Inactivation of hepatitis A virus, feline calicivirus, and Tulane virus on Formica coupons using ultraviolet light technologies.

Contaminated fomites can lead to hepatitis A virus (HAV) and human norovirus (HuNoV) disease outbreaks. Improved decontamination methods that are user-friendly, cost-effective, and waterless are being researched for sustainability. Traditional ultraviolet light (UV-C) technologies though effective for surface decontamination have drawbacks, using mercury lamps, that pose user-safety risk and environmental hazards. Therefore, UV-C light emitting diode (LED) systems are being designed for delivering required antiviral doses. The objective of this research was to determine the ability of UV-C LED (279 nm) systems to inactivate HuNoV surrogates, feline calicivirus (FCV-F9) and Tulane virus (TV), and HAV on Formica coupons in comparison to UV-C (254 nm) systems. FCV-F9 (∼6 log PFU/mL), TV (∼7 log PFU/mL), or HAV (∼6 log PFU/mL) at 100 µL were surface-spread on sterile Formica coupons (3 × 3 cm2), air-dried, and treated for up to 2.5 min with both systems. Each experiment was replicated thrice. Recovered infectious plaque counts were statistically analyzed using mixed model analysis of variance. FCV-F9, TV, and HAV showed D10 values of 23.37 ± 0.91 mJ/cm2, 16.32 ± 3.6 mJ/cm2, and 12.39 ± 0.70 mJ/cm2 using 279 nm UV-C LED, respectively and D10 values of 9.97 ± 2.44 mJ/cm2, 6.83 ± 1.13 mJ/cm2 and 12.40 ± 1.15 mJ/cm2, respectively with 254 nm UV-C. Higher 279 nm UV-C LED doses were required to cause HuNoV surrogate reduction than 254 nm UV-C, except similar doses with both systems were needed for HAV inactivation on Formica surfaces. It remains critical to measure UV intensity of optical sources and optimize exposure times for desired log reduction on surfaces.

Local recurrence following a complete radiologic response in hepatocellular carcinoma patients: comparison of transarterial chemoembolisation and transarterial radioembolisation.

AIM: To evaluate and compare the rates of local recurrence in hepatocellular carcinoma (HCC) patients who undergo selective transarterial radioembolisation (TARE) or transarterial chemoembolisation (TACE) and achieve a complete response (CR) radiologically. MATERIALS AND METHODS: All patients undergoing treatment with TARE or TACE at a single academic institution were reviewed retrospectively. Those who had been treated previously, presented with multifocal disease, had non-selective TARE or TACE, or did not achieve a complete response (CR) radiologically were excluded. RESULTS: In total 110 patients were included (TACE n=60 [54.5%]; TARE n=50 [45.5%]). TARE patients were older (66.4 ± 9.4 versus 61.2 ± 5.6 years, p<0.001) and had larger tumours (4.4 ± 2.2 versus 3 ± 1.4 cm, p=0.002). TACE patients were significantly more likely to suffer a local recurrence (31/60, 51.7% versus 9/50, 18%, p<0.001) and had a significantly shorter time to recurrence (median 8.3 {interquartile range [IQR]}: 12 versus median 17.9 [IQR: 23.5] months, p=0.001). A local time to progression (TTP) Kaplan-Meier curve demonstrated TACE patients had a significantly shorter local TTP (hazard ratio [HR]: 7.2; 95% confidence interval [CI]: 3.64-14.24; p<0.001) and treatment modality (TACE or TARE; HR: 0.05; 95% CI: 0.005-0.5; p=0.01) was found to be associated with local recurrences on multivariate Cox proportional HR analysis. When overall TTP was evaluated, again TACE patients were found to have a significantly shorter TTP (HR: 2.13 [1.28-3.53], p=0.004). CONCLUSION: In HCC patients undergoing selective treatment who achieve a CR radiologically, those treated with TARE may be less likely to suffer recurrence, either local or general, than those treated with TACE.

Heat stress of gilts around farrowing causes oxygen insufficiency in the umbilical cord and reduces piglet survival.

