Search

This paper proposes a phase-I clinical trial design that uses ordinal toxicity to locate group-specific doses when groups are partially or completely ordered prior to the start of the trial. There has been previous work on dose-finding for groups and on dose-finding with ordinal toxicity but a solution to the problem of dose-finding for groups with ordinal toxicity has not been proposed. Simulations compared the proposed method against two methods; one that uses ordinal toxicity but does not use group information and one that uses group information but does not use ordinal toxicity. One issue with the first method is the potential for reversals, when the recommended dose for a more sensitive group is higher than the recommended dose for a less sensitive group. The proposed method avoids reversals, allocates patients to optimal doses more frequently during the trial, and selects optimal doses more frequently at the end of the trial., Competing Interests: Declaration of Competing Interest The authors declare no potential conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Cystic fibrosis (CF) is a systemic autosomal recessive condition characterised by progressive lung disease. CF pulmonary exacerbations (PEx) are episodes of worsening respiratory status, and frequent PEx are a risk factor for accelerated lung function decline, yet many people with CF (PwCF) go untreated at the time of decline. The goal of this quality improvement (QI) initiative was to improve recognition, treatment and follow-up of PEx in PwCF., Methods: Using the Model for Improvement, the Cystic Fibrosis Learning Network (CFLN) initiated a QI innovation laboratory (iLab) with a global aim to decrease the rate of lung function decline in PwCF. The iLab standardised definitions for signals of PEx using a threshold for decline in forced expiratory volume in one second (FEV 1 ) and/or changes in symptoms. The FEV 1 decline signal was termed FIES (FEV 1 -indicated exacerbation signal). Processes for screening and recognition of FIES and/or symptom changes, a treatment algorithm and follow-up in the presence of a signal were tested concurrently in multiple settings., Specific Aims: The specific aim is to increase the per cent of PwCF assessed for a PEx signal at ambulatory encounters and to increase the per cent of recommendations to follow-up within 6 weeks for PwCF experiencing a PEx signal., Results: FIES recognition increased from 18.6% to 73.4% across all teams during the iLab, and every team showed an improvement. Of PwCF assessed, 15.8% experienced an FIES event (>10% decline in FEV 1 per cent predicted (FEV 1 pp)). Follow-up within 6 weeks was recommended for an average of 70.5% of those assessed for FIES and had an FEV 1 pp decline greater than 5%., Conclusion: The CFLN iLab successfully defined and implemented a process to recognise and follow-up PEx signals. This process has the potential to be spread to the larger CF community. Further studies are needed to assess the impact of these processes on PwCF outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Background: Whether extra-nodal extension (ENE+) and surgical margin positivity (margin+) are poor prognostic factors in HPV-associated (HPV+) oropharyngeal carcinoma (OPC) remains uncertain., Results: Our study evaluated if microscopic ENE+ and/or margin+ are associated poorer recurrence free survival (RFS) and overall survival (OS) in HPV+ OPC. Patients were classified as high risk (ENE+ and/or margin+) or low risk (ENE- and margins-). Of a total of 176 patients HPV+ OPC, 81 underwent primary surgery and dad data on ENE and margin status. There was no statistically significant difference in RFS (p = 0.35) or OS (p = 0.13) for high-risk versus low-risk groups. Ongoing smoking (p = 0.023), alcohol use (p = 0.044) and advanced stage (p = 0.019) were associated with higher risk of recurrence. Only advanced stage (p-value <0.0001) was associated poorer overall survival., Conclusions: The presence of ENE+ and/or margin+ was not an independent predictor of poor RFS or OS in HPV+ OPC., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To evaluate preliminary efficacy, fidelity, and integrity of data collection of a nurse-led, telemedicine-delivered video visit intervention aimed at improving management of rural survivors' cancer-related distress symptoms., Sample & Setting: 21 rural survivors participated in a nurse-led telemedicine intervention delivered six weeks after the end of active cancer treatment., Methods & Variables: Participants' symptom management was measured with the Short Form Survivor Unmet Needs Survey, a four-factor, 30-item instrument that measures the unmet needs of adult survivors. Data were collected preintervention and six weeks postintervention., Results: The mean difference between pre- and postintervention survey scores was -0.24, representing an overall improvement in management of unmet needs. The unmet emotional needs domain had the highest mean preintervention score and the largest mean reduction. All effect sizes were small., Implications for Nursing: A nurse-led, telemedicine-delivered video visit intervention may improve rural survivors' symptom management during early survivorship. Comparison with a control group using a sample size powered to detect clinically meaningful differences is an important next step to fully evaluate the impact of this model of care.

