Validation of an endoscopic anastomotic grading score as an intraoperative method for assessing stapled rectal anastomoses.

PURPOSE: Anastomotic leak is a dreaded complication of colorectal surgery. An endoscopic grading score of the perianastomotic mucosa has been previously developed at our institution (UCI) to assess colorectal anastomotic integrity. The objective of this study is to validate the UCI anastomotic score and determine its impact in anastomotic failure. METHODS: As a follow-up study of the UCI grading score implementation during 2011 to 2014, patients undergoing stapled colorectal anastomoses after sigmoidectomy or proctectomy at a single institution from 2015 to 2018 were retrospectively reviewed. Patients were grouped into three tiers based on endoscopic appearance (grade 1, circumferentially normal mucosa; grade 2, ischemia/congestion < 30% of circumference; grade 3, ischemia/congestion > 30% of circumference). RESULTS: On the basis of endoscopic mucosal evaluation, grade 1 anastomosis was observed in 299 patients (94%), grade 2 anastomosis in 14 patients (4.4%), and grade 3 anastomosis in 5 patients (1.6%). All grade 3 classifications were immediately and successfully revised intraoperatively with reclassification as a grade 1 anastomosis. The anastomotic leak rate of the follow-up study period from 2015 to 2018 was 6.4% which was lower compared to the anastomotic leak rate of 12.2% in the original study period from 2011 to 2014 (p = 0.07). Anastomotic leak rate for the entire patient series was 8.5%. A grade 2 anastomosis was associated with higher anastomotic leak rate compared to a grade 1 anastomosis (35.7% vs. 7.4%, p < 0.05). None of the five grade 3 anastomoses resulted in an anastomotic leak upon revision. CONCLUSION: This study further validates the anastomotic grading score and suggests that its systematic implementation can result in a reduction in anastomotic leaks.

Analysis of delay in adjuvant chemotherapy in locally advanced rectal cancer.

BACKGROUND: Adjuvant chemotherapy (AC) after neoadjuvant chemoradiation and surgical resection has been the standard of care for locally advanced rectal cancer. However, there are no evidence-based guidelines regarding the optimal timing of AC for rectal cancer. The objective of this study was to evaluate the effect of AC timing on overall survival for rectal cancer. METHODS: The National Cancer Database (NCDB) from 2004 to 2016 was queried for primary clinical stage II or III rectal cancer patients who had undergone neoadjuvant chemoradiation followed by surgery and AC. Patients were grouped based on AC initiation: early ≤ 4 weeks, intermediate 4-8 weeks, and delayed ≥ 8 weeks. The primary outcome was overall survival. RESULTS: We identified 8722 patients, of which 905 (10.4%) received early AC, 4621 (53.0%) intermediate AC, and 3196 (36.6%) delayed AC. Pathological lymph-node metastasis (ypN +) was positive in 73% of early AC, 74% intermediate AC, and 63% delayed AC (p < 0.05). The 5-year survival probability was 71.1% (95% CI 68-74%) for early AC, 73.2% (95% CI 72-75%) intermediate AC, and 65.8% (95% CI 64-68%) delayed AC (p < 0.001). Using Cox proportional hazard modeling, patients undergoing delayed AC had an associated decreased survival compared to patients receiving early AC (HR 1.18; 95% CI 1.028-1.353, p = 0.018) or intermediate AC (HR 1.28; 95% CI 1.179-1.395, p < 0.01). CONCLUSIONS: Delay in AC administration may be associated with decreased 5-year survival. Compared to early or intermediate AC, patients in the delayed AC group were observed to have increased risk of death, despite having lower proportions with ypN + disease. Patients with higher socioeconomic and education status were more likely to receive early chemotherapy.

Assessing the effectiveness of laser fistulectomy for anal fistula: a retrospective cohort study.

