quality-of-life scores at baseline, 30 days, six months, and one year. The only significant difference was in quality of life at two years. Patients with sutures and tacks had better quality-of-life scores compared with patients with tacks only (64 vs. 39, p<0.001).

Conclusion: Data available in the AHSQC database reviewed in this study indicate that there were no clinically significant differences between types of fixation methods when used in laparoscopic ventral hernia repair.
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May 2020

A preliminary evaluation of two different meshes in minimally invasive inguinal hernia surgery.

Surg Endosc 2021 Mar 30;35(3):1342-1347. Epub 2020 Mar 30.

Department of Surgery, New Hanover Regional Medical Center, 2131 South 17th Street, Wilmington, NC, 28402, USA.

Background: Many meshes are available for use in laparoscopic inguinal hernia repair. The surgeon must consider several factors when choosing a mesh for hernia repair including clinical outcomes, cost, and ease of use. The purpose of this study was to compare two different lightweight polypropylene meshes for laparoscopic and robotic inguinal hernia repairs.

Methods: Subjects were randomized immediately before surgery. Data were reported in N (%) and median [Q1-Q3], comparisons of mesh insertion time were tested using a 2 × 2 ANOVA on the ranked times, comparisons between categorical variables were tested with Fisher's Exact, and all data were analyzed using SAS® 9.4 (SAS Institute, Inc.).

Results: Between January 2015 and June 2016, 50 subjects were enrolled; two were excluded. Of 48 eligible subjects, most were Caucasian (N = 42, 88%), male (N = 37, 77%), with a median age of 63, and were randomized evenly between 3DMax™ mesh and Ultrapro® mesh. Robotic mesh placement significantly increased insertion time regardless of mesh type (p < .0001). When comparing NASA-TLX self-assessment surveys, there was no significant difference between the meshes in difficulty of placement. The type of mesh did not significantly impact the insertion time regardless of robot use (p = 0.523).

Conclusion: Our data demonstrate that mesh insertion times comparing two different lightweight polypropylene meshes were not significantly different. Increased insertion times associated with robotic repair are likely due to the mechanics of robotic suturing and associated learning curve. Our data suggest that these meshes can be used interchangeably based on the surgeon's preference.

Clinical Trial Registration Number: NCT01825187.
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http://dx.doi.org/10.1007/s00464-020-07512-9DOI Listing
March 2021

Methodological features of clinical pharmacokinetic-pharmacodynamic studies of antibacterials and antifungals: a systematic review.

J Antimicrob Chemother 2020 06;75(6):1374-1389

Bristol Centre for Antimicrobial Research & Evaluation, Infection Sciences, Pathology Science Quarter, North Bristol NHS Trust, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK.

Background: Pharmacokinetic (PK)-pharmacodynamic (PD) indices relate measures of drug exposure to antibacterial effect. Clinical PK-PD studies aim to correlate PK-PD indices with outcomes in patients. Optimization of dosing based on pre-clinical studies means that PK-PD relationships are difficult to establish; therefore studies need to be designed and reported carefully to validate pre-clinical findings.

Objectives: To describe the methodological features of clinical antibacterial and antifungal PK-PD studies that reported the relationship between PK-PD indices and clinical or microbiological responses.

Methods: Studies published between 1980 and 2015 were identified through systematic searches. Methodological features of eligible studies were extracted.

Results: We identified 85 publications containing 97 PK-PD analyses. Most studies were small, with fewer than 100 patients. Around a quarter were performed on patients with infections due to a single specific pathogen. In approximately one-third of studies, patients received concurrent antibiotics/antifungals and in some other studies patients received other treatments that may confound the PK-PD-outcome relationship. Most studies measured antimicrobial concentrations in blood/serum and only four measured free concentrations. Most performed some form of regression, time-to-event analysis or used the Hill/Emax equation to examine the association between PK-PD index and outcome. Target values of PK-PD indices that predict outcomes were investigated in 52% of studies. Target identification was most commonly done using recursive partitioning or logistic regression.

Conclusions: Given the variability in conduct and reporting, we suggest that an agreed set of standards for the conduct and reporting of studies should be developed.
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http://dx.doi.org/10.1093/jac/dkaa005DOI Listing
June 2020

An Evaluation of Fascial Closure Techniques in Open Ventral Hernia Repair: Practice Patterns and Short-Term Outcomes.