Late gestating sows are susceptible to high ambient temperatures, possibly causing farrowing complications and reducing piglet survival. This experiment aimed to quantify in the days leading up to farrowing the impact of sow heat stress (HS) on farrowing physiology and survival of the piglets. Pregnant primiparous sows (gilts) were allocated to either thermoneutral control (CON, n = 8; constant 20 °C) or cyclical HS conditions (n = 8; 0900 h to 1700 h, 30 °C; 1700 h to 0900 h, 28 °C) from d 110 of gestation until farrowing completion. Gilt respiration rate, skin temperature and rectal temperature were recorded daily, and farrowing duration was quantified by video analyses. Blood samples were collected from the piglet umbilical vein at birth. At 48 h of age, piglet growth was quantified by morphometric analyses. The thermal exposure model induced HS and respiratory alkalosis in the gilts, as indicated by increased respiration rate, rectal temperature, skin temperature (all P < 0.001), plasma cortisol (P = 0.01) and blood pH (P < 0.001). Heat-stressed gilts took longer to start expelling placentae (P = 0.003), although the active farrowing duration was not significantly different between treatments. Stillbirth rates were higher in the HS group (P < 0.001), with surviving piglets at birth having lower umbilical vein partial pressure of oxygen (P = 0.04), oxygen saturation rate (P = 0.03) and tending to have increased lactate concentrations (P = 0.07). At birth, piglet skin meconium staining scores were greater in the HS group (P = 0.022). At 48 h of age, piglets from the HS group had reduced small intestinal length (P = 0.02), reduced jejunal crypt depth (P = 0.02) and lighter absolute brain weight (P = 0.001). In contrast, piglet BW, growth rate, relative organ weight and small intestinal mucosal barrier function did not change between treatments. Collectively, these findings demonstrated gilt HS during late gestation caused farrowing complications and reduced the umbilical oxygen supply to the piglets at parturition, leading to increased risks of piglet stillbirth with implications on impaired neonatal survivability and development.

Microbiological Profile, Prevalence, and Characterization of Salmonella enterica in Peanuts, Pecans, Raisins, Sun-Dried Tomatoes, and Chocolate Sprinkles Sold in Bulk in Markets in Querétaro, Mexico.

ABSTRACT: In Mexico, the prevalence of Salmonella enterica in low-water-activity foods and its link to outbreaks are unknown. The aim of this study was to determine the microbiological profile and the prevalence of S. enterica in several low-water-activity foods, including peanuts, pecans, raisins, sun-dried tomatoes, and chocolate sprinkles, purchased in retail establishments in Querétaro, Mexico. Seventy samples of each food item sold in bulk were purchased. Aerobic plate count, molds, yeasts, total coliforms, Escherichia coli, and Staphylococcus aureus were quantified in 10-g samples. The prevalence of S. enterica in 25-g samples was determined. From positive samples, S. enterica isolates (60) were characterized based on their antimicrobial susceptibility to 14 antibiotics, the presence-absence of 13 virulence genes, and serotype. The concentration of aerobic plate count, molds, yeasts, total coliforms, and E. coli ranged from 3.1 to 5.2 log CFU g-1, from 2.0 to 2.4 log CFU g-1, from 2.0 to 3.0 log CFU g-1, from 0.6 to 1.1 log most probable number (MPN) g-1, and from 0.5 to 0.9 log MPN g-1, respectively. S. aureus was not detected in any sample (<10 CFU g-1). The prevalence of S. enterica in chocolate sprinkles, raisins, peanuts, pecans, and sun-dried tomatoes was 26, 29, 31, 40, and 52%, respectively. Most isolates (68.3%) were resistant to at least one antibiotic. Chromosome-associated virulence genes were found in all isolates, and only one strain had sopE, and 98.3% of the isolates were grouped in the same virulotype. Among the isolates, the most frequent serotype was Tennessee (51 of 60). According to the characteristics evaluated, we grouped the isolates into 24 clusters. The elevated prevalence of S. enterica highlights the role of low-water-activity food items sold in bulk at markets as potential vehicles for pathogen transmission. Regardless of the low variability among S. enterica isolates, their characterization could be helpful to elucidate which strains are circulating in these foods for improving epidemiological surveillance.

Use of bioelectrical impedance spectroscopy to provide a measure of body composition in sows.

