Publications by authors named "Robert Rutledge"

46 Publications

Personality Traits and Urinary Symptoms Are Associated with Mental Health Distress in Patients with a Diagnosis of Prostate Cancer.

Curr Oncol 2021 Aug 6;28(4):2993-3002. Epub 2021 Aug 6.

Department of Urology, Dalhousie University, Halifax, NS B3H 4R2, Canada.

Objective: With a prolonged natural history compared with many other cancers, prostate cancer patients have high rates of mental illness over the duration of their treatment. Here, we examine the relationship between personality and mental health distress in a sample of prostate cancer patients.

Methods: This study was conducted in the Canadian Maritime provinces, where a cohort of 189 men with prostate cancer were invited to complete a quality-of-life online survey between May 2017 and December 2019. The presence or absence of screening positive for mental health illness was the primary outcome and was assessed using Kessler's 10-item scale (K10). Urinary symptoms were assessed using the International Prostate Symptom Score (IPSS). The ten-item personality inventory (TIPI) assessed extraversion, agreeableness, conscientiousness, emotional stability (or neuroticism), and openness to experiences. A multivariate logistic regression model was created to examine the association between personality, urinary symptoms, and mental health distress, while controlling for time from diagnosis, treatment type, age, and multimorbidity.

Results: Screening positive for mental illness (18.0%) was associated with personality traits of low levels of emotional stability (OR = 0.07, 95% CI: 0.03-0.20) and moderate to severe urinary problems (OR = 5.21, 95% CI: 1.94-14.05)). There was no identified association between treatment received for prostate cancer and personality type.

Conclusion: Screening for mental health illness in this population may help reduce morbidity associated with cancer treatment, as well as identify patients who may be at risk of mental health distress and could benefit from individualized mental health support services. These findings suggest that multidisciplinary care is essential for the management of these patients.
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http://dx.doi.org/10.3390/curroncol28040262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395397PMC
August 2021

Post-Treatment Adverse Health Correlates among Prostate Cancer Survivors in a Sample of Men Residing in Atlantic Canada.

Curr Oncol 2021 Jul 25;28(4):2812-2822. Epub 2021 Jul 25.

Atlantic PATH, Dalhousie University, Halifax, NS B3H 4R2, Canada.

Background: Recent large population-based studies have shed light on an association between prostate cancer (PCa) survivorship and mental health, which emerged when the comparison group was either men without a history of cancer or those with any other type of cancer except prostate. Here we examine the role of surgery alone, compared to other types of treatment modalities in this association in a population-based sample of men with prostate or other types of cancer.

Methods: A cross-sectional analysis was conducted on a subsample of 632 male participants aged 36-69 from the 2009-2015 survey cycle of the Atlantic PATH cohort study. The primary outcomes were the presence of mild, moderate or severe depression or anxiety indicators and were assessed using the seven-item generalized anxiety disorder (GAD-7) scale and the nine-item Patient Health Questionnaire (PHQ-9), respectively. The presence of a lifetime history of PCa or other form of cancer (except PCa) was the main predictor variable and was assessed in cancer treatment modality (surgery or other types of treatment modalities) stratified analyses. Covariates included age, marital status, household income, comorbidity, and survivorship time.

Results: The presence of depression in this sample was prevalent among 17.7% of men, and of anxiety among 9.3% of men. Survivors who were treated with surgery for their PCa diagnosis had 7.55 statistically significantly higher odds of screening positive for current depression symptoms compared with those of other forms of cancer in controlled analyses. These differences were not observed for anxiety.

Conclusions: These findings emphasize the need for multidisciplinary survivorship care plans among PCa patients, especially those who undergo surgery. Targeted programming aimed at prioritizing and delivering comprehensive mental health support to PCa survivors early in the survivorship journey is justified.
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http://dx.doi.org/10.3390/curroncol28040246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395491PMC
July 2021

An Examination of the Role of Socioeconomic Status in the Relationship between Depression and Prostate Cancer Survivorship in a Population-Based Sample of Men from Atlantic Canada.

Oncology 2021 22;99(4):260-270. Epub 2021 Jan 22.

Atlantic PATH, Dalhousie University, Halifax, Nova Scotia, Canada.

Objective: Prostate and skin cancer are among the most prevalent forms of cancer among men and have favorable survival rates compared to other, more aggressive forms of cancers. Recent studies have shown that the odds of depression among men with a lifetime history of prostate cancer are higher compared to men without a lifetime history of prostate cancer. Here we extend previous findings and examine the role of socioeconomic status in the relationship between depression and cancer survivorship status in a population-based sample of men from Atlantic Canada.

