ABSTRACT
INTRODUCTION: Institutions have reported decreases in operative volume due to COVID-19. Junior residents have fewer opportunities for operative experience and COVID-19 further jeopardizes their operative exposure. This study quantifies the impact of the COVID-19 pandemic on resident operative exposure using resident case logs focusing on junior residents and categorizes the response of surgical residency programs to the COVID-19 pandemic. MATERIALS AND METHODS: A retrospective multicenter cohort study was conducted; 276,481 case logs were collected from 407 general surgery residents of 18 participating institutions, spanning 2016-2020. Characteristics of each institution and program changes in response to COVID-19 were collected via surveys. RESULTS: Senior residents performed 117 more cases than junior residents each year (P < 0.001). Prior to the pandemic, senior resident case volume increased each year (38 per year, 95% confidence interval 2.9-74.9) while junior resident case volume remained stagnant (95% confidence interval 13.7-22.0). Early in the COVID-19 pandemic, junior residents reported on average 11% fewer cases when compared to the three prior academic years (P = 0.001). The largest decreases in cases were those with higher resident autonomy (Surgeon Jr, P = 0.03). The greatest impact of COVID-19 on junior resident case volume was in community-based medical centers (246 prepandemic versus 216 during pandemic, P = 0.009) and institutions which reached Stage 3 Program Pandemic Status (P = 0.01). CONCLUSIONS: Residents reported a significant decrease in operative volume during the 2019 academic year, disproportionately impacting junior residents. The long-term consequences of COVID-19 on junior surgical trainee competence and ability to reach cases requirements are yet unknown but are unlikely to be negligible.
Subject(s)
COVID-19 , General Surgery , Internship and Residency , COVID-19/epidemiology , Clinical Competence , Cohort Studies , Education, Medical, Graduate , General Surgery/education , Humans , PandemicsABSTRACT
Ventral hernia repair (VHR) fixation techniques with current meshes on the market are prone to failure from intra-abdominal pressure spikes due to coughing or lifting, for example. The T-Line® Hernia Mesh (Deep Blue Medical Advances, Durham, North Carolina) is a new mesh with a novel fixation mechanism to enhance anchoring strength addressing hernia occurrence and recurrence. Used similarly to traditional mesh, the new mesh uses incorporated mesh sutures that are 15 times the surface area of sutures for fixation rather than monofilament sutures, providing ~275% stronger anchoring strength. The increased surface area of the mesh extensions decreases tension on the mesh and tissue and increases the strength of the repair overall. There is also the likelihood that anchoring gains strength over time as the extensions undergo bioincorporation. This novel mesh specifically addresses the most common complication of VHR and has the potential to significantly improve outcomes.
Subject(s)
Hernia, Ventral , Surgical Mesh , Hernia, Ventral/surgery , Herniorrhaphy/methods , Humans , Prostheses and Implants , Recurrence , SuturesABSTRACT
INTRODUCTION: Rectus diastases (RD) are caused by a weakening of the abdominal musculature and a widening of the linea alba. Some patients are often erroneously told that they are hernias. Despite the fact that they are not true hernias, they are often associated with true hernias and undergo concomitant repairs. Robotic plication of these diastases has been gaining more widespread use in the past few years, but literature regarding outcomes remains limited. MATERIAL AND METHODS: All patients with RD and concomitant ventral hernia that underwent robotic repair were assessed from 2016 to present. Demographics, perioperative morbidity, and outcomes were reviewed, and descriptive analyses were performed. RESULTS: This series consists of 14 patients with an average age of 50.7 years (range 33-78 years), 64% female, and 86% Caucasian. All patients had associated umbilical or ventral/incisional hernia with an average defect size of 7.1cm2 and average mesh size of 254cm2. Robotic transabdominal pre-peritoneal (RTAPP) repair was performed in 67% of cases and robotic extended total extraperitoneal (ReTEP) repair was performed in 33%. Two patients (17%) required conversion to open repair. Hospital length of stay was 0.7 days. There was no morbidity in these patients. At an average follow-up of 2.6 years (range 54-2122 days), the hernia/diastasis recurrence rate is 7.1%. CONCLUSION: The results of this study suggest that robotic plication with intraperitoneal sublay mesh could be an acceptable surgical approach for RD associated with concomitant ventral hernia repair. Further investigation is required to assess outcomes in a larger group of patients and to determine long-term recurrence and complication rates.