The ability to accurately estimate fat mass and fat-free mass (FFM) has the potential to improve the way in which sow body condition can be managed in a breeding herd. Bioelectrical impedance spectroscopy (BIS) has been evaluated as a practical technique for assessment of body composition in several livestock species, but similar work is lacking in sows. Bioelectrical impedance uses population-specific algorithms that require values for the apparent resistivities of body fluids and body proportion factors. This study comprised three major aims: (i) to derive apparent resistivity coefficients for extracellular water (ECW) and intracellular water (ICW) required for validation of BIS predictions of total body water (TBW) in live sows against standard reference tracer dilution methods; (ii) to develop predictions of TBW to body composition prediction algorithms, namely FFM, by developing a body geometry correction factor (Kb) and (iii) to compare the BIS predictions of FFM against existing impedance predictors and published prediction equations for use in sows, based on physical measurements of back-fat depth and BW (P2-based predictors). Whole body impedance measurements and the determination of TBW by deuterium dilution and ECW by bromide dilution were performed on 40 Large White x Landrace sows. Mean apparent resistivity coefficients of body fluids were 431.1 Ω.cm for ECW and 1827.8 Ω.cm for ICW. Using these coefficients, TBW and ECW were over-estimated by 6.5 and 3.3%, respectively, compared to measured reference values, although these differences were not statistically different (P > 0.05). Mean Kb was 1.09 ±â€¯0.14. Fat-free mass predictions were 194.9 kg, which equates to 60.9% of total sow weight, and 183.0 kg for BIS and the deuterium dilution method, respectively. Mean differences between the predicted and measured FFM values ranged from -8.2 to 32.7%, but were not statistically different (P > 0.05). Method validation (leave-one-out procedure) revealed that mean differences between predicted and measured values were not statistically significant (P > 0.05). Of the impedance-based predictors, equivalence testing revealed that BIS displayed the lowest test bias of 11.9 kg (8.2%), although the P2-based prediction equations exhibited the lowest bias and percentage equivalence, with narrow limits of agreement. Results indicate although differences between mean predicted and measured values were not significantly different, relatively wide limits of agreement suggest BIS as an impractical option for assessing body composition in individual sows compared to the use of existing prediction equations based on BW and back fat.

Value-added switchgrass extractives for reduction of Escherichia coli O157:H7 and Salmonella Typhimurium populations on Formica coupons.

Recurring outbreaks linked to Escherichia coli O157:H7-contaminated lettuce and Salmonella enterica-contaminated sprouts highlight the need for improved food safety measures. The aim of this study was to determine the ability of a bio-based antimicrobial extract prepared from switchgrass, a dedicated energy crop, to reduce E. coli O157:H7 and S. Typhimurium populations on Formica coupons, a model food-contact surface. Overnight cultures of ~7 log CFU/mL E. coli O157:H7 and S. Typhimurium, air-dried on Formica coupons were treated with 0.625% NaClO, 70% ethanol, sterile water or different batches of switchgrass extractives (SE1, SE2, and SE3) for up to 30 min. E. coli O157:H7 was reduced by 4.43 log CFU/mL after 1 min by SE3, and to non-detectable levels after 1 min by all other treatments. Populations of S. Typhimurium LT2 (15-min drying) were reduced by 3.30 log CFU/mL with 70% ethanol, 5.38 log CFU/mL with SE1, and to non-detectable levels with 0.625% NaClO after 1 min, while S. Typhimurium ATCC 23564 (1-h drying) was non-detectable after 1 min by all treatments. Under soiled conditions, 10-min treatment with SE1 and 70% ethanol reduced both bacteria to non-detectable levels. Studies with concentrated switchgrass extractives combined with various other natural disinfectants or in hurdle approaches warrant further investigation.

Salvage Re-irradiation With Single-modality Interstitial Brachytherapy for the Treatment of Recurrent Gynaecological Tumours in the Pelvis: A Multi-institutional Study.