Am Surg 2019 Nov;85(11):1213-1218

The best method for fascial closure during hernia repair remains unknown. This study evaluates the impact of fascial closure techniques on short-term outcomes. All patients undergoing open ventral hernia repair were queried using the Americas Hernia Society Quality Collaborative database. Analysis was stratified by suture type (absorbable and permanent) and technique (figure-of-eight, running, and interrupted). Outcome measures included SSI, surgical site occurrence (SSO), SSO requiring intervention, recurrence rate, and quality of life. Descriptive statistics and logistic regression were used. The study included 6544 patients. Two-thirds of surgeons closed fascia during ventral hernia repair with absorbable suture and one-third with permanent suture. In the absorbable group, 17 per cent used figure-of-eight, 46 per cent running, and 4 per cent interrupted suture. In the permanent group, 13 per cent used figure-of-eight, 8 per cent running, and 11 per cent interrupted suture. There was no significant association between SSO and closure technique ( = 0.2). However, SSO and suture type were significant ( < 0.001) with the odds of SSO for closure with absorbable suture being 62 per cent higher than the odds of permanent. Fascial closure technique and suture type had no significant association ( > 0.5) with SSI, SSO requiring intervention, hernia recurrence rate, or HerQLes or NIH PROMIS 3a scores at 30 days or 6 months. Fascial closure technique and suture material do not have a major impact on outcomes in ventral hernia repair. Despite a significantly higher rate of SSO for absorbable sutures than permanent, this did not increase the rate of interventions.
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November 2019

Practice Patterns and Attitudes of Surgeons on the Use of Prophylactic Mesh to Prevent Parastola Hernia: A Cross-sectional Survey.

Wound Manag Prev 2019 09;65(9):14-23

New Hanover Regional Medical Center, Wilmington, NC.

Information about surgeons' attitudes toward using prophylactic mesh (PM) for parastomal hernia (PSH) prevention is limited.

Purpose: A survey was conducted to assess attitudes/beliefs and surgical practice related to PM use for preventing PSH.

Methods: A cross-sectional email survey was conducted during April 2017 among members (surgeons) of the American Hernia Society, European Hernia Society, and International Hernia Collaboration. Survey items included participant demographic characteristics, knowledge about the incidence of PSH, number of permanent stomas created annually, beliefs/opinions (knowledge/interest) regarding the use of PM, and surgical practices (mesh type and position). Data were collected and tallied using SurveyMonkey. Descriptive statistics were used to analyze the data.

Results: Of the 5445 emails sent, 497 responses were received, 235 (47.3%) from the United States and 197 (39.6%) from Europe. The majority of participants were general surgeons (371, 74.6%); a small percentage were colorectal surgeons (37, 7.4%). Most respondents (353, 71.0%) reported at least 11 years of surgical experience, with 37.3% reporting >20 years' experience. The majority of respondents (340, 68.4%) created <15 ostomies per year, more than half (252, 50.7%) consider the incidence of PSH 30% or below, and 107 (22%) use PM. The most common reason for not using mesh was concern about mesh-related complications (141, 41.5%). When asked about type of mesh, most surgeons (153/245, 62.4%) preferred permanent mesh and an open retromuscular approach (97/278, 34.9%).

Conclusion: Results of the present survey show ongoing ambiguity regarding the use of PM for PSH prevention. Education to increase awareness about the incidence of PSH and well-designed safety and effectiveness studies of preventive strategies are needed to help surgeons optimize PSH prevention strategies.
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September 2019

Clinical Application of the Measurement of Abdominal Wall Tension in Hernia Repair.

Surg Technol Int 2019 11;35:129-134

Department of Surgery, New Hanover Regional Medical Center, Wilmington, NC.

Abdominal wall tension is an integral concept in hernia repair. Most of the described techniques attempt to reduce abdominal wall tension by using mesh prosthetics or myofascial release. Although the concept of a "tension-free" hernia repair is well-understood and appreciated by surgeons, quantitative information about abdominal wall tension is limited. This review evaluates the published literature related to abdominal wall tension and summarizes how the measurement of intraoperative tension can guide clinical decision-making. Most of the methods and techniques for measuring abdominal wall tension are similar and involve the use of tensiometers. However, there is no accepted standardized technique. Baseline tension measurements confirm the concept of a baseline physiological tension, and it has been observed that tension does not correlate with hernia width. When the tension is considered to be too great during hernia repair, intraoperative techniques such as myofascial release can be used to reduce tension to physiological values. Emerging data from clinical studies on tension have added to our understanding of the mechanics and physiology of the abdominal wall. Standardized devices and measurement techniques need to be developed and validated to foster the utility of tension measurements in hernia repair.
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November 2019

Enhanced Recovery after Surgery (ERAS) Protocols Expanded over Multiple Service Lines Improves Patient Care and Hospital Cost.

