Publications by authors named "Gregory Williams"

121 Publications

"Lest we forget": An overview of Australia's response to the recovery and identification of unrecovered historic military remains.

Forensic Sci Int 2021 Oct 4;328:111042. Epub 2021 Oct 4.

School of Archaeology and Anthropology, Australian National University, Canberra, ACT, Australia; School of Geosciences, University of Aberdeen, Aberdeen, United Kingdom.

The Australian Defence Force (ADF) is responsible for the recovery and identification of its historic casualties. With over 30,000 still unrecovered from past conflicts including World War One (WW1) and World War Two (WWII), the Australian Army and Royal Australian Air Force have teams that research, recover, identify and oversee the burial (or reburial) of the remains of soldiers and airmen who continue to be found each year. The Royal Australian Navy is also responsible for its unrecovered casualties. Collectively the priorities of the various services within the ADF are the respectful recovery and treatment of the dead, thorough forensic identification efforts, resolution for families and honouring the ADF's proud history of service and sacrifice. What is unique about the approach of the ADF is that the respective services retain responsibility for their historic losses, while a joint approach is taken on policies and in the utilisation of the pool of forensic specialists. Section One describes the process undertaken by the Australian Army in the recovery, identification and burial or repatriation of soldiers through its specialised unit Unrecovered War Casualties - Army (UWC-A). Section Two describes the role of the Royal Australian Air Force in the recovery of aircraft and service personnel through their specialised unit Historic Unrecovered War Casualties - Air Force (HUWC-AF). An overview of the operations of each service and case studies is presented for each section.
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http://dx.doi.org/10.1016/j.forsciint.2021.111042DOI Listing
October 2021

Seroconversion and fever are dose-dependent in a nonhuman primate model of inhalational COVID-19.

PLoS Pathog 2021 08 23;17(8):e1009865. Epub 2021 Aug 23.

National Biodefense Analysis and Countermeasures Center (NBACC), Operated by Battelle National Biodefense Institute for the US Department of Homeland Security, Frederick, Maryland, United States of America.

While evidence exists supporting the potential for aerosol transmission of SARS-CoV-2, the infectious dose by inhalation remains unknown. In the present study, the probability of infection following inhalation of SARS-CoV-2 was dose-dependent in a nonhuman primate model of inhalational COVID-19. The median infectious dose, assessed by seroconversion, was 52 TCID50 (95% CI: 23-363 TCID50), and was significantly lower than the median dose for fever (256 TCID50, 95% CI: 102-603 TCID50), resulting in a group of animals that developed an immune response post-exposure but did not develop fever or other clinical signs of infection. In a subset of these animals, virus was detected in nasopharyngeal and/or oropharyngeal swabs, suggesting that infected animals without signs of disease are able to shed virus and may be infectious, which is consistent with reports of asymptomatic spread in human cases of COVID-19. These results suggest that differences in exposure dose may be a factor influencing disease presentation in humans, and reinforce the importance of public health measures that limit exposure dose, such as social distancing, masking, and increased ventilation. The dose-response data provided by this study are important to inform disease transmission and hazard modeling, and, ultimately, mitigation strategies. Additionally, these data will be useful to inform dose selection in future studies examining the efficacy of therapeutics and vaccines against inhalational COVID-19, and as a baseline in healthy, young adult animals for assessment of the importance of other factors, such as age, comorbidities, and viral variant, on the infectious dose and disease presentation.
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http://dx.doi.org/10.1371/journal.ppat.1009865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412324PMC
August 2021

Yield of Surveillance Colonoscopy in Older Adults with a History of Polyps: A Systematic Review and Meta-Analysis.

Dig Dis Sci 2021 Aug 18. Epub 2021 Aug 18.

The Dartmouth Institute of Health Policy and Clinical Practice, Lebanon, NH, USA.

Background: The benefit of surveillance colonoscopy in older adults is not well described.

Aims: To quantify the detection of colorectal cancer (CRC) and advanced polyps during surveillance colonoscopy in older adults with a history of colon polyps.

Methods: We conducted a systematic review (MEDLINE, Cochrane Library, Web of Science, and Embase) for all published studies through May 2020 in adults age > 70 undergoing surveillance colonoscopy. The main outcome was CRC and advanced polyps detection. We performed meta-analysis to pool results by age (>70 vs. 50-70).

Results: The search identified 6239 studies, of which 569 underwent full-text review and 64 data abstraction, of which 19 were included. The risk of detecting CRC (N = 11) was higher in those >70 compared to 50-70 (risk ratio 1.5 (95% CI 1.1-2.2); risk difference 0.8% (95% CI -0.2%-1.8%)). Similarly, the risk of detecting advanced polyps (N = 8) was higher in those >70 compared to 50-70 (risk ratio 1.3 (95% CI 1.2-1.3), risk difference 2.7% (95% CI 1.3%-4.0%)). Most studies did not stratify results by baseline polyp risk.

Conclusions: The detection of CRC and advanced polyps during surveillance colonoscopy in older individuals was higher than in younger controls; however, the absolute risk increase for both was small. These differences must be weighed against competing medical problems and limited life expectancy in older adults when making decisions about surveillance colonoscopy. More primary data on the risks of CRC and advanced polyps accounting for number of past colonoscopies, prior polyp risk, and duration of time since last polyp are needed.
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http://dx.doi.org/10.1007/s10620-021-07198-6DOI Listing
August 2021

Profiling Human Cytomegalovirus-Specific T Cell Responses Reveals Novel Immunogenic Open Reading Frames.

J Virol 2021 Oct 11;95(21):e0094021. Epub 2021 Aug 11.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USA.