Methods: A cross-sectional analysis was conducted on a subsample of 6,585 male participants aged 49-69 years from the 2009-2015 survey cycle of the Atlantic PATH study. The primary outcome was screening positive for mild, moderate or severe depression using the Patient Health Questionnaire (PHQ-9). The main predictor variable was cancer survivorship status (the presence of a lifetime history of prostate cancer, skin cancer, forms of cancer other than prostate or skin cancer, or absence of a lifetime cancer diagnosis). Covariates included age, education, marital status, household income, province, ethnicity, comorbidity, and survivorship time.

Results: An estimated 14.7% of men in this sample screened positive for mild, moderate or severe depression. Men with a history of prostate cancer were 2.60 (95% CI: 1.02, 6.65) times more likely to screen positive for depression than men with a history of any other form of cancer. The odds ratios were 10.23 (95% CI: 2.82, 37.49) or 4.00 (95% CI: 1.20, 13.34) times higher for survivors of prostate or skin cancer who reported a low household income to screen positive for depression compared to men with a history of any other form of cancer and high household income.

Conclusions: These results extend current evidence of the association between prostate cancer survivorship and depression compared with men who never had a history of cancer diagnosis by indicating that this association still stands when the survivors of prostate cancer are compared to survivors of any other form of cancer, and further indicates that this association is moderated by household income. The findings highlight the importance of delivering mental health screening and support to prostate cancer survivors during the cancer journey, especially those with low household incomes.
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http://dx.doi.org/10.1159/000512444DOI Listing
April 2021

Assessment of Current Mental Health Status in a Population-Based Sample of Canadian Men With and Without a History of Prostate Cancer Diagnosis: An Analysis of the Canadian Longitudinal Study on Aging (CLSA).

Front Psychiatry 2020 16;11:586260. Epub 2020 Dec 16.

Department of Community Health and Epidemiology, Dalhousie University, Halifax Regional Municipality, NS, Canada.

Small-scale studies indicate an increase in mental health disorders among prostate cancer survivors compared to the general population, but large population-based data assessing this relationship are scarce. The present study examined the prevalence of lifetime history of prostate cancer in a cross-sectional sample of Canadian men and assessed the contribution of lifetime history of a prostate cancer diagnosis, multimorbidity, and current alcohol and smoking status to the association with current mental health outcomes in this population. The analytical sample included 25,183 men (aged 45 to 85 years old), who completed a survey as part of the Canadian Longitudinal Study on Aging (CLSA). The Center for Epidemiological Studies Depression Scale (CES-D10), Kessler's Psychological Distress Scale (K10), and self-reported mental health were mental health outcomes. Multiple logistic regression analyses, and controlling for the complexity of the design and covariates, evaluated the association between prostate cancer survivorship, multimorbidity, alcohol and smoking status, and current mental health outcomes. The prevalence of lifetime history of prostate cancer diagnosis in this population-based sample of men was 4% (95% CI: 3.7, 4.4). Our results indicate statistically significantly higher odds of current psychological distress (aOR = 1.52, 95% CI: 1.09, 2.11) and screening positive for depression (aOR = 1.24; 95% CI: 1.02, 1.51) among survivors of prostate cancer, compared to men without a history of prostate cancer diagnosis in demographics controlled analyses. After addition of multimorbidity and substance use, the odds of screening positive for depression among survivors of prostate cancer are 1.32 (95% CI: 1.06, 1.64) higher compared to men who never had a history of prostate cancer diagnosis. Patient education and empowerment programs aimed at addressing concerns during the diagnosis and treatment and enhancing survivorship care plans by adding routine screening for mental distress to help survivors overcome poor mental health during the cancer survivorship journey, are warranted.
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http://dx.doi.org/10.3389/fpsyt.2020.586260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772192PMC
December 2020

Sequence Inversion to Facilitate Concurrent Radiotherapy and Systemic Therapy. A Proof of Principle Study in the Setting of a Phase II Randomized Trial in Prostate Cancer.

Front Oncol 2020 30;10:570660. Epub 2020 Sep 30.

Department of Radiation Oncology, Dalhousie University, Halifax, NS, Canada.