Am Surg 2019 Sep;85(9):1044-1050

Enhanced recovery after surgery (ERAS) may improve patients' postoperative course. Our center implemented the ERAS protocol for the colorectal service in 2016, and then expanded to multiple service lines over the course of 1.5 years. Our aim was to determine whether broad implementation of ERAS protocols across different service lines could improve patient care. All ERAS patients from 2018 were captured prospectively. For each service line using ERAS, one full year of data preceding ERAS was compared. ERAS service lines included colorectal, gynecology laparoscopic, gynecology open, hepatopancreaticobiliary, urology - nephrectomy and cystectomy, spinal fusion, cardiac surgery-coronary artery bypass grafting. ERAS and pre-ERAS services were compared based on length of stay (LOS), complications, readmission, and mortality rates. In addition, hospital costs were collected during this time frame. ERAS protocols significantly decreased LOS for colorectal, gynecology, and spine. Complications were significantly decreased in colorectal, gynecology, urology, and spine. Readmissions did not significantly increase in any service line except spine. There was no significant change in mortality. ERAS proved to save the hospital 1847 days and cost saving of almost $5 million in 2018. Implementing ERAS broadly improved patient outcomes (LOS, complications, readmission, and mortality) while providing cost savings to the hospital.
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September 2019

Physiologic Tension: Technique for Measuring and Baseline Values.

Am Surg 2019 Sep;85(9):998-1000

Tension is one of the most discussed terms related to hernia surgery and repair. Despite the universally accepted opinion that tension and reduction of tension are important concepts in hernia repair, there is very little known about the physiologic tension of the abdominal wall related to ventral hernia repair. The purpose of this project was to attempt to measure physiologic tension in patients without hernia repair and help determine a normal baseline tension. Patients were enrolled in a prospective institutional review board-approved protocol to measure abdominal wall tension from February 2014 to present. Patients undergoing abdominal surgery without hernia repair were included. Demographic information and operative details were documented. Abdominal wall tensions were measured using scales attached to Kocher clamps that are clamped to the fascia and then brought together in the midline. Total tension, surgeon's estimation of tension, and grading of the fascia were recorded. Descriptive statistics were calculated. Eleven patients met the inclusion criteria and had tension measurements performed during surgery. The average age was 58 years, with 55 per cent of them being white and 82 per cent being male, with an average BMI of 27. Operations included exploratory laparotomy for small bowel pathology in six patients, colorectal surgery in three patients, and splenectomy in a trauma patient. Average tension measurements for these patients were 1.9 lbs. Surgeon grading of tension was an average of 2.2 (range, 1-5). Obtaining tension measurements is feasible during abdominal surgery. Physiologic tension seems to be approximately 2 pounds. Further study is needed with a larger sample of patients.
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September 2019

Amphotericin B Penetrates into the Central Nervous System Through Focal Disruption of the Blood Brain Barrier in Experimental Hematogenous Meningoencephalitis.

Antimicrob Agents Chemother 2019 Oct 7. Epub 2019 Oct 7.

Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, NY, USA.

Hematogenous meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeability and low cerebrospinal fluid (CSF) concentrations, but is effective in treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An BBB model was serially infected with Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml were then provided, vascular and CNS compartments were sampled 4h later. For correlation, rabbits with experimental HCME received a single dose of DAMB 1 mg/kg or LAMB 5 mg/kg, and were euthanized after 1, 3, 6 and 24h. Evans blue solution (2%) 2 ml/kg administered IV one hour prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using UPLC. For selected rabbits, MRI scans performed on days 1-7 postinoculation were acquired before and after IV bolus Gd-DTPA at 15min intervals through 2h post-injection. The greatest degree of penetration of DAMB and LAMB through the BBB occurred after 24h of exposure (=0.0022). the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue (≤0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low CSF concentrations.
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http://dx.doi.org/10.1128/AAC.01626-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879260PMC
October 2019

Mid-Year Medical Knowledge Milestones and ABSITE Scores in First-Year Surgery Residents.