AIMS: Recurrent gynaecological tumours can cause significant morbidity with limited salvage options. This study investigates the strategy of salvage single-modality interstitial brachytherapy (SM-ISBT) for recurrent gynaecological pelvic cancer at two specialised ISBT centres. MATERIALS AND METHODS: Patients who had received salvage SM-ISBT for pelvic recurrence of gynaecological cancers from September 2008 to January 2017 were included. None had distant metastasis at the time of recurrence. Local control, progression-free and overall survival and long-term toxicities were evaluated. RESULTS: Twenty-six patients with a median follow-up of 24 months (range 2.5-106.3 months) after SM-ISBT were included. Primary cancer sites were endometrium (20), cervix (4), vulva (1) and vagina (1). All patients had prior whole-pelvic external beam irradiation and 16 had prior brachytherapy. The median disease-free survival prior to SM-ISBT was 20.3 months (interquartile range 9.9-30.5). SM-ISBT was delivered with high dose rate technique over three to six fractions. The median high-risk clinical target volume was 34.6 cm3, with a median D90 of 29.1 Gy (range 16.1-64.6). The median bladder, rectum and sigmoid D2cm3 were 15.5, 18.7 and 3.7 Gy, respectively. After SM-ISBT, complete and partial responses were achieved in 17 (64%) and 5 (19%) patients, respectively. Two (7.4%) patients had grade 3 toxicities (both vaginal stenosis), with no grade 4 complications. Eighteen patients (69%) recurred, including local, regional and metastatic in 14 (54%), 8 (30%) and 5 (19%) patients, respectively. Two-year local control, progression-free survival and overall survival were 50, 38 and 78%, respectively. In follow-up, 12 patients (46%) remained in local control. CONCLUSIONS: Salvage SM-ISBT re-irradiation for pelvic recurrence of gynaecological malignancies was feasible and safe. With limited salvage options, the local control obtained in more than a quarter of patients seems reasonable. Further efforts are needed to establish a consensus about the optimal patient selection, dose fractionation, implant technique and combination with systemic therapies.

The impact of proton LET/RBE modeling and robustness analysis on base-of-skull and pediatric craniopharyngioma proton plans relative to VMAT.

Purpose: Pediatric craniopharyngioma, adult base-of-skull sarcoma and chordoma cases are all regarded as priority candidates for proton therapy. In this study, a dosimetric comparison between volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) was first performed. We then investigated the impact of physical and biological uncertainties. We assessed whether IMPT plans remained dosimetrically superior when such uncertainty estimates were considered, especially with regards to sparing organs at risk (OARs).Methodology: We studied 10 cases: four chondrosarcoma, two chordoma and four pediatric craniopharyngioma. VMAT and IMPT plans were created according to modality-specific protocols. For IMPT, we considered (i) variable RBE modeling using the McNamara model for different values of (α/ß)x, and (ii) robustness analysis with ±3 mm set-up and 3.5% range uncertainties.Results: When comparing the VMAT and IMPT plans, the dosimetric advantages of IMPT were clear: IMPT led to reduced integral dose and, typically, improved CTV coverage given our OAR constraints. When physical robustness analysis was performed for IMPT, some uncertainty scenarios worsened the CTV coverage but not usually beyond that achieved by VMAT. Certain scenarios caused OAR constraints to be exceeded, particularly for the brainstem and optical chiasm. However, variable RBE modeling predicted even more substantial hotspots, especially for low values of (α/ß)x. Variable RBE modeling often prompted dose constraints to be exceeded for critical structures.Conclusion: For base-of-skull and pediatric craniopharyngioma cases, both physical and biological robustness analyses should be considered for IMPT: these analyses can substantially affect the sparing of OARs and comparisons against VMAT. All proton RBE modeling is subject to high levels of uncertainty, but the clinical community should remain cognizant possible RBE effects. Careful clinical and imaging follow-up, plus further research on end-of-range RBE mitigation strategies such as LET optimization, should be prioritized for these cohorts of proton patients.

Percutaneous gastric tube placement: Comparison of trans-abdominal and trans-oral approach in patients with chronic ascites.

PURPOSE: The purpose of this study was to compare the trans-abdominal (TA) and trans-oral (TO) approaches for fluoroscopic-guided gastrostomy tube placement in patients with chronic ascites. MATERIALS AND METHODS: A 10-year review of clinical imaging and medical records at a single institution identified 29 patients with chronic recurrent ascites who underwent gastrostomy (GT) or gastro-jejunostomy tube (GJT) placement. In 22 patients (18 women, 4 men) aged from 22 to 76 years of age (mean age, 57.7±13.1 years), a GT or GJT was placed with the TO approach, and in 7 (7 women) from 31 to 86 years of age (mean age, 63±16.8 years) with the TA approach. RESULTS: Technical success was 100% in both groups with one (1/22; 5%) immediate complication in the TO group. Fluoroscopy time was significantly greater in the TO group (P=0.002). Leakage of ascites was significantly more frequent in the TA group (P=0.04). There was no significant difference in bleeding or inflammation (P=0.14 and P=0.43, respectively). The cumulative tract related complication rate was significantly greater in the TA group (P=0.03). CONCLUSION: Fluoroscopy times and the overall incidence of tract-related complications, in particular leakage of ascites from the stoma, are more frequent in patients in chronic ascites who underwent TA gastrostomy tube placement compared to those who underwent TO placement.