Despite the prevalence and medical significance of human cytomegalovirus (HCMV) infections, a systematic analysis of the targets of T cell recognition in humans that spans the entire genome and includes recently described potential novel open reading frames (ORFs) is not available. Here, we screened a library of epitopes predicted to bind HLA class II that spans over 350 different HCMV ORFs and includes ∼150 previously described and ∼200 recently described potential novel ORFs by using an gamma interferon (IFN-γ) FluoroSpot assay. We identified 235 unique HCMV-specific epitopes derived from 100 ORFs, some previously described as immunodominant and others that were not previously described to be immunogenic. Of those, 41 belong to the set of recently reported novel ORFs, thus providing evidence that at least some of these are actually expressed in humans. These data reveal that the breadth of the human T cell response to HCMV is much greater than previously thought. The ORFs and epitopes identified will help elucidate how T cell immunity relates to HCMV pathogenesis and instruct ongoing HCMV vaccine research. To understand the crucial role of adaptive immunity in controlling cytomegalovirus infection and disease, we systematically analyzed the CMV "ORFeome" to identify new CMV epitopes targeted primarily by CD4 T cells in humans. Our study identified >200 new T cell epitopes derived from both canonical and novel ORFs, highlighting the substantial breadth of the anti-CMV T cell response and providing new targets for vaccine design.
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http://dx.doi.org/10.1128/JVI.00940-21DOI Listing
October 2021

Improved outcomes with minimally invasive pancreaticoduodenectomy in patients with dilated pancreatic ducts: a prospective study.

Surg Endosc 2021 Jul 7. Epub 2021 Jul 7.

Division of Hepatobiliary, Pancreatic, and Gastrointestinal Surgery, Department of Surgery, Barnes-Jewish Hospital, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8109, Saint Louis, MO, 63110, USA.

Background: Little is known about what factors predict better outcomes for patients who undergo minimally invasive pancreaticoduodenectomy (MIPD) versus open pancreaticoduodenectomy (OPD). We hypothesized that patients with dilated pancreatic ducts have improved postoperative outcomes with MIPD compared to OPD.

Methods: All patients undergoing pancreaticoduodenectomy were prospectively followed over a time period of 47 months, and perioperative and pathologic covariates and outcomes were compared. Ideal outcome after PD was defined as follows: (1) no complications, (2) postoperative length of stay < 7 days, and (3) negative (R0) margins on pathology. Patients with dilated pancreatic ducts (≥ 3 mm) who underwent MIPD were 1:3 propensity score-matched to patients with dilated ducts who underwent OPD and outcomes compared. Likewise, patients with non-dilated pancreatic ducts (< 3 mm) who underwent MIPD were 1:3 propensity score-matched to patients with non-dilated ducts who underwent OPD and outcomes were compared.

Results: 371 patients underwent PD-74 (19.9%) MIPD and 297 (80.1%) underwent OPD. Overall, patients who underwent MIPD had significantly less intraoperative blood loss. After 1:3 propensity score matching, patients with dilated pancreatic ducts who underwent MIPD (n = 45) had significantly lower overall complication and 90-day readmission rates compared to matched OPD patients (n = 135) with dilated ducts. Patients with dilated duct who underwent MIPD were more likely to have an ideal outcome than patients with OPD (29 vs 15%, p = 0.035). There were no significant differences in postoperative outcomes among propensity score-matched patients with non-dilated pancreatic ducts who underwent MIPD (n = 29) compared to matched patients undergoing OPD (n = 87) with non-dilated ducts.

Conclusions: MIPD is safe with comparable perioperative outcomes to OPD. Patients with pancreatic ducts ≥ 3 mm appear to derive the most benefit from MIPD in terms of fewer complications, lower readmission rates, and higher likelihood of ideal outcome.
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http://dx.doi.org/10.1007/s00464-021-08611-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262764PMC
July 2021

Enhanced recovery pathway after open pancreaticoduodenectomy reduces postoperative length of hospital stay without reducing composite length of stay.

HPB (Oxford) 2021 Jun 16. Epub 2021 Jun 16.

Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Background/purpose: There is no data regarding the impact of enhanced recovery pathways (ERP) on composite length of stay (CLOS) after procedures with increased risk of morbidity and mortality, such as pancreaticoduodenectomy.

Methods: Patients undergoing open pancreaticoduodenectomy before and after implementation of ERP were prospectively followed for 90 days after surgery and complications were severity graded using the Modified Accordion Grading System. A retrospective analysis of patient outcomes were compared before and after instituting ERP. 1:1 propensity score matching was used to compare ERP patient outcomes to those of matched pre-ERP patients. CLOS is defined as postoperative length of hospital stay (PLOS) plus readmission length of hospital stay within 90 days after surgery.

Results: 494 patients underwent open pancreaticoduodenectomy - 359 pre-ERP and 135 ERP. In a 1:1 propensity-score-matched analysis of 110 matched pairs, ERP patients had significantly decreased superficial surgical site infections (5.5% vs 15.5% p = 0.015) and significantly increased rates of urinary retention (29.1% vs 7.3% p < 0.0001) compared to matched pre-ERP patients. However, overall complication rate and 90-day readmission rate were not significantly different between matched groups. Propensity score-matched ERP patients had significantly decreased PLOS (7 days vs 8 days p = 0.046) compared to matched pre-ERP patients, but CLOS was not significantly different (9 days vs 9.5 days p = 0.615).

Conclusion: ERP may reduce PLOS but might not impact the total postoperative time spent in the hospital (i.e. CLOS) within 90 days after pancreaticoduodenectomy.
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http://dx.doi.org/10.1016/j.hpb.2021.05.014DOI Listing
June 2021

Inability to manage non-severe complications on an outpatient basis increases non-white patient readmission rates after pancreaticoduodenectomy: A large metropolitan tertiary care center experience.

Am J Surg 2021 Apr 16. Epub 2021 Apr 16.