BACKGROUND: Laser fistulectomy is a minimally invasive, sphincter-sparing procedure for treatment of anal fistula. In several studies, this method has been shown to be safe and effective, with reported success rates ranging from 40 to 88%. We hypothesized that with longer follow-up, these rates would decrease. METHODS: A retrospective case analysis assessing the effectiveness of laser fistulectomy in curing fistula-in-ano tracts within a cohort of patients at a single academic institution was conducted. All patients having laser ablation between March 2016 and July 2018 were analyzed. Cure of the fistula was determined by history and postoperative physical exam, and was defined as complete closure of fistula tract with resolution of symptoms. Secondary symptoms of fecal incontinence, infection, and pain were evaluated. RESULTS: Eighteen patients (10 males, mean age 41 ± 13 years) were analyzed. Transphincteric fistula was the most common type (67%, N = 12). The mean number of previous fistula procedures was 1.33 ± 1.64. There was a 22% (N = 4) success rate at an average postoperative follow-up period of 29 ± 8 months (range 18-46 months). Of those who failed, 64% (N = 9) had a subsequent fistula procedure. There were no cases of fecal incontinence, but 3 cases (17%) of postoperative infection were reported and 8 patients (44%) had a subjective increase in pain at first follow-up appointment. CONCLUSIONS: Our data showed a much higher failure rate of laser fistulectomy compared to those reported in the literature. However, the small sample size, a large amount of heterogeneity in our patient population with a mixture of fistula types present, and various laser techniques applied decreased the power of this study.

Robotic ventral mesh rectopexy for rectal prolapse: a single-institution experience.

BACKGROUND: Robotic ventral mesh rectopexy (RVMR) is an appealing approach for the treatment of rectal prolapse and other conditions. The aim of this study was to evaluate the outcomes of RVMR for rectal prolapse. METHODS: We performed a retrospective chart review for patients who underwent RVMR for rectal prolapse at our institution between July 2012 and May 2016. Any patient who underwent RVMR during this time frame was included in our analysis. Any cases involving colorectal resection or other rectopexy techniques were excluded. RESULTS: Of the 24 patients who underwent RVMR, 95.8% of patients were female. Median age was 67.5 years old (IQR 51.5-73.3), and 79.2% of patients were American Society of Anesthesiologists class III or IV. Median operative time was 191 min (IQR 164.3-242.5), and median length of stay was 3 days (IQR 2-3). There were no conversions, RVMR-related complications or mortality. Patients were followed for a median of 3.8 (IQR 1.2-15.9) months. Full-thickness recurrence occurred in 3 (12.4%) patients. Rates of fecal incontinence improved after surgery (62.5 vs. 41.5%, respectively) as did constipation (45.8 vs. 33.3%, respectively). No patients reported worsening symptoms postoperatively. Only one (4.2%) patient reported de novo constipation postoperatively. CONCLUSIONS: RVMR is a feasible, safe and effective option for the treatment of rectal prolapse, with low short-term morbidity and mortality. Multicenter and long-term studies are needed to better assess the benefits of this procedure.

Low- and high-gamma oscillations deviate in opposite directions from zero-phase synchrony in the limbic corticostriatal loop.

The loop structure of cortico-striatal anatomy in principle enables both descending (cortico-striatal) and ascending (striato-cortical) influences, but the factors that regulate the flow of information in these loops are not known. We report that low- and high-gamma oscillations (∼50 and ∼80 Hz, respectively) in the local field potential of freely moving rats are highly synchronous between the infralimbic region of the medial prefrontal cortex (mPFC) and the ventral striatum (vStr). Strikingly, high-gamma oscillations in mPFC preceded those in vStr, whereas low-gamma oscillations in mPFC lagged those in vStr, with short (∼1 ms) time lags. These systematic deviations from zero-phase synchrony were consistent across measures based on amplitude cross-correlation and phase slopes and were robustly maintained between behavioral states and different individual subjects. Furthermore, low- and high-gamma oscillations were associated with distinct ensemble spiking patterns in vStr, even when controlling for overt behavioral differences and slow changes in neural activity. These results imply that neural activity in vStr and mPFC is tightly coupled at the gamma timescale and raise the intriguing possibility that frequency-specific deviations from this coupling may signal transient leader-follower switches.