Clinical utility of one month imaging following selective internal radiation therapy.

PURPOSE: The goal of this retrospective review was to determine the clinical relevance of one-month post-treatment imaging in the selective internal radiation therapy (SIRT) patient population by reporting the incidence of change in clinical management. MATERIALS AND METHODS: Between January 2012 and January 2016, 85 patients underwent 109 SIRT treatments for either primary or secondary hepatic malignancies. There were 59 men and 26 women with a mean age of 62.4 years (range: 39-89 years). Patients' medical records were retrospectively reviewed for procedural, historical, laboratory and imaging information. The imaging study was considered to have changed patients' clinical management if it resulted in the addition of a new procedure, canceling of a planned procedure or change in systemic therapy. RESULTS: The one-month post-treatment imaging findings led to management changes in 10 of 109 (9.2%) of treatments. When evaluated by cancer type, 2/61 (3.3%) hepatocellular carcinoma (HCC) treatments had management changed while 8/48 (16.7%) non-HCC treatments underwent management change (P=0.03). This difference was also significant at multivariate analysis (P=0.03; odds ratio: 0.17 [0.03-082]). CONCLUSION: Management is rarely changed by one-month post-SIRT imaging in patients with HCC and thus is likely unwarranted. Conversely, in non-HCC patients, one month post-SIRT imaging led to a significant percentage of clinical management changes suggesting that one month imaging in this setting is likely warranted.

Toward adaptive radiotherapy for lung patients: feasibility study on deforming planning CT to CBCT to assess the impact of anatomical changes on dosimetry.

Changes in lung architecture during a course of radiotherapy can alter the planned dose distribution to the extent that it becomes clinically unacceptable. This study aims to validate a quantitative method of determining whether a replan is required during the course of conformal radiotherapy. The proposed method uses deformable image registration (DIR) to flexibly map planning CT (pCT) data to the anatomy of online CBCT images. The resulting deformed CT (dCT) images are used as a basis for assessing the effect of anatomical change on dose distributions. The study used retrospective data from a sample of seven replanned lung patients. The settings of an in-house, open-source DIR algorithm were first optimised for CT-to-CBCT registrations of the anatomy of the thorax. Using these optimised parameters, each patient's pCT was deformed to the CBCT acquired immediately before the replan. Registration accuracy was rigorously validated both geometrically and dosimetrically to confirm that the dCTs could reliably be used to inform replan decisions. A retrospective evaluation of the changes in dose delivered over time was then carried out for a single patient to demonstrate the clinical application of the proposed method. The geometric analysis showed good agreement between deformed structures and those same structures manually outlined on the CBCT images. Results were consistently better than those achieved with rigid-only registration. In the dosimetric analysis, dose distributions derived from the dCTs were found to match closely to the 'gold standard' replan CT (rCT) distributions across dose volume histogram and absolute dose difference measures. The retrospective analysis of serial CBCTs of a single patient produced reliable quantitative assessment of the dose delivery. Had the proposed method been available at the time of treatment, it would have enabled a more objective replan decision. DIR is a valuable clinical tool for dose recalculation in adaptive radiotherapy protocols for lung cancer patients.

Electrical stimulation or moisture infusion improves the eating quality attributes of loin and silverside cuts from female and immunocastrated male pigs.

This study validated the effect of gender (female, immunocastrated male; n = 50), electrical stimulation (none or 150 mA constant current for 30 s at 2 min post-slaughter) and ageing period (2 or 14 d) on the eating quality of pork roast and stir fry sourced from the loin (M. longissimus thoracis et lumborum) and silverside (M. biceps femoris) and steak from the loin only. Moisture infusion was applied to 2 d aged, non-stimulated primals as a positive control treatment. Neither gender nor ageing period influenced (P > 0.05) eating quality. Electrical stimulation and moisture infusion were each effective interventions in improving pork eating quality, but their effects were inconsistent between the five cuts evaluated. No interventions achieved the fail rate target of <10% for quality grade for all cuts, indicating that additional interventions are needed to enable industry to consistently deliver high quality pork.