Glioblastoma is an aggressive brain cancer characterized by diffuse infiltration. Infiltrated glioma cells persist in the brain post-resection where they interact with glial cells and experience interstitial fluid flow. We use patient-derived glioma stem cells and human glial cells (i.e., astrocytes and microglia) to create a four-component 3D model of this environment informed by resected patient tumors. We examine metrics for invasion, proliferation, and putative stemness in the context of glial cells, fluid forces, and chemotherapies. While the responses are heterogeneous across seven patient-derived lines, interstitial flow significantly increases glioma cell proliferation and stemness while glial cells affect invasion and stemness, potentially related to CCL2 expression and differential activation. In a screen of six drugs, we find in vitro expression of putative stemness marker CD71, but not viability at drug IC 50 , to predict murine xenograft survival. We posit this patient-informed, infiltrative tumor model as a novel advance toward precision medicine in glioblastoma treatment., (© 2022. The Author(s).)

Introduction: Quality palliative care, which prioritizes comfort and symptom control, can reduce global suffering from non-communicable diseases, such as cancer. To address this need, the Nepalese Association of Palliative Care (NAPCare) created pain management guidelines (PMG) to support healthcare providers in assessing and treating serious pain. The NAPCare PMG are grounded in World Health Organization best practices but adapted for the cultural and resource context of Nepal. Wider adoption of the NAPCare PMG has been limited due to distribution of the guidelines as paper booklets., Methods: Building on a long-standing partnership between clinicians and researchers in the US and Nepal, the NAPCare PMG mobile application ("app") was collaboratively designed. Healthcare providers in Nepal were recruited to pilot test the app using patient case studies. Then, participants completed a Qualtrics survey to evaluate the app which included the System Usability Scale (SUS) and selected items from the Mobile App Rating Scale (MARS). Descriptive and summary statistics were calculated and compared across institutions and roles. Regression analyses to explore relationships (α = 0.05) between selected demographic variables and SUS and MARS scores were also conducted., Results: Ninety eight healthcare providers ( n = 98) pilot tested the NAPCare PMG app. Overall, across institutions and roles, the app received an SUS score of 76.0 (a score > 68 is considered above average) and a MARS score of 4.10 (on a scale of 1 = poor, 5 = excellent). 89.8% ( n = 88) "agreed" or "strongly agreed" that the app will help them better manage cancer pain. Age, years of experience, and training in palliative care were significant in predicting SUS scores ( p -values, 0.0124, 0.0371, and 0.0189, respectively); institution was significant in predicting MARS scores ( p = 0.0030)., Conclusion: The NAPCare PMG mobile app was well-received, and participants rated it highly on both the SUS and MARS. Regression analyses suggest end-user variables important to consider in designing and evaluating mobile apps in lower resourced settings. Our app design and pilot testing process illustrate the benefits of cross global collaborations to build research capacity and generate knowledge within the local context., Competing Interests: BHa is the founder of and employed by Hass Software Consulting. RD provides consultative services for Warm Health Technologies, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 LeBaron, Horton, Adhikari, Chapagain, Dhakal, Gongal, Kattel, Koirala, Kutcher, Hass, Maurer, Munday, Neupane, Sharma, Shilpakar, Shrestha, Shrestha, Thapa, Dillingham and Paudel.)