J Surg Educ 2020 Mar - Apr;77(2):273-280. Epub 2019 Sep 28.

Department of Surgery, Good Samaritan Hospital TriHealth, Cincinnati, Ohio.

Objective: Accreditation Council for Graduate Medical Education (ACGME) Surgery milestone ratings in the "Knowledge of Diseases and Conditions" (MK1) sub competency have been shown to correlate with American Board of Surgery In Training Examination (ABSITE) scores, and hypothesized to predict them. To better assess the predictive value of the MK1 milestone and avoid the potential bias caused by previous years' ABSITE scores, we designed a study including only first-year (PGY-1) residents and analyzed the correlation between their mid-year MK1 ratings and their scores in the ABSITE they took approximately a month later.

Methods: De-identified United States Medical Licensing Examination (USMLE) Step 1 and Step 2 scores, mid-year MK1 milestone ratings and the subsequent ABSITE standard scores for the five academic years from 2014-2015 to 2018-2019 were collected and tabulated for 247 PGY-1 preliminary- and categorical-track residents from ten ACGME-accredited surgery residency programs.

Results: The mid-year rating of PGY-1 residents' MK1 was predictive of their subsequent first ABSITE score for the entire cohort and for the categorical residents' subset. Notably, controlling for all other independent predictors, each half-point increase in MK1 rating was associated with a 25-point increase in ABSITE score. Preliminary residents performed significantly worse on the ABSITE, and their scores did not correlate significantly with their MK1 ratings.

Conclusions: The mid-year rating of PGY-1 residents' MK1 was predictive of their subsequent first ABSITE score for the entire cohort and for the categorical but not the preliminary residents. This finding suggests that evaluators correctly rated MK1 higher in the categorical residents who did perform better on the subsequent ABSITE.
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http://dx.doi.org/10.1016/j.jsurg.2019.09.012DOI Listing
September 2019

Pharmacodynamics of Isavuconazole in a Rabbit Model of Cryptococcal Meningoencephalitis.

Antimicrob Agents Chemother 2019 09 23;63(9). Epub 2019 Aug 23.

Duke University Medical Center, Durham, North Carolina, USA.

spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis.
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http://dx.doi.org/10.1128/AAC.00546-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709487PMC
September 2019

Population Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy Subjects.

Antimicrob Agents Chemother 2019 06 24;63(6). Epub 2019 May 24.

University of Liverpool, Liverpool, United Kingdom.

VL-2397, a novel, systemic antifungal agent, has potent and fungicidal activity against species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397. Healthy subjects aged 18 to 55 years received single doses of VL-2397, ranging from 3 to 1,200 mg, multiple daily doses of 300, 600, or 1,200 mg for 7 days, or 300 mg three times/day for 7 days followed by 600 mg daily for 21 days. Plasma samples were collected throughout the dosing intervals. Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time were increased less than dose proportionally for doses above 30 mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment nonlinear saturable binding model fit the data well. Clearance increased with dose, and mean values ranged from 0.4 liters/h at 3 mg to 8.5 liters/h at 1,200 mg. Mean volume in the central compartment ranged from 4.8 to 6.9 liters across doses. In the first 24 h, once-daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/liter, regardless of dose, with slow clearance over time. Administration of 300 mg every 8 h achieved concentrations above 1 mg/liter over an entire 24-h period. There was a significant relationship between body surface area and clearance. The data suggest that VL-2397 has nonlinear saturable binding kinetics. Protein binding is the likely primary source of the nonlinearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets.
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http://dx.doi.org/10.1128/AAC.00163-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535549PMC
June 2019

Generating Robust and Informative Nonclinical and Bacterial Infection Model Efficacy Data To Support Translation to Humans.

Antimicrob Agents Chemother 2019 05 25;63(5). Epub 2019 Apr 25.