Guaranteeing the quality and integrity of pork - An Australian case study.

The Australian pork industry is strongly committed to assuring the integrity of its product, with substantial research investment made over the past ten years to develop and implement systems to assure the consistency and quality of fresh pork and to enable accurate tracing of unpackaged fresh pork back to property of origin using trace elemental profiling. These initiatives are pivotal to allow Australian pork of guaranteed eating quality to be successfully positioned as higher value products, across a range of international and domestic markets, whilst managing any threats of product substitution. This paper describes the current status of the development of a predictive eating quality model for Australian pork, utilizing eating quality datasets generated from recent Australian studies. The implementation of trace elemental profiling, by Physi-Trace™, to verify and defend provenance claims and support the supply of consistently high eating quality Australian pork to its customers, is also discussed.

Validating post-slaughter interventions to produce consistently high quality pork cuts from female and immunocastrated male pigs.

Eating quality attributes of pork loin (M. longissimus thoracis et lumborum) and silverside (M. biceps femoris) from female and immunocastrated male carcases hung from either the Achilles tendon or aitchbone, aged for either 2 or 7 days post-slaughter and cooked as roasts, stir fry and steak (loin only) (n = 25/gender) was assessed. A positive control treatment of moisture infusion (10% injection rate) was applied to Achilles hung sides with cuts aged for 2 d post-slaughter. Neither gender nor ageing period influenced consumer sensory scores. Beneficial effects of aitchbone hanging on eating quality compared with Achilles hanging were largely observed after 2 d ageing, with improvements (P < 0.05) in overall liking scores found for loin stir fry and silverside stir fry and roasts. Overall liking scores of all cuts, except silverside stir fry, were increased (P < 0.05) when moisture infused compared with those from aitchbone-hung sides. However, targeted fail rates of <10% were not consistently achieved across all cuts evaluated.

Eating quality traits of shoulder roast and stir fry cuts outperformed loin and silverside cuts sourced from entire and immunocastrated male pigs.

This study investigated the effects of ageing period (2 or 7days), endpoint temperature (70 or 75°C), cut type (loin (M. longissimus thoracis et lumborum), silverside (M. biceps femoris), blade (M. triceps brachii) and chuck tender (M. supraspinatus)), cooking method (roast and stir fry (all cuts) and steak (loin only)) on eating quality attributes of pork from entire and immunocastrated male pigs. Higher intramuscular fat levels were found in all cuts from immunocastrated males compared with entire males. Of the seven cut type×cooking method combinations evaluated, shoulder cuts had the lowest fail rate (P<0.001) and loin steak and silverside cuts scored lowest (P<0.001) for tenderness, juiciness, overall liking, quality grade and re-purchase intention. Although no differences in sensory scores due to gender were observed, boar taint was identified in 10% of entire males. Minimising adverse risks in eating quality due to boar taint in males remains a key industry issue to ensure consistent delivery of high quality pork.

Diet composition and slaughter age up to 24weeks have minimal impact on pork eating quality of loin steaks and silverside roasts from female pigs.

Female crossbred pigs were randomly allocated at 16weeks of age to one of three dietary treatments (A: corn and soybean meal; B: wheat and canola meal; C: wheat and sorghum) matched for digestible energy (13.6MJ DE/kg) and total lysine (0.93-0.95%) and fed for 4, 5 or 8weeks, respectively, prior to slaughter. Loin (M. longissimus thoracis et lumborum) and silverside (M. biceps femoris) were obtained from 20 pigs per dietary treatment group and prepared into steaks and roasts, respectively, for consumer evaluation with ageing treatments of 7 and 28days post-slaughter allocated within muscle. Neither dietary treatment/age at slaughter nor ageing treatment influenced sensory traits of either cut. Intramuscular fat levels were also not influenced by dietary treatment. Higher (P<0.001) fail rates for silverside roasts compared with loin steaks indicate that different interventions are needed at a cut level to optimise pork eating quality consistency and consumer expectations.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Cannabis-associated psychosis: Neural substrate and clinical impact.