Blowfly strike or cutaneous myiasis, caused principally by the Australian sheep blowfly Lucilia cuprina is endemic to Australian sheep producing areas and is a major cause of suffering and economic loss. This article reports incidence and control practices as determined by three cross-sectional surveys of Australian sheep farmers covering the years 2003 (n = 1365), 2011 (n = 575) and 2018 (n = 354) with more questions relating to blowfly strike in the latter two surveys. Breech strike was reported at a higher rate than body strike in all survey years. Reported annual incidence of breech strike ranged from 2.2 to 4.7% of sheep nationally with minor differences between ewes and lambs. The incidence of body strike ranged from 1.0 to 7.1% with higher incidence in younger sheep in all years. The use of fixed time routine preventative chemical treatments increased during the survey period (43%, 46% and 66%, in 2003, 2011 and 2018 respectively) with dicyclanil (54%-58%) and cyromazine (23-36%) the main insecticides used for control since 2011. The use of the Mules operation (mulesing) to remove skin wrinkles from the breech area as a preventative modification did not change between 2011 and 2018 (47% in both), however, the use of pain relief at mulesing of replacement ewe lambs increased substantially between 2011 (59%) and 2018 (87%). The most commonly used methods to assist with flystrike control were timing of crutching (clipping of wool from susceptible areas) and shearing, with few respondents destroying maggots from treated sheep (21-26%) and very low use of fly traps (5-8%). Phenotypic selection of ewes for reduced susceptibility to flystrike based on visual traits was practiced by 61% of respondents in 2011 and 56% in 2018. Selection of rams for reduced susceptibility using estimated breeding values increased from 10% in 2011 to 17% in 2018. Breeding for resistance was the most commonly nominated (21%) most important change made to flystrike management in 2018. The results indicate that concern for sheep welfare has increased with almost universal use of pain relief at mulesing. Increased use of selection for blowfly resistance indicates farmer commitment to planning for a future without mulesing, although the practice remains prevalent. An increase in the reliance on preventative chemical treatments increases the risk of insecticide resistance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: The role of chemotherapy in the management of advanced melanoma is limited due to low response rates and short survival. Improved outcomes to chemotherapy administered after immunotherapy for metastatic melanoma and other solid tumors have been reported. We studied the outcomes of subjects treated at the University of Virginia (UVA) with chemotherapy following progression on prior systemic immunotherapy and compared the results with the existing literature., Materials and Methods: Subjects were identified through an institutional database of patients treated with immunotherapy at UVA. Demographic, pathologic and clinical factors were collected, along with dates of therapy, investigator-assessed best response as per Response Evaluation Criteria for Solid Tumors version 1.1 and dates of death or last follow up. Kaplan-Meier survival estimates and log-rank tests were used to perform time to event analysis of progression free survival and overall survival., Results: Forty-five patients were identified who met the inclusion criteria including 24 men and 21 women with a median age of 61 years. All patients had received at least one line of immunotherapy including 64.4% with prior anti-PD1 treatment. The cytotoxic chemotherapy regimens used included carboplatin with paclitaxel (55.6%), temozolomide (31.1%) and nab- paclitaxel (13.3%). The overall response rate for cytotoxic chemotherapy 22.2% and the disease control rate was 35.6%. The median progression-free survival was 1.7 months and median overall survival was 4.7 months. Nineteen (42.2%) patients survived greater than 6 months and seven (15.5%) patients survived over 12 months. Fourteen patients were able to proceed to further therapy., Discussion: Our results reveal that receipt of immunotherapy prior to chemotherapy for metastatic melanoma does not appear to improve the benefit of chemotherapy. The palliation of symptoms, maintenance of performance status and disease control may be valuable for some patients during this time of robust research and discovery for metastatic melanoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors EG., (Copyright © 2022 Gaughan and Horton.)