Nitrogen isotopic discrimination in dietary amino acids: The threonine anomaly.

RATIONALE: The "Threonine Anomaly" relates to an observation made 25 years ago on the change in Thr nitrogen isotopic ratio in mammalian metabolism. Unlike all other amino acids, Thr in body protein is found to be depleted (rather than enriched) in 15 N relative to dietary Thr. Interpreting isotopic discrimination has become a useful source of ecological and palaeodietary information and it is desirable that the underlying processes are understood. METHODS: The principal enzyme of threonine catabolism, suggested to be responsible for the anomaly, threonine dehydratase, was prepared from rat liver. A time course of incubation of the enzyme with pure threonine was followed, and samples of residual threonine prepared for isotopic analysis by combustion in an automated carbon and nitrogen analyser coupled to a continuous flow isotope ratio mass spectrometer. RESULTS: We show experimentally, in vitro, that the enzymic reaction catabolising Thr cannot be responsible for its 15 N depletion. Plots of delta 15 N against both reaction time course and percentage completion show in fact an accelerating enrichment. CONCLUSIONS: A previously advanced suggestion that the unique catabolic mechanism for threonine was responsible for the anomalous depletion in 15 N is clearly not the case. We therefore offer alternative explanations, based on threonine's role at an organismal rather than cellular level. Copyright © 2016 John Wiley & Sons, Ltd.

Repair of complex parastomal hernias.

Development of parastomal hernias (PH) is very common after stoma formation and carries a risk of subsequent bowel incarceration, obstruction and strangulation. The management of PH remains a challenge for the colorectal surgeon, and there are currently no standardized guidelines for the treatment of PH. Even more difficult is the management of complex parastomal hernias (CPH). We conducted a review of the literature to identify recent developments in the treatment of CPH, including analysis of the use of synthetic and biologic mesh prostheses, method of mesh placement and surgical approach.

Design solutions for the hodoscope of the magnetic proton recoil neutron spectrometer of the SPARC tokamak.

A new 14 MeV neutron spectrometer utilizing the magnetic proton recoil (MPR) technique is under development for the SPARC tokamak. This instrument measures neutrons by converting them into protons, whose momenta are subsequently analyzed using a series of magnets before detection by an array of scintillators known as the hodoscope. In this work, we explore various solutions for the hodoscope detectors through laboratory tests with radioactive sources and simulations. We present findings on light collection and pulse shape discrimination based on detector types, as well as optimal solutions for photo-detectors studying the differences between SiPM and PMT. Our results also led to the determination of a better optimized design for the hodoscope detectors, consisting of a 0.7 cm width and a 13 cm length EJ276D scintillation rod.

Is there an anatomical marker for the deep peroneal nerve in midfoot surgical approaches?

The deep peroneal nerve (DPN) passes over the dorsum of the foot and is susceptible to injury during surgical approaches. The purpose of this anatomical study is to examine the relationship of the extensor hallucis brevis (EHB) as it passes over the DPN. Ten cadaver feet specimens were dissected and the anatomical structures surrounding the neurovascular bundle containing the DPN were examined. In nine out of the ten specimens the DPN was under the EHB musculotendinous junction. In one case it passed through the musculotendinous junction. This cadaver study has found a consistent easily identifiable landmark for protecting the neurovascular bundle containing the DPN during dorsal midfoot surgery.

Improving Accessibility in the Emergency Department for Patients with Disabilities: A Qualitative Study.