Antibacterial Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA

In June 2017, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled "Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens." The aims were to discuss details of various PK/PD models and identify sound practices for deriving and utilizing PK/PD relationships to design optimal dosage regimens for patients. Workshop participants encompassed individuals from academia, industry, and government, including the United States Food and Drug Administration. This and the accompanying review on clinical PK/PD summarize the workshop discussions and recommendations. Nonclinical PK/PD models play a critical role in designing human dosage regimens and are essential tools for drug development. These include and efficacy models that provide valuable and complementary information for dose selection and translation from the laboratory to human. It is crucial that studies be designed, conducted, and interpreted appropriately. For antibacterial PK/PD, extensive published data and expertise are available. These have been leveraged to develop recommendations, identify common pitfalls, and describe the applications, strengths, and limitations of various nonclinical infection models and translational approaches. Despite these robust tools and published guidance, characterizing nonclinical PK/PD relationships may not be straightforward, especially for a new drug or new class. Antimicrobial PK/PD is an evolving discipline that needs to adapt to future research and development needs. Open communication between academia, pharmaceutical industry, government, and regulatory bodies is essential to share perspectives and collectively solve future challenges.
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http://dx.doi.org/10.1128/AAC.02307-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6496039PMC
May 2019

A Preliminary Assessment of Abdominal Wall Tension in Patients Undergoing Retromuscular Hernia Repair.

Surg Technol Int 2019 May;34:251-254

epartment of Surgery, New Hanover Regional Medical Center, Wilmington, North Carolina.

A common technique for ventral and incisional hernia repair is the retrorectus repair (Rives-Stoppa). The posterior rectus sheath is incised bilaterally, and mesh is placed retromuscularly. There is little information on how this component separation technique affects abdominal wall tension. We evaluated abdominal wall tension in patients undergoing retrorectus repair of abdominal wall hernias. Patients undergoing retrorectus repair of their ventral hernias were enrolled in a prospective, Institutional Review Board-approved protocol to measure abdominal wall tension from 8/1/2013 to 8/2/2017. Demographic information and operative details were documented. Abdominal wall tensions were measured using scales attached to Kocher clamps that were clamped to the fascia and brought together in the midline. Measurements were made before and after incising the posterior rectus sheaths. Data were analyzed with a repeated measures analysis of variance (ANOVA), and differences between individual groups were analyzed by least square differences. Forty-five patients had tension measurements. Average age was 58 years (range 29-81)-78% Caucasian, 51% female, an average body mass index (BMI) of 35 kg/m2 (range 20-62), and 38% recurrent hernias. The average hernia defect was 121.9 cm2, and the average mesh size was 607.8 cm2. There was a significant reduction in tension after bilateral posterior rectus sheath incision (3.1 lbs vs. 5.6 lbs, p<0.0001). In this evaluation, abdominal wall tension measurements are shown to be a feasible adjunct during open hernia repair with retrorectus repair. Transection of the posterior rectus sheath decreases tension during hernia repair and may help guide surgeons regarding when to use this procedure.
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May 2019

Outcomes by MIC Values for Patients Treated with Isavuconazole or Voriconazole for Invasive Aspergillosis in the Phase 3 SECURE and VITAL Trials.

Antimicrob Agents Chemother 2019 01 21;63(1). Epub 2018 Dec 21.

University of Liverpool, Liverpool, United Kingdom.

This pooled analysis evaluated the relationship of isavuconazole and voriconazole MICs of pathogens at baseline with all-cause mortality and clinical outcomes following treatment with either drug in the SECURE and VITAL trials. Isavuconazole and voriconazole may have had reduced efficacy against pathogens with drug MICs of ≥16 µg/ml, but there was no relationship with clinical outcomes in cases where the MIC was <16 µg/ml for either drug.
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http://dx.doi.org/10.1128/AAC.01634-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325202PMC
January 2019

Rationale and Technique for Measuring Abdominal Wall Tension in Hernia Repair.

Am Surg 2018 Sep;84(9):1446-1449

We describe a method to measure abdominal wall tension during hernia surgery and evaluate a possible correlation between hernia defect width and abdominal wall tension. After Institutional Review Board approval and informed consent, a prospective trial to measure intraabdominal tension was undertaken (May 2013 through March 2017). Tension measurements were obtained using tensiometers. Total tension, hernia defect width, and surgeon's estimation of tension were recorded. Correlation between defect width and total abdominal wall tension was assessed using multivariate analysis and a multiple linear regression analysis. An r-squared value > 0.6 was considered significant. Fifty-nine patients underwent hernia repair with concomitant tension measurements obtained at surgery. The average patient age was 61 years (range 29-81 years), 85 per cent were white, and 56 per cent female. The average total tension was 6.7 pounds (range 0.2-22 pounds) and average defect width was 8.6 cm (range 2-25 cm). The surgeon rated the fascia to be excellent in 15 per cent, good in 58 per cent, and fair in 27 per cent. The average estimation of tension by the surgeon was 5 pounds (range 2-10 pounds). We found no correlation between hernia defect size and total abdominal wall tension and no correlation between the surgeon-estimated tension and objectively measured tension. We found no correlation between the width of the hernia defect and tension associated with approximating the midline. Further study regarding the practicality and usefulness of abdominal wall tension measurements during hernia surgery is needed.
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September 2018

Prophylactic Mesh for Hernia Prevention: Has the Time Arrived?