The sheep body louse (Bovicola ovis) is a parasite of major economic concern in Australia. This article reports lice incidence and control practices on Australian sheep farms as determined by three cross-sectional surveys of the years 2003, 2011 and 2018. The incidence of live lice detected within a flock was similar across the survey years with a slight decline in 2018 (2003: 20%, 2011: 18.6% and 2018: 13.9%). In an average year, most farmers did not see any direct or indirect evidence of lice infestation (2011: 59.3% and 2018: 69.5%), however, over a five-year period 38.9% (2003), 66.3% (in 2011) and 55.8% (in 2018) reported seeing evidence of lice infestation at least once with significant variation between sheep producing regions in 2011. In an average year, nearly three quarters of respondents treated for lice (2011:73.5% and 2018: 73.3%) with the majority treating immediately following shearing and very few treating sheep with long wool. Even higher percentages treated for lice at least once in the preceding five-year period (2011: 86.2% and 2018: 87.5%). Backliner was the most popular method of chemical application for lice control in sheep off-shears or with short wool (2003: 77%, 2011: 73% and 2018: 74.3%). For long wool treatments, hand jetting declined in popularity from 2003 (64%) to 2011 (54%) and 2018 (8.6%) as backliners became more popular (2003: 36%, 2011: 51% and 2018: 60%). The use of benzoylphenyl urea insect growth regulators (IGR) for off-shears/short wool treatment declined from 2003 (92.8%) to 2011 (51%) and 2018 (2.9%) and were largely replaced by neonicotinoids and spinosad for backliner/spray-on products. The use of organophosphates declined for plunge dipping (2003: 83.8%, 2011: 83% and 2018: 7.7%). Spinosad use for plunge dipping off-shears/short wool increased over the survey years (2003, 0%, 2011: 9% and 2018:46.2%). The use of IGRs declined for backliner application on long wool and were mainly replaced by spinosad in 2011 and 2018. Fewer respondents reported suspected resistance to lice control products in 2018 (8%) compared with 2003 (26%) and 2011 (13%) with most reporting suspected resistance to IGR and synthetic pyrethroids and emerging suspicions of resistance to neonicotinoids in 2018. Resistance to lice control products also reduced in importance as a reason for recurring lice infestations between 2011 (ranked 2nd) and 2018 (ranked 6th). Biosecurity was important to sheep producers with the highest ranked reason for recurring lice infestations being from stray or purchased sheep., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Immunotherapy and chemotherapy combinations have proven to be a safe and efficacious treatment approach in multiple settings. However, it is not clear whether approved doses of chemotherapy developed to achieve a maximum tolerated dose are the ideal dose when combining cytotoxic chemotherapy with immunotherapy to induce immune responses. This trial of a modulated dose chemotherapy and Pembrolizumab, with or without a second immunomodulatory agent, uses a Bayesian design to select the optimal treatment combination by balancing both safety and efficacy of the chemotherapy and immunotherapy agents within each of two cohorts. The simulation study provides evidence that the proposed Bayesian design successfully addresses the primary study aim to identify the optimal dose combination for each of the two independent patient cohorts. This conclusion is supported by the high percentage of simulated trials which select a treatment combination that is both safe and highly efficacious. The proposed trial was funded and was being finalized when the sponsoring company decided not to proceed due to negative findings in another patient population. The proposed trial design will continue to be relevant as multiple chemotherapy and immunotherapy combinations become the standard of care and future research will require evaluating the appropriate doses of various components of multiple drug regimens.

Purpose: Operating characteristics for proposed clinical trial designs provide insight into performance regarding safety and accuracy, allowing the study team and review entities to determine the design's suitability to achieve the study's proposed objectives. Advances in cancer therapeutics have augmented the needs of early phase clinical trial design. Additionally, advances in research on early-phase trial design have led to the availability of a wide range of methods that show vast improvement over outdated approaches., Methods: Three trials utilizing variations of the 3 + 3 decision rule are discussed. The protocols lacked detail, including operating characteristics and guidance for decision-making that deviated from the 3 + 3 decision rule and MTD determination. We provide a discussion of the statistical issues associated with each design and operating characteristics for the proposed design compared to alternatives better suited to achieve the aims of each trial., Results: Our results illustrate how operating characteristics inform a design's safety and accuracy. Operating characteristics can unmask poor behavior, such as a high percentage of particiapnts exposed to overly toxic doses, a low probability of correctly identifying the MTD, and inappropriate early study termination., Conclusion: Selection of early-phase trial design has significant implications on a trial's ability to meet its objectives. Operating characteristics are a necessary component in the design and review of a protocol, determining if the study's objectives can be achieved and documenting the study's scientific validity. Continued use of outdated approaches due to historical acceptance hinders scientific rigor and the effort to move effective agents through the drug development process., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Rapid evolution of telemedicine technology requires procedures in telemedicine to adapt frequently. An example in urology, telecystoscopy, allows certified advanced practice providers to perform cystoscopy, endoscopic examination of the bladder, in rural areas with real-time interpretation and guidance by an off-site urologist. We have previously shown the technological infrastructure for optimized video quality. Introduction: Newer models of cystoscope and coder/decoder (codec) are available with anticipation that components used in our original model will become unavailable. Our objective is to assess the diagnostic ability of two cystoscopes (Storz, Wolf) with old (SX20) and new (DX70) codecs. Materials and Methods: A single urologist performed flexible cystoscopy on an ex vivo porcine bladder. Combinations of cystoscope (Storz vs. Wolf), codec (SX20 vs. DX70), and internet transmission speed were used to create eight distinct recordings. Deidentified videos were reviewed by expert urologist reviewers via electronic survey with questions on video quality and diagnostic ability. A logistic regression model was used to assess the ability to make a diagnosis. Results: Eight transmitted cystoscopy videos were reviewed by 16 urologists. Despite new technology, the Storz cystoscope combined with the SX20 codec (the original combination) provides the best diagnostic capacity. Discussion: Technical infrastructure must be routinely validated to assess the component impact on overall quality because newer is not always better. Should the SX20 become obsolete, ex vivo animal models are safe, inexpensive anatomic models for testing. Conclusions: As technology continues to evolve, procedures in telemedicine must critically scrutinize the impact of new technologic components to uphold quality.