Department of Surgery, Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address:

Background: Pancreaticoduodenectomy (PD) has a high rate of readmission, and racial disparities in care could be an important contributor.

Methods: Patients undergoing PD were prospectively followed, and their complications graded using the Modified Accordion Grading System (MAGS). Patient factors and perioperative outcomes for patients with and without postoperative readmission were compared in univariate and multivariate analysis by severity.

Results: 837 patients underwent PD, the overall 90-day readmission rate was 27.5%. Non-white race was independently associated with readmission (OR 1.83, p = 0.007). 51.3% of readmissions were for non-severe complications (MAGS <3). Non-white race was independently associated with MAGS non-severe readmission (OR 2.13, p = 0.006), but not MAGS severe readmission.

Conclusions: Non-white patients are more likely to be readmitted, particularly for non-severe complications. Follow up protocols should be tailored to address race disparities in the rates of readmission as readmission for less severe complications could potentially be avoidable.
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http://dx.doi.org/10.1016/j.amjsurg.2021.04.011DOI Listing
April 2021

The stability of an isolate of the SARS-CoV-2 B.1.1.7 lineage in aerosols is similar to three earlier isolates.

J Infect Dis 2021 Apr 2. Epub 2021 Apr 2.

National Biodefense Analysis and Countermeasures Center, operated by Battelle National Biodefense Institute for the US Department of Homeland Security, Frederick, Maryland, USA.

Background: Our laboratory previously examined the influence of environmental conditions on the stability of an early isolate of SARS-CoV-2 (hCoV-19/USA/WA-1/2020) in aerosols generated from culture medium or simulated saliva. However, genetic differences have emerged among SARS-CoV-2 lineages, and it is possible that these differences may affect environmental stability and the potential for aerosol transmission.

Methods: The influence of temperature, relative humidity, and simulated sunlight on the decay of four SARS-CoV-2 isolates in aerosols, including one belonging to the recently emerged B.1.1.7 lineage, were compared in a rotating drum chamber. Aerosols were generated from simulated respiratory tract lining fluid to represent aerosols originating from the deep lung.

Results: No differences in the stability of the isolates were observed in the absence of simulated sunlight at either 20°C or 40°C. However, a small but statistically significant difference in the stability was observed between some isolates in simulated sunlight at 20°C and 20% relative humidity. .

Conclusions: The stability of SARS-CoV-2 in aerosols does not vary greatly among currently circulating lineages, including B.1.1.7, suggesting that the increased transmissibility associated with recent SARS-CoV-2 lineages is not due to enhanced survival in the environment.
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http://dx.doi.org/10.1093/infdis/jiab171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083468PMC
April 2021

Measuring Negative Emotion Differentiation Via Coded Descriptions of Emotional Experience.

Assessment 2021 Apr 2:10731911211003949. Epub 2021 Apr 2.

University of Toronto Scarborough, Toronto, Ontario, Canada.

Emotion differentiation (ED) has been defined in terms of two abilities: (a) making fine-grained distinctions emotional experiences, and (b) describing emotional experiences with a high degree of nuance and specificity. Research to date has almost exclusively focused on the former, with little attention paid to the latter. The current study sought to address this discrepant focus by testing two novel measures of negative ED (i.e., based on negatively valenced emotions only) via coded open-ended descriptions of individual emotional experiences, both past and present. As part of a larger study, 307 participants completed written descriptions of two negative emotional experiences, as well as a measure of emotion regulation difficulties and indices of psychopathological symptom severity. Negative ED ability, as measured via consistency between emotional experiences, was found to be unrelated to negative ED ability exhibited via coding of language within experiences. Within-experience negative ED may offer an incrementally adaptive function to that of ED between emotional experiences. Implications for ED theory are discussed.
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http://dx.doi.org/10.1177/10731911211003949DOI Listing
April 2021

Predicting Outcomes in Patients Undergoing Pancreatectomy Using Wearable Technology and Machine Learning: Prospective Cohort Study.

J Med Internet Res 2021 03 18;23(3):e23595. Epub 2021 Mar 18.

Washington University in St Louis, St Louis, MO, United States.

Background: Pancreatic cancer is the third leading cause of cancer-related deaths, and although pancreatectomy is currently the only curative treatment, it is associated with significant morbidity.

Objective: The objective of this study was to evaluate the utility of wearable telemonitoring technologies to predict treatment outcomes using patient activity metrics and machine learning.

Methods: In this prospective, single-center, single-cohort study, patients scheduled for pancreatectomy were provided with a wearable telemonitoring device to be worn prior to surgery. Patient clinical data were collected and all patients were evaluated using the American College of Surgeons National Surgical Quality Improvement Program surgical risk calculator (ACS-NSQIP SRC). Machine learning models were developed to predict whether patients would have a textbook outcome and compared with the ACS-NSQIP SRC using area under the receiver operating characteristic (AUROC) curves.

Results: Between February 2019 and February 2020, 48 patients completed the study. Patient activity metrics were collected over an average of 27.8 days before surgery. Patients took an average of 4162.1 (SD 4052.6) steps per day and had an average heart rate of 75.6 (SD 14.8) beats per minute. Twenty-eight (58%) patients had a textbook outcome after pancreatectomy. The group of 20 (42%) patients who did not have a textbook outcome included 14 patients with severe complications and 11 patients requiring readmission. The ACS-NSQIP SRC had an AUROC curve of 0.6333 to predict failure to achieve a textbook outcome, while our model combining patient clinical characteristics and patient activity data achieved the highest performance with an AUROC curve of 0.7875.

Conclusions: Machine learning models outperformed ACS-NSQIP SRC estimates in predicting textbook outcomes after pancreatectomy. The highest performance was observed when machine learning models incorporated patient clinical characteristics and activity metrics.
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http://dx.doi.org/10.2196/23595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074869PMC
March 2021

CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease.