Plast Reconstr Surg 2018 09;142(3 Suppl):180S-186S

From the Department of Surgery, New Hanover Regional Medical Center; and Division of Plastic Surgery, Department of Surgery, University of Pennsylvania.

Incisional and parastomal hernias continue to be vexing problems for patients and surgeons. Risk factors are generally patient-related and/or technical in nature, and in some cases, can be altered, resulting in improved outcomes. Improved fascial closure techniques can only partly reduce the risk of incisional hernia formation. Even under optimal circumstances, using time tested closure techniques and materials, the rate remains high, due primarily to factors that are not modifiable or are unidentifiable. In such cases, there may be a beneficial role for prophylactic mesh augmentation (PMA), wherein mesh is implanted at the time of initial surgery or stoma formation. Several high-risk groups that might benefit from PMA have been identified, including patients undergoing open abdominal aneurysm repair or colorectal procedures, obese patients, and patients requiring creation of permanent gastrointestinal or urological stomas. Although the initial results of PMA are promising, the benefits of this strategy must be weighed against potential risks. Outcome measures to assess efficacy should include not only hernia recurrence but also quality of life, surgical-site occurrences, and cost. Further studies are warranted to predict which specific patient populations might benefit most from PMA and to identify ideal mesh materials as well as preferred implantation sites and methods of mesh fixation.
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http://dx.doi.org/10.1097/PRS.0000000000004876DOI Listing
September 2018

Measuring Success in Complex Abdominal Wall Reconstruction: The Role of Validated Outcome Scales.

Plast Reconstr Surg 2018 09;142(3 Suppl):163S-170S

From the Division of Gastrointestinal and Minimally Invasive Surgery, Department of Surgery, Carolinas Medical Center; and Department of Surgery, New Hanover Regional Medical Center, UNC-Chapel Hill.

Background: Diminished quality of life (QOL) often drives patients to hernia repair, and patient-reported outcomes have gained importance in hernia research. Functional outcomes provide a patient-centered evaluation of a treatment, and improved QOL is a desired outcome assessing treatment effectiveness.

Methods: Properties of validated QOL measure are reviewed and distinctions between generic and disease-specific measures are discussed. Based on a review of the literature, current validated outcome scales are evaluated and compared.

Results: Currently, there is little agreement over the best means to measure QOL. As a result, several measures have been created, focusing on several distinct aspects of QOL. While generic measures provide global assessments, disease-specific measures report changes as they relate to the hernia itself and hernia surgery. With the introduction of new QOL measures, it is important to understand the properties of a good QOL measure.

Conclusions: Several questions remain unanswered regarding QOL, including which measures best assess hernia patients, what is the ideal time to evaluate QOL, and for how long postoperatively should QOL be measured. The introduction of guidelines to address these issues may enable improvement in value assessment.
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http://dx.doi.org/10.1097/PRS.0000000000004873DOI Listing
September 2018

Abdominal Wall Reconstruction Risk Stratification Tools: A Systematic Review of the Literature.

Plast Reconstr Surg 2018 09;142(3 Suppl):9S-20S

From the Surgery Department, Center for Surgical Trials and Evidence-Based Practice, University of Texas Health Science Center at Houston; and the Surgery Departments of John Hopkins University School of Medicine, New Hanover Regional Medical Center, University of Iowa, University of Nevada School of Medicine, Oregon Health and Science University, University of Kentucky Medical Center; and Ventral Hernia Outcomes Collaborative.

Background: Ventral hernias are a common pathology encountered by surgeons. Multiple risk stratification tools have been developed in attempts to predict a patient's postoperative risk for complication. The aim of this systematic review was to identify published stratification tools, to assess their generalizability, and develop an ensemble risk score model.