Purpose: This prospective trial's objective was to determine feasibility and outcomes of an exercise-based intervention for rural overweight/obese female cancer survivors., Materials and Methods: Survivors of endometrial, breast, or ovarian cancer enrolled in a 6-month program of increased aerobic activity (30 minutes daily walking) and strength-training exercises using exercise bands (THERABAND; Akron, OH) with personalized telephone motivational coaching. Baseline demographics, anthropomorphic measurements, quality of life (QOL), fitness, and readiness to adopt exercise changes were assessed; daily steps, band use, and follow-up measurements were assessed at 3 and 6 months. Study completion was modeled using logistic regression., Results: The mean age of the 99 women was 59.9 years, the mean body mass index (BMI) was 35.9 kg/m 2 , 88.9% were white, and 41.4% reported current exercise. Fifty-five women (55.6%) completed the 6-month program, and 36 (36.4%) completed exercise interventions. Using logistic regression to model study completion, only baseline QOL scores (physical component summary) and mental component summary) remained significant predictors. The mean weight change was a gain (0.88 kg). Higher MCS baseline scores and prior regular exercise predicted continued exercise and increased step counts, whereas higher BMI and baseline sleep predicted decreased QOL. Top walking barriers were feeling unwell and weather; barriers to strength exercises were band dislike and pain., Conclusion: The most significant predictor of trial completion and improved exercise outcomes was a higher baseline mental QOL. Motivation, belief in the importance of exercise, and prescribed/monitored exercise regimens were not sufficient; supportive and cognitive behavioral therapy interventions for survivors are needed to sustain uptake.

The International Federation of Nurse Anesthetists (IFNA) is a federation of 45 national anesthesia organizations. Among its activities are setting global standards for anesthesia practice, patient monitoring, and anesthesia education, as well as creating a code of ethics. This article focuses on the use of its education standards as the foundation for the International Federation of Nurse Anesthetists' Anesthesia Program Approval Process. The approval process strongly encourages educational institutions throughout the world to improve the education of nurse anesthetists and other nonphysician anesthetists, with the ultimate goal being patient safety. The approval process also promotes the use of nurses to administer anesthesia whenever adequate resources are available., Competing Interests: The IFNA Education and Research Foundation awarded a grant to the IFNA Education Committee for a Pilot Accreditation Project in 2010. Additional grants have been awarded by the IFNA Board of Directors Executive Committee in support of on-site visits to some nurse anesthesia schools. The authors are current or retired members of IFNA’s Education Committee, which developed and administered the APAP. The authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request., (Copyright© by the American Association of Nurse Anesthetists.)

Patient heterogeneity, in which patients can be grouped by risk of toxicity, is a design challenge in early phase dose finding trials. Carrying out independent trials for each group is a readily available approach for dose finding. However, this often leads to dose recommendations that violate the known order of toxicity risk by group, or reversals in dose recommendation. In this manuscript, trials for partially ordered groups are simulated using four approaches: independent parallel trials using the continual reassessment method (CRM), Bayesian optimal interval design, and 3 + 3 methods, as well as CRM for partially ordered groups. Multiple group order structures are considered, allowing for varying amounts of group frailty order information. These simulations find that parallel trials in the presence of partially ordered groups display a high frequency of trials resulting in reversals. Reversals occur when dose recommendations do not follow known order of toxicity risk by group, such as recommending a higher dose level in a group of patients known to have a higher risk of toxicity. CRM for partially ordered groups eliminates the issue of reversals, and simulation results indicate improved frequency of maximum tolerated dose selection as well as treating a greater proportion of trial patients at this dose compared with parallel trials. When information is available on differences in toxicity risk by patient subgroup, methods designed to account for known group ordering should be considered to avoid reversals in dose recommendations and improve operating characteristics.