Brain 2021 08;144(7):2047-2059

Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.

α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation of the innate and adaptive immune system. This immune activation includes microgliosis, increased inflammatory cytokines, and the infiltration of T cells into the CNS. More recently, peripherally circulating CD4 and CD8 T cells derived from individuals with Parkinson's disease have been shown to produce Th1/Th2 cytokines in response to α-synuclein, suggesting there may be a chronic memory T cell response present in Parkinson's disease. To understand the potential effects of these α-syn associated T cell responses we used an α-synuclein overexpression mouse model, T cell-deficient mice, and a combination of immunohistochemistry and flow cytometry. In this study, we found that α-synuclein overexpression in the midbrain of mice leads to the upregulation of the major histocompatibility complex II (MHCII) protein on CNS myeloid cells as well as the infiltration of IFNγ producing CD4 and CD8 T cells into the CNS. Interestingly, genetic deletion of TCRβ or CD4, as well as the use of the immunosuppressive drug fingolimod, were able to reduce the CNS myeloid MHCII response to α-synuclein. Furthermore, we observed that CD4-deficient mice were protected from the dopaminergic cell loss observed due to α-syn overexpression. These results suggest that T cell responses associated with α-synuclein pathology may be damaging to key areas of the CNS in Parkinson's disease and that targeting these T cell responses could be an avenue for disease modifying treatments.
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http://dx.doi.org/10.1093/brain/awab103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370411PMC
August 2021

Thunderbeat™ Integrated Bipolar and Ultrasonic Forceps in the Whipple Procedure: A Prospective Randomized Trial.

Mo Med 2020 Nov-Dec;117(6):559-562

Associate Professor of Surgery, Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.

Thunderbeat™ is a device that uses both ultrasonic and advanced bipolar energies to achieve hemostasis. It has been evaluated in a variety of clinical contexts, but no literature exists regarding its application to pancreatic surgery. Using a prospective, randomized controlled trial, we evaluated its safety and efficacy in the Whipple procedure. Thirty-two participants were enrolled in the study. The Thunderbeat™ device during the Whipple procedure showed similar safety profile compared to standard of care.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721432PMC
August 2021

Development of a novel intraoperative difficulty score for minimally invasive cholecystectomy.

HPB (Oxford) 2021 Jul 17;23(7):1025-1029. Epub 2020 Nov 17.

Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Background: The rate of biliary injuries from minimally invasive cholecystectomy has remained high for over two decades. To improve outcomes there are multiple bail-out methods described, including aborting the procedure, converting to open, or performing a sub-total cholecystectomy. However, the intraoperative difficulty threshold for when a bail-out method should be implemented is poorly understood.

Methods: From 1/2014 to 2/2019 cholecystectomy videos were collected, de-identified, edited to include the 2-3 minutes when the gallbladder was first visualized, and accelerated. They were then rated on a 5-point difficulty scale. Inter-coder reliability was evaluated using Krippendorff's alpha and regression models were used to evaluate the scores ability to predict the need for a bail-out technique.

Results: 62 videos were analyzed with a median length after editing of 37.5 (29.0-43.3) seconds. A median time of 46.2 (38.3-53.4) seconds was required for grading. The bail-out rate was 42.9%. The inter-coder reliability between 2 surgeons and 8 non-clinical reviewers was 0.675 with an average difficulty score of 3.0 (SD = 1.01). Regression models showed that the scale was able to significantly predict conversion (β=0.56,p<.01).

Conclusion: This novel difficulty score was able to predict conversion to a bail-out technique early in the course of minimally invasive cholecystectomy.
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http://dx.doi.org/10.1016/j.hpb.2020.10.020DOI Listing
July 2021

Brain Alchemy: Transforming Astrocytes into Neurons for Neurodegenerative Disease.

Mov Disord Clin Pract 2020 Nov 25;7(8):902-903. Epub 2020 Sep 25.

Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology The University of Alabama at Birmingham Birmingham Alabama USA.

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http://dx.doi.org/10.1002/mdc3.13090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604624PMC
November 2020

NEVBD Pesticide Resistance Monitoring Network: Establishing a Centralized Network to Increase Regional Capacity for Pesticide Resistance Detection and Monitoring.

J Med Entomol 2021 03;58(2):787-797

Department of Entomology, Cornell University, Ithaca, NY.

Pesticide resistance in arthropod vectors of disease agents is a growing issue globally. Despite the importance of resistance monitoring to inform mosquito control programs, no regional monitoring programs exist in the United States. The Northeastern Regional Center for Excellence in Vector-Borne Diseases (NEVBD) is a consortium of researchers and public health practitioners with a primary goal of supporting regional vector control activities. NEVBD initiated a pesticide resistance monitoring program to detect resistant mosquito populations throughout the northeastern United States. A regionwide survey was distributed to vector control agencies to determine needs and refine program development and in response, a specimen submission system was established, allowing agencies to submit Culex pipiens (L.) (Diptera:Culicidae) and Aedes albopictus (Skuse) (Diptera: Culicidae) for pesticide resistance testing. NEVBD also established larvicide resistance diagnostics for Bacillus thuringiensis israelensis (Bti) and methoprene. Additional diagnostics were developed for Cx. pipiens resistance to Lysinibacillus sphaericus. We received 58 survey responses, representing at least one agency from each of the 13 northeastern U.S. states. Results indicated that larvicides were deployed more frequently than adulticides, but rarely paired with resistance monitoring. Over 18,000 mosquitoes were tested from six states. Widespread low-level (1 × LC-99) methoprene resistance was detected in Cx. pipiens, but not in Ae. albopictus. No resistance to Bti or L. sphaericus was detected. Resistance to pyrethroids was detected in many locations for both species. Our results highlight the need for increased pesticide resistance testing in the United States and we provide guidance for building a centralized pesticide resistance testing program.
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http://dx.doi.org/10.1093/jme/tjaa236DOI Listing
March 2021

Safety and feasibility of initiating a hepatic artery infusion pump chemotherapy program for unresectable colorectal liver metastases: A multicenter, retrospective cohort study.