Methods: A systematic review of the literature was performed using PubMed and following the PRISMA guidelines. Two independent reviewers identified articles describing hernia stratification tools or validating an established tool. Inclusion criteria included articles that studied ventral hernia risk score models developed through expert consensus or from data of at least 500 subjects, performed a multivariable analysis of at least 500 patients, or assessed a previously reported model. Studies were grouped by primary outcome, and the odds ratios for correlated variables were compiled. Outcomes described in 4 or more articles were then stacked to generate a cumulative risk score model for patients undergoing abdominal wall repair.

Results: A total of 20 articles were found to meet our inclusion criteria and used to develop our ensemble model. Surgical-site infection, surgical-site occurrence, and hernia recurrence were the 3 primary outcomes used to calculate our stacked cumulative risk stratification score.

Conclusions: There are multiple risk score tools published; however, all have their strengths and limitations. For this reason, we created a composite score model with data from major articles to predict a patient's risk for postoperative complications. This model aims to ease the shared-decision making process for patients, surgeons, and institutions.
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http://dx.doi.org/10.1097/PRS.0000000000004833DOI Listing
September 2018

Exposure-Response Analysis of Micafungin in Neonatal Candidiasis: Pooled Analysis of Two Clinical Trials.

Pediatr Infect Dis J 2018 06;37(6):580-585

From the Global Development, Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.

Background: Neonatal candidiasis causes significant morbidity and mortality in high risk infants. The micafungin dosage regimen of 10 mg/kg established for the treatment of neonatal candidiasis is based on a laboratory animal model of neonatal hematogenous Candida meningoencephalitis and pharmacokinetic (PK)-pharmacodynamic (PD) bridging studies. However, little is known about the how these PK-PD data translate clinically.

Methods: Micafungin plasma concentrations from infants were used to construct a population PK model using Pmetrics software. Bayesian posterior estimates for infants with invasive candidiasis were used to evaluate the relationship between drug exposure and mycologic response using logistic regression.

Results: Sixty-four infants 3-119 days of age were included, of which 29 (45%) infants had invasive candidiasis. A 2-compartment PK model fits the data well. Allometric scaling was applied to clearance and volume normalized to the mean population weight (kg). The mean (standard deviation) estimates for clearance and volume in the central compartment were 0.07 (0.05) L/h/1.8 kg and 0.61 (0.53) L/1.8 kg, respectively. No relationship between average daily area under concentration-time curve or average daily area under concentration-time curve:minimum inhibitory concentration ratio and mycologic response was demonstrated (P > 0.05). Although not statistically significant, mycologic response was numerically higher when area under concentration-time curves were at or above the PD target.

Conclusions: While a significant exposure-response relationship was not found, PK-PD experiments support higher exposures of micafungin in infants with invasive candidiasis. More patients would clarify this relationship; however, low incidence deters the feasibility of these studies.
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http://dx.doi.org/10.1097/INF.0000000000001957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110378PMC
June 2018

Umbilical Hernia Repair: Overview of Approaches and Review of Literature.

Surg Clin North Am 2018 Jun 12;98(3):561-576. Epub 2018 Mar 12.

Department of Surgery, New Hanover Regional Medical Center, South East Area Health Education Center, 2131 South 17th Street, PO Box 9025, Wilmington, NC 28401, USA. Electronic address:

Umbilical hernias are ubiquitous, and surgery is indicated in symptomatic patients. Umbilical hernia defects can range from small (<1 cm) to very large/complex hernias, and treatment options should be tailored to the clinical situation. Open, laparoscopic, and robotic options exist for repair, with each having its advantages and disadvantages. In general, mesh should be used for repair, because it has been shown to decrease recurrence rates, even in small hernias. Although outcomes are generally favorable after umbilical hernia repairs, some patients have chronic complaints that are mostly related to recurrences.
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http://dx.doi.org/10.1016/j.suc.2018.02.001DOI Listing
June 2018

Role of Prophylactic Mesh Placement for Laparotomy and Stoma Creation.

Surg Clin North Am 2018 Jun;98(3):471-481

Department of Surgery, Division of Plastic Surgery, University of Pennsylvania, South Pavilion - 14th Floor, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Electronic address:

Incisional and parastomal hernias are a cause of significant morbidity and have a substantial effect on quality of life and economic costs for patients and hospital systems. Although many aspects of abdominal hernias are understood, prevention is a feature that is still being realized. This article reviews the current literature and determines the utility of prophylactic mesh placement in prevention of incisional and parastomal hernias.
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http://dx.doi.org/10.1016/j.suc.2018.01.003DOI Listing
June 2018