INTRODUCTION: The emergency department (ED) is a critical service area for patients living with disabilities in the United States. Despite this, there is limited research on best practices from the patient experience regarding accommodation and accessibility for those with disabilities. In this study we investigate the ED experience from the perspective of patients living with physical and cognitive disability, as well as visual impairment and blindness, to better understand the barriers to accessibility in the ED for these populations. METHODS: Twelve individuals with either physical or cognitive disabilities, visual impairments or blindness were interviewed regarding their ED experiences, particularly related to accessibility. Interviews were transcribed and coded for qualitative analysis with generation of significant themes relating to accessibility in the ED. RESULTS: Major themes from coded analysis were as follows: 1) inadequate communication between staff and patients with visual impairments and physical disabilities; 2) the need for electronic delivery for after-visit summaries for individuals with cognitive and visual disabilities; 3) the importance of mindful listening and patience by healthcare staff; 4) the role of increased hospital support including greeters and volunteers; and 5) comprehensive training with both prehospital and hospital staff around assistive devices and services. CONCLUSION: This study serves as an important first step toward improving the ED environment to ensure accessibility and inclusivity for patients presenting with various types of disabilities. Implementing specific training, policies, and infrastructure changes may improve the experiences and healthcare of this population.

Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours.

BACKGROUND: Olaparib (AZD2281) is a potent oral poly(ADP-ribose) polymerase inhibitor with anti-tumour activity and acceptable toxicity as monotherapy in patients with BRCA-deficient cancers. The vascular endothelial growth factor receptor inhibitor bevacizumab has been incorporated into standard of care with chemotherapy in various tumours. This phase I study established the safety, tolerability and clinical pharmacokinetics of olaparib alone and in combination with bevacizumab. METHODS: Patients with advanced solid tumours received increasing doses of continuous oral olaparib (100, 200 and 400 mg b.i.d. capsule formulation) in combination with bevacizumab (10 mg kg(-1) intravenous q2w). RESULTS: In all, 12 patients enrolled and received treatment. The most common adverse events (AEs) related to olaparib were grade 1/2 nausea and fatigue. No haematological parameters were reported as AEs. No serious AEs related to olaparib or dose-limiting toxicities (DLTs) were reported. Three patients discontinued due to AEs, two patients discontinued both olaparib and bevacizumab and one patient discontinued olaparib. Five patients received combination treatment for over 6 months. There was no evidence that bevacizumab affected olaparib. CONCLUSION: The combination of olaparib 400 mg b.i.d. with bevacizumab 10 mg kg(-1) q2w was generally well tolerated with no DLTs. This combination could be considered for future clinical investigation.

Immune regulation of procalcitonin: a biomarker and mediator of infection.

Procalcitonin (PCT) has recently emerged as a powerful biomarker for an early and accurate diagnosis of bacterial infection. Here we summarize our current understanding of the expression pathways of PCT, its potential cellular sources including immune cells, and factors inducing its secretion. Also addressed is the significance of increased blood PCT concentration, which may allow this molecule not only to act as a clinical biomarker but also as an active participant in the development and progression of infectious processes. Experimental approaches to delineate a better understanding of PCT functions, molecular pathways that modulate its expression and therapeutic opportunities to curtail its biological actions are discussed, as well.

Essential components of effective HIV care: a policy paper of the HIV Medicine Association of the Infectious Diseases Society of America and the Ryan White Medical Providers Coalition.

Human immunodeficiency virus (HIV) antiretroviral agents and effective HIV care management transformed HIV disease from a death sentence to a chronic condition for many in the United States. A comprehensive HIV care model was developed to meet the complex needs of HIV patients, with support from the Ryan White program, the Veterans Administration, and others. This paper identifies the essential components of an effective HIV care model. As access to health care expands under the National HIV/AIDS Strategy and the Patient Protection and Affordable Care Act, it will be critical to build upon the HIV care model to realize positive health outcomes for people with HIV infection.

A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours.

BACKGROUND: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment. PATIENTS AND METHODS: Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells. RESULTS: The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma. CONCLUSION: This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.

A high-pressure flow through test vessel for neutron imaging and neutron diffraction-based strain measurement of geological materials.