Background: Limited options are available for dose-finding clinical trials requiring group-specific dose selection. While conducting parallel trials for groups is an accessible approach to group-specific dose selection, this approach allows for maximum tolerated dose selection that does not align with clinically meaningful group order information., Methods: The two-stage continual reassessment method is developed for dose-finding in studies involving three or more groups where group frailty order is known between some but not all groups, creating a partial order. This is an extension of the existing continual reassessment method shift model for two ordered groups. This method allows for dose selection by group, where maximum tolerated dose selection follows the known frailty order among groups. For example, if a group is known to be the most frail, the recommended maximum tolerated dose for this group should not exceed the maximum tolerated dose recommended for any other group., Results: With limited alternatives for dose-finding in partially ordered groups, this method is compared to two alternatives: (1) an existing method for dose-finding in partially ordered groups which is less computationally accessible and (2) independent trials for each group using the two-stage continual reassessment method. Simulation studies show that when ignoring information on group frailty, using independent continual reassessment method trials by group, 30% of simulations would result in maximum tolerated dose selection that is out of order between groups. In addition, the two-stage continual reassessment method for partially ordered groups selects the maximum tolerated dose more often and assigns more patients to the maximum tolerated dose compared to using independent continual reassessment method trials within each group. Simulation results for the proposed method and the less computationally accessible approach are similar., Conclusion: The proposed continual reassessment method for partially ordered groups ensures appropriate maximum tolerated dose order and improves accuracy of maximum tolerated dose selection, while allowing for trial implementation that is computationally accessible.

Free-range laying hen systems provide individuals a choice between indoor and outdoor areas where range use may be socially influenced. This study used radio-frequency identification technology to track the ranging of individually-tagged hens housed in six experimental free-range pens from 28 to 38 weeks of age (46⁻50 hens/pen). All daily visits to the range were used to study group behaviour. Results showed that 67.6% (SD = 5.0%) of all hen movements through the pop-holes outdoors or indoors were following the movement of another hen ('pop-hole-following') compared to only 50.5% of movements in simulated random data. The percentage overlap in time that all combinations of hen pairs within each pen spent simultaneously outdoors or indoors showed a median value of overlap greater than the 90th percentile of random data. Pens housing hens that had been provided variable enrichments from 4 to 21 days (n = 3 pens) showed higher 'pop-hole-following' behaviour and a higher percentage of hen-pair association compared to hens reared in non-enriched conditions (n = 3 pens). These results show that birds in each free-range pen were primarily a cohesive flock and early enrichment improved this social cohesiveness. These results have implications for understanding free-range flock-level behaviour.

Background: Brachytherapy (BT) is a vital component of the curative treatment of locally advanced cervical cancer. The American Brachytherapy Society has published guidelines for high dose rate (HDR) BT with recommended dose limits. However, recent reports suggest lower doses may be needed to avoid toxicity. The purpose of this study is to investigate incidence and predictive factors influencing gastrointestinal (GI) and genitourinary (GU) toxicity following HDR intracavitary brachytherapy for locally advanced cervical cancer., Methods: We retrospectively evaluated a cohort of patients with locally advanced cervical cancer who received CT-based HDR BT. Cumulative doses were calculated using the linear-quadratic model. Statistical analyses were used to investigate clinical and dosimetric predictors of GI and GU toxicity following HDR brachytherapy according to CTCAE v4.0 grading criteria., Results: Fifty-six women with FIGO IB1 - IVA cervical cancer were included. The overall rate of any GU adverse event (Grade 1+) was 23.3% (n = 13) and severe adverse events (Grade 3+) was 7.1% (n = 4). Of those, the bladder equivalent dose in 2- Gray (Gy) fractions (EQD 2 ) D 2cc was ≥80 for three of the four patients. The overall rate of any GI adverse event was 26.8% (n = 15) and the rate of severe adverse events was 14.3% (n = 8). Of those, six of the eight patients had a rectal EQD 2 D 2cc  ≥ 65 Gy and seven patients had a sigmoid D2cc ≥ 65 Gy. Amongst clinically meaningful factors for development of adverse events (i.e. diabetes, smoking status, ovoid size, and treatment duration), there were no statistically significant prognostic factors identified., Conclusions: Severe adverse events are observed even with adherence to current ABS guidelines. In the era of recent multi-institutional study results, our data also supports more stringent dosimetric goals. We suggest cumulative D2cc dose limits of: less than 80 Gy for the bladder and less than 65 Gy for the rectum and sigmoid.