ABSTRACT
Coccidioides spp. are important pathogens in regions where they are endemic, and new treatment options are needed. Here, isavuconazonium sulfate (ISAVUSULF) and fluconazole (FLU) were evaluated in experimental disseminated coccidioidomycosis to characterize drug exposures associated with efficacy. Broth macrodilution was performed on Coccidioides isolates to measure minimal effective concentrations (MEC) and minimal fungicidal concentrations (MFC). Mice were inoculated with Coccidioides posadasii (Silveira strain). Treatment started 4 days postinoculation. In model 1, mice were treated for 19 days, followed by 30 days of off-therapy observation, measuring survival through day 49 and residual fungal burden. Treatments included ISAVUSULF (prodrug; 186, 279, or 372 mg/kg twice daily), FLU (20 or 100 mg/kg once daily), and no treatment. Model 2 included 7-day treatment with ISAVUSULF (prodrug; 74.4, 111.6, or 148.8 mg/kg twice daily), FLU (20 or 100 mg/kg once daily), and no treatment. Serial plasma and tissues samples were obtained for pharmacokinetics (PK) and fungal burden measurement, respectively. Fifty percent minimal effective concentration (MEC50) values were 0.39 mg/liter (isavuconazole [ISAV]) and 12.5 mg/liter (FLU). Treatment with ISAVUSULF186 or with either FLU dose resulted in higher survival compared to that in the untreated group. Treatment with ISAVUSULF186 or ISAVUSULF279 twice daily or FLU100 reduced fungal burden in all organs (model 1). In model 2, a >1 log10 CFU/organ reduction was demonstrated, with ISAV area under the concentration-time curve (AUC) values achieved with 111.6 mg/kg twice daily (56.8 mg · h/liter) in the spleen and liver. FLU AUC values of 100 and 500 mg·h/liter for 20 and 100 mg/kg doses, respectively, resulted in a >1 log10 CFU/organ mean reduction in all organs. ISAVUSULF and FLU improved survival and reduced fungal burden. Increasing plasma drug exposures resulted in decreases in fungal burden.
Subject(s)
Coccidioidomycosis , Pharmaceutical Preparations , Animals , Antifungal Agents/therapeutic use , Coccidioides , Coccidioidomycosis/drug therapy , Fluconazole/therapeutic use , Mice , Models, Theoretical , Nitriles , Pyridines , TriazolesABSTRACT
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.
Subject(s)
Hernia, Inguinal/surgery , Herniorrhaphy/methods , Laparoscopy/methods , Surgical Mesh/standards , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle AgedABSTRACT
PURPOSE: Hernia prevention following abdominal surgery has become a subject of growing interest in general surgery. Prophylactic mesh augmentation (PMA) is an emerging technique to prevent incisional hernia in high-risk populations. The aim of this study was to determine the efficacy and safety of PMA using an absorbable mesh. METHODS: A retrospective review was performed on patients who underwent PMA between July 2014 and March 2020. A prophylactic synthetic absorbable mesh (Phasix™; Becton Dickinson, Franklin Lakes, NJ) was placed at the surgeon's discretion according to the indication for the primary operation. The primary outcome was the incisional hernia rate. Secondary outcomes included mesh-related or other complications. RESULTS: Fifty patients underwent PMA following cystectomy with ileal conduit, open aortic surgery, or colostomy creation/takedown. Overall, 10 patients (20%) developed hernia at a median follow-up of 2.2 years. Six of these 10 hernias occurred at incisions where mesh was not placed. There were no documented mesh infections. One mesh (2%) in the AAA group was explanted due to an infected endograft, but there was no evidence of mesh complication. Two patients (4%) developed seroma. Two (4%) patients developed superficial surgical site infections (SSI). There were no documented deep-space SSI. CONCLUSION: PMA is an emerging technique with a low rate of incisional hernia in high-risk patients, such as those undergoing stoma creation or open aortic intervention. The use of an absorbable mesh seems promising, however more and longer-term research is needed.
Subject(s)
Hernia, Ventral , Incisional Hernia , Surgical Stomas , Urinary Diversion , Hernia, Ventral/epidemiology , Hernia, Ventral/surgery , Humans , Incisional Hernia/epidemiology , Incisional Hernia/prevention & control , Retrospective Studies , Surgical MeshABSTRACT
Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-ß-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 in vivo, under zinc limitation, than in vitro Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed ß-lactam-ß-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.