J Surg Oncol 2021 Jan 23;123(1):252-260. Epub 2020 Oct 23.

Division of General Surgery, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.

Introduction: Hepatic artery infusion pump (HAIP) chemotherapy is a specialized therapy for patients with unresectable colorectal liver metastases (uCRLM). Its effectiveness was demonstrated from a high volume center, with uncertainty regarding the feasibility and safety at other centers. Therefore, we sought to assess the safety and feasibility of HAIP for the management of uCRLM at other centers.

Methods: We conducted a multicenter retrospective cohort study of patients with uCRLM treated with HAIP from January 2003 to December 2017 at six North American centers initiating the HAIP program. Outcomes included the safety and feasibility of HAIP chemotherapy.

Results: We identified 154 patients with HAIP insertion and the median age of 54 (48-61) years. The burden of disease was >10 intra-hepatic metastatic foci in 59 (38.3%) patients. Patients received at least one cycle of systemic chemotherapy before HAIP insertion. Major complications occurred in 7 (4.6%) patients during their hospitalization and 13 (8.4%) patients developed biliary sclerosis during follow-up. A total of 148 patients (96.1%) received at least one-dose of HAIP chemotherapy with a median of 5 (4-7) cycles. 78 patients (56.5%) had a complete or partial response and 12 (7.8%) received a curative liver resection.

Conclusion: HAIP programs can be safely and effectively initiated in previously inexperienced centers with good response.
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http://dx.doi.org/10.1002/jso.26270DOI Listing
January 2021

Re-defining a high volume center for pancreaticoduodenectomy.

HPB (Oxford) 2021 May 28;23(5):733-738. Epub 2020 Sep 28.

Department of Surgery, Washington University in Saint Louis, USA; Division of Hepatobiliary & Pancreatic Surgery, Washington University in Saint Louis, USA.

Background: The purpose of this study was to re-evaluate the previously utilized definitions of high volume center for pancreaticoduodenectomy to determine/establish an objective, evidence based threshold of hospital volume associated with improvement in perioperative mortality.

Methods: Patients who underwent pancreaticoduodenectomy were identified using the National Cancer Database from 2004 to 2015. The relationship between hospital volume and 90-day mortality was assessed using a logistic regression model. Receiver Operator Characteristic analysis was performed and Youden's statistic was utilized to calculate the optimal cut offs.

Results: 42,402 patients underwent elective Pancreaticoduodenectomy at 1238 unique hospitals. A logistic regression was performed which showed a significant inverse linear association between institutional volume and overall 90 day mortality. The maximum improvement in 90 day mortality is seen if the average annual hospital volume was greater than 9 (OR = 0.647 (0.595-0.702), p < 0.0001). When analysis is limited to hospitals that performed >9 cases per year, the maximum improvement in 90 day mortality was noticed at 36 cases per year (OR = 0.458 (0.399-0.525), p < 0.0001).

Conclusions: Based on our results, we recommend defining low, medium, and high volume centers for pancreaticoduodenectomy as hospitals with average annual volume less than 9, 9 to 35, and more than 35 cases per year, respectively.
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http://dx.doi.org/10.1016/j.hpb.2020.09.009DOI Listing
May 2021

The development of autonomous unmanned aircraft systems for mosquito control.

PLoS One 2020 18;15(9):e0235548. Epub 2020 Sep 18.

Center for Vector Biology, Rutgers University, New Brunswick, New Jersey, United States of America.

We constructed an electric multi-rotor autonomous unmanned aerial system (UAS) to perform mosquito control activities. The UAS can be equipped with any of four modules for spraying larvicides, dropping larvicide tablets, spreading larvicide granules, and ultra-low volume spraying of adulticides. The larvicide module sprayed 124 μm drops at 591 mL/min over a 14 m swath for a total application rate of 1.6 L/ha. The tablet module was able to repeatedly deliver 40-gram larvicide tablets within 1.1 m of the target site. The granular spreader covered a 6 m swath and treated 0.76 ha in 13 min at an average rate of 1.8 kg/ha. The adulticide module produced 16 μm drops with an average deposition of 2.6 drops/mm2. UAS pesticide applications were made at rates prescribed for conventional aircraft, limited only by the payload capacity and flight time. Despite those limitations, this system can deliver pesticides with much greater precision than conventional aircraft, potentially reducing pesticide use. In smaller, congested environments or in programs with limited resources, UAS may be a preferable alternative to conventional aircraft.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235548PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500627PMC
October 2020

HDAC3 deacetylates the DNA mismatch repair factor MutSβ to stimulate triplet repeat expansions.

Proc Natl Acad Sci U S A 2020 09 8;117(38):23597-23605. Epub 2020 Sep 8.