We investigated how individuality and lameness altered social organisation by assessing food-directed movement patterns in sheep. One hundred and ninety-six mature Merino ewes were walked in 16 different runs around a 1.1 km track following a food source. Flock position and lameness were measured and temperament was assessed using an Isolation Box Test. The mean value for the correlations of position between a run and the run preceding it was r = 0.55 ± SEM 0.03. All correlations between runs were positive (r = 0.08-0.76) and all but two were statistically significant (P < 0.05). The weakest and least statistically significant correlations were for run 14: where all 16 runs were conducted approximately 3 times a week, except with an interval of 20 weeks between runs 13 and 14. Additionally, there were differences in overall positions for a lame versus a non-lame individual (all P < 0.05) with lame sheep being further back in position when compared to their non-lame mean positions. These results indicate the movement patterns, as measured by flock position during a food-directed forced movement order are relatively stable provided tests occur frequently, possibly on a bi-weekly basis. However, further work will be required to better account for individual animal variation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Prior work has shown that digital images and microscopic slides can be interpreted with comparable diagnostic accuracy. Although accuracy has been well-validated, the interpretative time for digital images has scarcely been studied and concerns about efficiency remain a major barrier to adoption. We investigated the efficiency of digital pathology when compared with glass slide interpretation in the diagnosis of surgical pathology biopsy and resection specimens. Slides were pulled from 510 surgical pathology cases from 5 organ systems (gastrointestinal, gynecologic, liver, bladder, and brain). Original diagnoses were independently confirmed by 2 validating pathologists. Diagnostic slides were scanned using the Philips IntelliSite Pathology Solution. Each case was assessed independently on digital and optical by 3 reading pathologists, with a ≥6 week washout period between modalities. Reading pathologists recorded assessment times for each modality; digital times included time to load the case. Diagnostic accuracy was determined based on whether a rendered diagnosis differed significantly from the original diagnosis. Statistical analysis was performed to assess for differences in interpretative times across modalities. All 3 reading pathologists showed comparable diagnostic accuracy across optical and digital modalities (mean major discordance rates with original diagnosis: 4.8% vs. 4.4%, respectively). Mean assessment times ranged from 1.2 to 9.1 seconds slower on digital versus optical. The slowest reader showed a significant learning effect during the course of the study so that digital assessment times decreased over time and were comparable with optical times by the end of the series. Organ site and specimen type did not significantly influence differences in interpretative times. In summary, digital image reading times compare favorably relative to glass slides across a variety of organ systems and specimen types. Mean increase in assessment time is 4 seconds/case. This time can be minimized with experience and may be further balanced by the improved ease of electronic chart access allowed by digital slide viewing, as well as quantitative assessments which can be expedited on digital images.

Purpose: Genetic and preclinical studies have implicated FGFR signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor of FGFR activity, may be active in ACC. Experimental Design: In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500 mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate and change in tumor growth rate. Progression-free survival, overall survival, metabolic response, biomarker, and quality of life were secondary endpoints. Results: Of 34 evaluable patients, 2 (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on treatment ( P < 0.001). Toxicity was moderate; 63% of patients developed grade 3-4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on 18 FDG-PET scans was seen in 3 of 15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with overexpression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Conclusions: Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably with those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine whether FGFR signaling is a valid therapeutic target in ACC. Clin Cancer Res; 23(15); 4138-45. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Glioblastomas, the most common primary malignant brain tumors, have a distinct tissue microenvironment. Although non-neoplastic cells contribute to glioblastoma progression, very few quantitative studies have shown the effect of tumor microenvironmental influences on patient survival. We examined relationships of the cellular microenvironment, including astrocytes, microglia, oligodendrocytes, and blood vessels, to survival in glioblastoma patients. Using histological staining and quantitative image analyses, we examined the tumor-associated parenchyma of 33 patients and developed statistical models to predict patient outcomes based on the cellular picture of the tumor parenchyma. We found that blood vessel density correlated with poorer prognosis. To examine the role of adjacent parenchymal versus higher tumor cell density bulk parenchymal tissue, we examined the glial components in these highly variable regions. Comparison of bulk and adjacent astrocytes and microglia in tissue yielded the strongest prediction of survival, with high levels of adjacent astrocytes predicted poor prognosis and high levels of microglia correlated with a better prognosis. These results indicate that parenchymal components predict survival in glioblastoma patients and in particular that the balance between reactive glial populations is important for patient prognosis., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)