Subject(s)
Anti-Bacterial Agents , beta-Lactamases , Anti-Bacterial Agents/therapeutic use , Asia , Gram-Negative Bacteria , beta-Lactamase Inhibitors/therapeutic use , beta-Lactamases/geneticsABSTRACT
An estimated 40 million women of reproductive age are infected with one of three species of the waterborne parasite Schistosoma 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 S. japonicum in Leyte, Philippines. Specifically, we studied the PK properties of PZQ among early- and late-gestation pregnant women (n = 15 each) and lactating postpartum women (n = 15) with schistosomiasis. We found that women in early pregnancy had increased apparent clearance and lower area-under-the-curve (AUC0-24) 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.
Subject(s)
Anthelmintics , Schistosoma japonicum , Schistosomiasis , Animals , Anthelmintics/therapeutic use , Female , Humans , Lactation , Philippines , Praziquantel/therapeutic use , Pregnancy , Schistosoma mansoni , Schistosomiasis/drug therapyABSTRACT
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 Pseudomonas aeruginosa and Acinetobacter baumannii 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.
Subject(s)
Acinetobacter baumannii , Anti-Bacterial Agents , Animals , Anti-Bacterial Agents/therapeutic use , Drug Development , Mice , Models, Animal , Rabbits , Swine , United States , United States Food and Drug AdministrationABSTRACT
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.
Subject(s)
Anti-Infective Agents , Antifungal Agents , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Antifungal Agents/pharmacology , Area Under Curve , HumansABSTRACT
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.
Subject(s)
Hernia, Ventral , Laparoscopy , Hernia, Ventral/surgery , Herniorrhaphy , Humans , Quality of Life , Recurrence , Retrospective Studies , Surgical MeshABSTRACT
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.
Subject(s)
Abdominal Wound Closure Techniques , Incisional Hernia , Animals , Humans , Laparotomy , Models, Educational , Surgical Mesh , Suture Techniques , SwineABSTRACT
VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus 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.
Subject(s)
Antifungal Agents/pharmacokinetics , Aspergillosis/drug therapy , Coordination Complexes/pharmacokinetics , Peptides, Cyclic/pharmacokinetics , Adolescent , Adult , Antifungal Agents/administration & dosage , Antifungal Agents/blood , Aspergillosis/microbiology , Coordination Complexes/administration & dosage , Coordination Complexes/blood , Dose-Response Relationship, Drug , Healthy Volunteers , Humans , Kinetics , Middle Aged , Peptides, Cyclic/administration & dosage , Peptides, Cyclic/blood , Young AdultABSTRACT
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 in vitro and in vivo 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.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Animals , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Bacterial Infections/metabolism , Humans , MiceABSTRACT
This pooled analysis evaluated the relationship of isavuconazole and voriconazole MICs of Aspergillus 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.
Subject(s)
Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Aspergillus/drug effects , Nitriles/therapeutic use , Pyridines/therapeutic use , Triazoles/therapeutic use , Voriconazole/therapeutic use , Aspergillosis/microbiology , Aspergillosis/mortality , Aspergillus/isolation & purification , Humans , Invasive Fungal Infections/drug therapy , Invasive Fungal Infections/microbiology , Microbial Sensitivity TestsABSTRACT
Cryptococcus 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.
Subject(s)
Antifungal Agents/pharmacokinetics , Meningitis, Cryptococcal/drug therapy , Meningoencephalitis/drug therapy , Nitriles/pharmacokinetics , Pyridines/pharmacokinetics , Triazoles/pharmacokinetics , Animals , Area Under Curve , Brain/drug effects , Brain/microbiology , Cryptococcus neoformans/drug effects , Disease Models, Animal , Male , Meningitis, Cryptococcal/microbiology , Meningoencephalitis/microbiology , Microbial Sensitivity Tests , Models, Theoretical , RabbitsABSTRACT
Hematogenous Candida 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 in vitro BBB model was serially infected with C. albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 µg/ml were then provided, vascular and CNS compartments were sampled 4h later. For in vivo 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 in vitro BBB occurred after 24h of exposure (P=0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue (P≤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.
ABSTRACT
There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 µg/mL-greater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.
ABSTRACT
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.
Subject(s)
Abdominal Wall/physiopathology , Hernia, Ventral/physiopathology , Hernia, Ventral/surgery , Herniorrhaphy/methods , Rectus Abdominis/physiopathology , Rectus Abdominis/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Manometry , Middle Aged , Prospective Studies , Recurrence , Surgical MeshABSTRACT
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.