Centre for Chromosome Biology, National University of Ireland Galway, H9W2TY Galway, Ireland;

Trinucleotide repeat (TNR) expansions cause nearly 20 severe human neurological diseases which are currently untreatable. For some of these diseases, ongoing somatic expansions accelerate disease progression and may influence age of onset. This new knowledge emphasizes the importance of understanding the protein factors that drive expansions. Recent genetic evidence indicates that the mismatch repair factor MutSβ (Msh2-Msh3 complex) and the histone deacetylase HDAC3 function in the same pathway to drive triplet repeat expansions. Here we tested the hypothesis that HDAC3 deacetylates MutSβ and thereby activates it to drive expansions. The HDAC3-selective inhibitor RGFP966 was used to examine its biological and biochemical consequences in human tissue culture cells. HDAC3 inhibition efficiently suppresses repeat expansion without impeding canonical mismatch repair activity. Five key lysine residues in Msh3 are direct targets of HDAC3 deacetylation. In cells expressing Msh3 in which these lysine residues are mutated to arginine, the inhibitory effect of RGFP966 on expansions is largely bypassed, consistent with the direct deacetylation hypothesis. RGFP966 treatment does not alter MutSβ subunit abundance or complex formation but does partially control its subcellular localization. Deacetylation sites in Msh3 overlap a nuclear localization signal, and we show that localization of MutSβ is partially dependent on HDAC3 activity. Together, these results indicate that MutSβ is a key target of HDAC3 deacetylation and provide insights into an innovative regulatory mechanism for triplet repeat expansions. The results suggest expansion activity may be druggable and support HDAC3-selective inhibition as an attractive therapy in some triplet repeat expansion diseases.
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http://dx.doi.org/10.1073/pnas.2013223117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519323PMC
September 2020

The safety of hepatectomy after transarterial radioembolization: Single institution experience and review of the literature.

J Surg Oncol 2020 Nov 13;122(6):1114-1121. Epub 2020 Jul 13.

Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.

Background And Objectives: The liver is a frequent site of malignancy, both primary and metastatic. The treatment goal of patients with liver cancer may include transarterial radioembolization (TARE). There are limited reports on the safety of hepatectomy following TARE. Our study's purpose is to review patients who have received TARE followed by hepatectomy.

Methods: A retrospective study was performed on patients diagnosed with any liver cancer from 2013 to 2019 who underwent TARE followed by hepatectomy. Postoperative complications were prospectively collected. Descriptive statistics and the Kaplan-Meier test were used to assess survival outcomes.

Results: Twelve patients were treated with a TARE followed by a hepatectomy (nine with ≥4 segments resected). Diagnoses included: six HCC, four cholangiocarcinoma, one metastatic neuroendocrine tumor, and one metastatic colorectal cancer. There were no 90-day post-hepatectomy mortalities and the overall morbidity was 66% (16% severe ≥MAGS 3). Hepatectomy-specific complications after hepatectomy included two (16%) bile leaks and no post-hepatectomy liver failures. The median recurrence free survival was 26 months. Overall survival at 1-year was 78% and at 3 years was 47%.

Conclusions: Our results support the safety of hepatectomy in select patients after TARE. Additional comparison to patients who receive hepatectomy as a first-line treatment for liver cancers should be investigated.
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http://dx.doi.org/10.1002/jso.26115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855767PMC
November 2020

Increasing Temperature and Relative Humidity Accelerates Inactivation of SARS-CoV-2 on Surfaces.

mSphere 2020 07 1;5(4). Epub 2020 Jul 1.

National Biodefense Analysis and Countermeasures Center (NBACC), Operated by Battelle National Biodefense Institute (BNBI) for the U.S. Department of Homeland Security Science and Technology Directorate, Fort Detrick, Maryland, USA

Coronavirus disease 2019 (COVID-19) was first identified in China in late 2019 and is caused by newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Previous studies had reported the stability of SARS-CoV-2 in cell culture media and deposited onto surfaces under a limited set of environmental conditions. Here, we broadly investigated the effects of relative humidity, temperature, and droplet size on the stability of SARS-CoV-2 in a simulated clinically relevant matrix dried on nonporous surfaces. The results show that SARS-CoV-2 decayed more rapidly when either humidity or temperature was increased but that droplet volume (1 to 50 μl) and surface type (stainless steel, plastic, or nitrile glove) did not significantly impact decay rate. At room temperature (24°C), virus half-life ranged from 6.3 to 18.6 h depending on the relative humidity but was reduced to 1.0 to 8.9 h when the temperature was increased to 35°C. These findings suggest that a potential for fomite transmission may persist for hours to days in indoor environments and have implications for assessment of the risk posed by surface contamination in indoor environments. Mitigating the transmission of SARS-CoV-2 in clinical settings and public spaces is critically important to reduce the number of COVID-19 cases while effective vaccines and therapeutics are under development. SARS-CoV-2 transmission is thought to primarily occur through direct person-to-person transfer of infectious respiratory droplets or through aerosol-generating medical procedures. However, contact with contaminated surfaces may also play a significant role. In this context, understanding the factors contributing to SARS-CoV-2 persistence on surfaces will enable a more accurate estimation of the risk of contact transmission and inform mitigation strategies. To this end, we have developed a simple mathematical model that can be used to estimate virus decay on nonporous surfaces under a range of conditions and which may be utilized operationally to identify indoor environments in which the virus is most persistent.
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http://dx.doi.org/10.1128/mSphere.00441-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333574PMC
July 2020

Airborne SARS-CoV-2 Is Rapidly Inactivated by Simulated Sunlight.

J Infect Dis 2020 07;222(4):564-571

National Biodefense Analysis and Countermeasures Center, Operated by Battelle National Biodefense Institute for the US Department of Homeland Security Science and Technology Directorate, Frederick, Maryland, USA.

Aerosols represent a potential transmission route of COVID-19. This study examined effect of simulated sunlight, relative humidity, and suspension matrix on stability of SARS-CoV-2 in aerosols. Simulated sunlight and matrix significantly affected decay rate of the virus. Relative humidity alone did not affect the decay rate; however, minor interactions between relative humidity and other factors were observed. Mean decay rates (± SD) in simulated saliva, under simulated sunlight levels representative of late winter/early fall and summer were 0.121 ± 0.017 min-1 (90% loss, 19 minutes) and 0.306 ± 0.097 min-1 (90% loss, 8 minutes), respectively. Mean decay rate without simulated sunlight across all relative humidity levels was 0.008 ± 0.011 min-1 (90% loss, 286 minutes). These results suggest that the potential for aerosol transmission of SARS-CoV-2 may be dependent on environmental conditions, particularly sunlight. These data may be useful to inform mitigation strategies to minimize the potential for aerosol transmission.
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http://dx.doi.org/10.1093/infdis/jiaa334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313838PMC
July 2020

Simulated Sunlight Rapidly Inactivates SARS-CoV-2 on Surfaces.