Neutron scattering and neutron imaging have emerged as powerful methods for experimentally investigating material deformation and fluid flow in the interior of otherwise inaccessible or opaque structures. This paper describes the design and provides example uses of a pressure cell developed for investigating such behaviors within geological materials. The cell can accommodate cylindrical samples with diameters up to 38.1 mm and lengths up to 154 mm. Ports in the cell and a pressure isolating sleeve around the sample allow the independent application of confining pressure up to 69 MPa and axial pressure up to 34.5 MPa. Two material versions of the cell have been manufactured and used to date. An aluminum version is typically used for temperatures below 40 °C, because of its relative transparency to neutrons, while a titanium version, which is comparatively more neutron attenuating, is used for experiments requiring triaxial pressurization under conditions up to 350 °C. The pressure cells were commissioned at the VULCAN engineering diffractometer at the Oak Ridge National Laboratory (ORNL), Spallation Neutron Source, and have since been used at the ORNL high flux isotope reactor CG1-D imaging beamline, National Institute of Standard and Technology (NIST) BT-2, and NIST NG6 imaging beamlines.

Prader-Willi syndrome phenocopy due to duplication of Xq21.1-q21.31, with array CGH of the critical region.

We report on a 4-year-old male with an interstitial tandem duplication of Xq21.1-q21.31 who presented with clinical features of Prader-Willi syndrome (PWS). The duplication was maternally inherited. Abnormalities of the X chromosome have previously been reported in association with a PWS phenotype, but to date, specific duplications of Xq21.1-q21.31 have not. We refined the chromosomal breakpoints seen on initial G-banded karyotyping in our case with comparative genomic hybridization by microarray (array CGH). The duplication was between 11.1 and 14.4 Mb in length and overlaps with three loci to which mental retardation with PWS-like features have been previously mapped, showing the utility of array CGH in helping to identify candidate genes. We conclude that duplication of chromosomal region Xq21.1-q21.31 potentially results in a PWS-like phenotype. Reviewing the literature on similar duplications, we further conclude that distal Xq duplications can result in features typically seen in infants with PWS, while proximal duplications can result in features typically seen in older children and adults with PWS. Duplications of chromosome Xq should be considered in the differential diagnosis of PWS, especially in males.

Cytochrome c impaled: investigation of the extended lipid anchorage of a soluble protein to mitochondrial membrane models.

Cyt c (cytochrome c) has been traditionally envisioned as rapidly diffusing in two dimensions at the surface of the mitochondrial inner membrane when not engaged in redox reactions with physiological partners. However, the discovery of the extended lipid anchorage (insertion of an acyl chain of a bilayer phospholipid into the protein interior) suggests that this may not be exclusively the case. The physical and structural factors underlying the conformational changes that occur upon interaction of ferrous cyt c with phospholipid membrane models have been investigated by monitoring the extent of the spin state change that result from this interaction. Once transiently linked by electrostatic forces between basic side chains and phosphate groups, the acyl chain entry may occur between two parallel hydrophobic polypeptide stretches that are surrounded by positively charged residues. Alteration of these charges, as in the case of non-trimethylated (TML72K) yeast cyt c and Arg91Nle horse cyt c (where Nle is norleucine), led to a decline in the binding affinity for the phospholipid liposomes. The electrostatic association was sensitive to ionic strength, polyanions and pH, whereas the hydrophobic interactions were enhanced by conformational changes that contributed to the loosening of the tertiary structure of cyt c. In addition to proposing a mechanistic model for the extended lipid anchorage of cyt c, we consider what, if any, might be the physiological relevance of the phenomenon.

Evaluation and utilization of beam simulation codes for the SNS ion source and low energy beam transport development.

Beam simulation codes PBGUNS, SIMION, and LORENTZ-3D were evaluated by modeling the well-diagnosed SNS base line ion source and low energy beam transport (LEBT) system. Then, an investigation was conducted using these codes to assist our ion source and LEBT development effort which is directed at meeting the SNS operational and also the power-upgrade project goals. A high-efficiency H(-) extraction system as well as magnetic and electrostatic LEBT configurations capable of transporting up to 100 mA is studied using these simulation tools.