Prospective epidemiological studies have consistently demonstrated that cannabis use is associated with an increased subsequent risk of both psychotic symptoms and schizophrenia-like psychoses. Early onset of use, daily use of high-potency cannabis, and synthetic cannabinoids carry the greatest risk. The risk-increasing effects are not explained by shared genetic predisposition between schizophrenia and cannabis use. Experimental studies in healthy humans show that cannabis and its active ingredient, delta-9-tetrahydrocannabinol (THC), can produce transient, dose-dependent, psychotic symptoms, as well as an array of psychosis-relevant behavioral, cognitive and psychophysiological effects; the psychotogenic effects can be ameliorated by cannabidiol (CBD). Findings from structural imaging studies in cannabis users have been inconsistent but functional MRI studies have linked the psychotomimetic and cognitive effects of THC to activation in brain regions implicated in psychosis. Human PET studies have shown that acute administration of THC weakly releases dopamine in the striatum but that chronic users are characterised by low striatal dopamine. We are beginning to understand how cannabis use impacts on the endocannabinoid system but there is much still to learn about the biological mechanisms underlying how cannabis increases risk of psychosis. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".

Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242.

There is a need to develop treatments for cognitive impairment associated with schizophrenia (CIAS). The significant role played by N-methyl-d-aspartate receptors (NMDARs) in both the pathophysiology of schizophrenia and in neuronal plasticity suggests that facilitation of NMDAR function might ameliorate CIAS. One strategy to correct NMDAR hypofunction is to stimulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as AMPAR and NMDAR functioning are coupled and interdependent. In rats and nonhuman primates (NHP), AMPAR potentiators reduce spatial working memory deficits caused by the nonselective NMDAR antagonist ketamine. The current study assessed whether the AMPAR potentiator PF-04958242 would attenuate ketamine-induced deficits in verbal learning and memory in humans. Healthy male subjects (n=29) participated in two randomized treatment periods of daily placebo or PF-04958242 for 5 days separated by a washout period. On day 5 of each treatment period, subjects underwent a ketamine infusion for 75 min during which the effects of PF-04958242/placebo were assessed on ketamine-induced: (1) impairments in verbal learning and recall measured by the Hopkins Verbal Learning Test; (2) impairments in working memory on a CogState battery; and (3) psychotomimetic effects measured by the Positive and Negative Syndrome Scale and Clinician-Administered Dissociative Symptoms Scale. PF-04958242 significantly reduced ketamine-induced impairments in immediate recall and the 2-Back and spatial working memory tasks (CogState Battery), without significantly attenuating ketamine-induced psychotomimetic effects. There were no pharmacokinetic interactions between PF-04958242 and ketamine. Furthermore, PF-04958242 was well tolerated. 'High-impact' AMPAR potentiators like PF-04958242 may have a role in the treatment of the cognitive symptoms, but not the positive or negative symptoms, associated with schizophrenia. The excellent concordance between the preclinical (rat, NHP) and human studies with PF-04958242, and in silico modeling of AMPAR-NMDAR interactions in the hippocampus, highlights the translational value of this study.

Reducing Patient Waiting Times for Radiation Therapy and Improving the Treatment Planning Process: a Discrete-event Simulation Model (Radiation Treatment Planning).

AIMS: We analysed the radiotherapy planning process at the London Regional Cancer Program to determine the bottlenecks and to quantify the effect of specific resource levels with the goal of reducing waiting times. MATERIALS AND METHODS: We developed a discrete-event simulation model of a patient's journey from the point of referral to a radiation oncologist to the start of radiotherapy, considering the sequential steps and resources of the treatment planning process. We measured the effect of several resource changes on the ready-to-treat to treatment (RTTT) waiting time and on the percentage treated within a 14 calendar day target. RESULTS: Increasing the number of dosimetrists by one reduced the mean RTTT by 6.55%, leading to 84.92% of patients being treated within the 14 calendar day target. Adding one more oncologist decreased the mean RTTT from 10.83 to 10.55 days, whereas a 15% increase in arriving patients increased the waiting time by 22.53%. The model was relatively robust to the changes in quantity of other resources. CONCLUSIONS: Our model identified sensitive and non-sensitive system parameters. A similar approach could be applied by other cancer programmes, using their respective data and individualised adjustments, which may be beneficial in making the most effective use of limited resources.