J Infect Dis 2020 06;222(2):214-222

National Biodefense Analysis and Countermeasures Center, Operated by Battelle National Biodefense Institute for the US Department of Homeland Security, Frederick, Maryland, USA.

Previous studies have demonstrated that SARS-CoV-2 is stable on surfaces for extended periods under indoor conditions. In the present study, simulated sunlight rapidly inactivated SARS-CoV-2 suspended in either simulated saliva or culture media and dried on stainless steel coupons. Ninety percent of infectious virus was inactivated every 6.8 minutes in simulated saliva and every 14.3 minutes in culture media when exposed to simulated sunlight representative of the summer solstice at 40°N latitude at sea level on a clear day. Significant inactivation also occurred, albeit at a slower rate, under lower simulated sunlight levels. The present study provides the first evidence that sunlight may rapidly inactivate SARS-CoV-2 on surfaces, suggesting that persistence, and subsequently exposure risk, may vary significantly between indoor and outdoor environments. Additionally, these data indicate that natural sunlight may be effective as a disinfectant for contaminated nonporous materials.
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http://dx.doi.org/10.1093/infdis/jiaa274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313905PMC
June 2020

Innate and adaptive immune responses in Parkinson's disease.

Prog Brain Res 2020 5;252:169-216. Epub 2019 Dec 5.

Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, United States. Electronic address:

Parkinson's disease (PD) has classically been defined as a movement disorder, in which motor symptoms are explained by the aggregation of alpha-synuclein (α-syn) and subsequent death of dopaminergic neurons of the substantia nigra pars compacta (SNpc). More recently, the multisystem effects of the disease have been investigated, with the immune system being implicated in a number of these processes in the brain, the blood, and the gut. In this review, we highlight the dysfunctional immune system found in both human PD and animal models of the disease, and discuss how genetic risk factors and risk modifiers are associated with pro-inflammatory immune responses. Finally, we emphasize evidence that the immune response drives the pathogenesis and progression of PD, and discuss key questions that remain to be investigated in order to identify immunomodulatory therapies in PD.
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http://dx.doi.org/10.1016/bs.pbr.2019.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185735PMC
January 2021

Tumor-insular Complex in Neoadjuvant Treated Pancreatic Ductal Adenocarcinoma Is Associated With Higher Residual Tumor.

Am J Surg Pathol 2020 06;44(6):817-825

Department of Pathology and Immunology.

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a vital role in treatment response, and therefore, patient survival. We and others have observed an intimate association of neoplastic ductal cells with non-neoplastic islet cells, recapitulating the ductoinsular complex. We define this phenomenon as tumor-insular complex (TIC). Herein, we describe the clinicopathologic characteristics of TIC in neoadjuvant treated PDAC cases for the first time. We retrospectively reviewed the pathology of 105 cases of neoadjuvant treated PDAC resected at our institution. TIC was noted in 35 cases (33.3%), the mean tumor bed size was 2.7±1.0 cm, mean percentage of residual tumor 40±28% and mean Residual Tumor Index (RTI) (an index previously established as a prognostic parameter by our group) was 1.1±1.0. TIC was significantly associated with perineural invasion (P=0.001), higher tumor bed size (P=0.007), percentage of residual tumor (P=0.009), RTI (P=0.001), ypT stage (P=0.045), and poor treatment response, grouped by a previously established criteria (P=0.010). Using our prior binary reported prognostic cutoff for RTI of ≤0.35 and >0.35, TIC was associated with a RTI >0.35 (P=0.002). Moreover, patients who did not receive neoadjuvant radiation were associated with a higher frequency of TIC (P=0.003). In this cohort, RTI but not TIC was also shown to be a significant independent prognosticator for recurrence-free survival and overall survival on multivariate analysis. In conclusion, TIC is significantly associated with a more aggressive neoplasm which shows a poor treatment response. Further studies will be needed to better understand the tumor biology of TICs.
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http://dx.doi.org/10.1097/PAS.0000000000001454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225071PMC
June 2020

Extending Enhanced Recovery after Surgery Protocols to the Post-Discharge Setting: A Phone Call Intervention to Support Patients after Expedited Discharge after Pancreaticoduodenectomy.

Am Surg 2020 Jan;86(1):42-48

The goal of this pilot study was to track patient outcomes after an expedited discharge after enhanced recovery after surgery (ERAS) pathway for pancreaticoduodenectomy (PD). A quantitative content analysis approach was used. All PD patients in a single academic medical center between February 2017 and June 2018 were called twice by specialized physician extenders after discharge. A semi-structured interview approach was used to identify patient's symptoms or concerns, proactively educate them, and provide outpatient management when indicated. A detailed narrative of the conversation was documented. Ninety patients (mean age 66.3; 58.1% males) were included in the study. Of all, 88.9 per cent of the patients received follow-up phone calls in accordance with our PD ERAS protocol. Among the 80 patients called, 71 (88.8%) reported at least one symptom, issue, or self-care need. The most common issues involved bowel movements and nutrition. A total of 147 interventions were performed to address patient needs including medication management, local care coordination, and outpatient referral to a healthcare provider. The intervention led to the identification of 15 patients for earlier evaluation. This identification was associated with the total number of reported symptoms (² = 15.6, = 0.004). Most patients require additional care after discharge after traditional ERAS pathways. ERAS transitional care protocols uncovered an unmet need for additional patient support after PD.
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January 2020

T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease.

Acta Neuropathol 2020 05 29;139(5):855-874. Epub 2020 Jan 29.

Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham (UAB), 1719 6th Ave. South, CIRC 446, Birmingham, AL, 35294-0021, USA.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson's disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3, CD4, and CD8 T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-β or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying.
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http://dx.doi.org/10.1007/s00401-020-02126-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181566PMC
May 2020

Heterodissemination: precision targeting container Aedes mosquitoes with a cohabiting midge species carrying insect growth regulator.

Pest Manag Sci 2020 Jun 22;76(6):2105-2112. Epub 2020 Feb 22.

Center for Vector Biology, Rutgers University, New Brunswick, NJ, USA.

Background: Management of Aedes albopictus and Ae. aegypti is challenging in large part due to the cryptic nature of their larval habitats. Autodissemination, using conspecific species to transfer pesticide, is unable to provide proactive control. Here we report results from a new hypothesis, heterodissemination, wherein females of the cohabiting non-biting midge, Chironomus decorus, reared in the laboratory, treated with pyriproxyfen, and released to transfer lethal concentrations to shared mosquito larval habitats.

Results: Pyriproxyfen-impregnated oil and powder formulations were developed. The average payload for each female midge treated with oil followed by powder formulations was 5.07 ± 0.92 μg of active ingredient or 1660 times the median lethal concentration (LC ) for Ae. albopictus or Ae. aegypti in 200 mL of water. Subsequent residue analysis showed pyriproxyfen transference from chironomids, treated with oil formulation only, into water-holding containers up to 2.06 ppb or 171.7 times the LC . Releasing 20 laboratory reared and contaminated Chironomus decorus into a small room resulted in 80.42 ± 0.67% and 75.67 ± 3.14% Ae. albopictus pupal mortality in open and cryptic sentinel ovicups, respectively. Container water volumes ranging up to 4 L did not affect efficacy. In a large field cage, 90.3 ± 2.5% Ae. albopictus mortality was resulted from releasing 100 treated female midges. Releasing 400 contaminated midges into a residential backyard resulted in 74.3% pupal mortality in sentinel ovicups.

Conclusions: Room, large field cage and field release trials demonstrated that adult midges reared and treated in the laboratory transfer highly lethal concentrations of pyriproxyfen to Ae. albopictus container habitats. Heterodissemination provides a potential approach for precision, proactive mosquito control, which may draw attention for further studies. © 2020 Society of Chemical Industry.
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http://dx.doi.org/10.1002/ps.5749DOI Listing
June 2020

Composite Length of Stay, An Outcome Measure of Postoperative and Readmission Length of Stays in Pancreatoduodenectomy.

J Gastrointest Surg 2020 09 16;24(9):2062-2069. Epub 2019 Dec 16.

Section of Hepato-Pancreato-Biliary Surgery, Department of Surgery, Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine, Saint Louis, MO, USA.

Purpose: Postoperative length of stay (PLOS) and readmission rate are pancreatoduodenectomy (PD) outcome measures, which are reported individually but may be interrelated. The purpose of this study was to evaluate how well a composite length of stay measure (CLOS) that included PLOS and readmission length of stay describes outcomes. To do so, we evaluated how well CLOS correlated to postoperative complications absolutely and compared to PLOS.

Methods: A total of 668 PDs performed between 2011 and 2018 were evaluated. CLOS was calculated from PLOS and readmission length of stay. Complication severity was judged by the Modified Accordion Grading System (MAGS). Multinomial logistical regression models (MLRM) were used to investigate the relationship between either PLOS or CLOS and complications. Multilevel and pairwise area under curves (AUC) using SAS macro %MultAUC were provided for both models.

Results: A total of 432 of 668 patients (65%) developed complications. One hundred seventy-seven patients (27%) were readmitted. Mean PLOS was 10.2 days (7.1 SD) and mean CLOS was 12.3 days (10.1 SD). PLOS and CLOS both were correlated linearly to MAGS grade. Spearman correlation coefficient for CLOS vs. MAGS of 0.68 was higher than that of 0.49 for PLOS vs. MAGS. Multilevel AUC from MLRM using PLOS was 0.66, but multilevel AUC from MLRM using CLOS was 0.71.

Discussion: CLOS provides an accurate estimate of hospital day utilization per patient for PD, reflecting not only the basal hospital recovery time for PD but the added time needed because of readmissions due to complications. It is tightly correlated to number and severity of postoperative complications.
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http://dx.doi.org/10.1007/s11605-019-04475-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295670PMC
September 2020

Analysis of predictor variables for mosquito species identification from dual-wavelength polarization-sensitive lidar measurements.

Proc SPIE Int Soc Opt Eng 2018 Sep 24;10779. Epub 2018 Oct 24.

New Jersey Institute of Technology, 323 Dr Martin Luther King Jr Blvd, Newark, NJ, USA.

Mosquito-borne diseases are a major challenge for Human health as they affect nearly 700 million people every year. Monitoring insects is generally done through trapping methods that are tedious to set up, costly and present scientific biases. Entomological lidars are a potential solution to remotely count and identify mosquito species and gender in real-time. In this contribution, a dual-wavelength polarization sensitive lidar is used in laboratory conditions to retrieve the wingbeat frequency as well as optical properties of flying mosquitoes transiting through the laser beam. From the lidar signals, predictive variables are retrieved and used in a Bayesian classification. This paper focuses on determining the relative importance of the predictive variables used in the classification. Results show a strong dominance of the wingbeat frequency, the impact of predictive variables based on depolarization and backscattering ratios are discussed, showing a significant increase in classification accuracy.
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http://dx.doi.org/10.1117/12.2323432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813783PMC
September 2018
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