Concomitant chemo-radiation for pelvic cancers remains challenging to be delivered at full doses. We hypothesized that fewer delays in chemotherapy would occur if the sequence of radiotherapy would be reversed, starting with the boost volume followed by the elective nodal volume. We report the result of a Phase II randomized study for high risk prostate cancer. The study was a double-blinded phase II randomized trial. Patients were eligible if they had non-metastatic high-risk prostate cancer. All patients received 2.5 years of hormonal therapy and 46.5 Gy in 25 fractions to the pelvic lymph nodes. Patients received a radiation boost to the prostate, either before or after whole pelvic irradiation. Concurrent (20 mg/m) Docetaxel was given on the first day of radiotherapy and weekly thereafter for a total of eight treatments until predefined toxicity stopping rules. Ninety patients were included and randomized. Four were ineligible for the analysis. In total, 42 patients were randomized to the standard sequence, 44 patients to the experimental sequence. There were statistically fewer GI or GU toxicities leading to a docetaxel dose reduction or omission in the experimental sequence compared to the standard sequence, 5 vs. 15 events ( = 0.027). There was no difference in overall survival, cause-specific survival, or biochemical-relapse free survival between the two sequences. This is the first study to test sequence inversion for pelvic radio-chemotherapy in a randomized double-blind trial. Less chemotherapy interruptions or dose reductions occurred by inverting the radiation sequence of the large field and the boost. The trial was registered with Clinicaltrials.gov: NCT00452556.
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http://dx.doi.org/10.3389/fonc.2020.570660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556110PMC
September 2020

Current Mental Distress Among Men With a History of Radical Prostatectomy and Related Adverse Correlates.

Am J Mens Health 2020 Sep-Oct;14(5):1557988320957535

Department of Urology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.

Recent reviews and observational studies have reported that patients with prostate cancer (PCa) are at increased risk of mental health issues, which in turn negatively affects oncological outcomes. Here, we examine possible explanatory variables of mental distress in a population-based cohort of men who have undergone radical prostatectomy (RP). Data were derived from a Maritimes-Canada online survey assessing patient-reported quality of life outcomes between 2017 and 2019 administered to 136 men (47-88 years old, currently in a relationship) who have undergone RP for their PCa diagnosis. The primary outcome was a validated assessment of mental distress, the Kessler Psychological Distress Scale (K10). Urinary function was assessed using the International Prostate Symptom Score, and relationship satisfaction was assessed using the Dyadic Assessment Scale. A multivariate logistic regression assessed the contribution of urinary function, relationship satisfaction, age, multimorbidity, additional treatments, medication for depression and/or anxiety, and survivorship time. A total of 16.2% men in this sample screened positive for mental distress. The severity of urinary problems was positively associated with increased mental distress ( = 4.79, 95% CI [1.04, 22.03]), while increased age ( = 0.87, 95% CI [0.78, 0.97]), relationship satisfaction ( = 0.14, 95% CI [0.3, .077]), and current medication for anxiety, depression, or both ( = 0.09, 95% CI [0.02, 0.62]) were protective factors. Survivorship time, the presence of additional comorbidities, or PCa treatments were not identified to be statistically significant contributions to the fitted model. Here, we report that RP survivors are prone to presenting with increased mental distress long after treatment. Screening for mental distress during RP survivorship is recommended.
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http://dx.doi.org/10.1177/1557988320957535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503014PMC
August 2021

Adolescent traumatic brain injuries: Onset, mechanism and links with current academic performance and physical injuries.

PLoS One 2020 12;15(3):e0229489. Epub 2020 Mar 12.

Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.

Background: Traumatic brain injuries (TBIs) in adolescence are associated with adverse outcomes, but whether the timing of the onset of TBIs leads to greater deficits has not been determined. We evaluate the relationship between the first and most recent TBI, and current academic performance and medically treated physical injuries.

Methods: Data were derived from the 2015 Ontario Student Drug Use and Health Survey (OSDUHS) administered to adolescents in grades 7 to 12 (ages 12 to 18). TBI was defined as a head injury that resulted in loss of conscious for at least five minutes or at least one overnight hospitalization.

Results: One in five students reported having had a history of TBI in their lifetime and were more prevalent in males. Odds ratios were 2 times higher for males to have had their first (or only) and most recent TBI in grades 5 to 8, compared to females. Sports-related TBIs accounted for 41.1% of all TBIs. Hockey related TBIs were more frequent compared to soccer related TBIs. Reports of history of TBI was associated with lower academic performance and more physical injuries. First or only TBI occurring in grades 9-12 (occurring on average between 14 to 19 years of age) had higher significant odds of poorer academic performance than TBIs occurring in earlier grades (younger ages than 14 years old). Students who reported more visits for medical treatment of physical injuries in the past year had higher odds to report a history of TBIs in higher school grades.

Conclusions: Adverse physical and academic outcomes among young TBI survivors are associated with the onset and frequency of history of lifetime TBI. Prevention efforts to minimize TBIs during youth is critical.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229489PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067417PMC
June 2020

Anxiety and depression symptoms in adult males in Atlantic Canada with or without a lifetime history of prostate cancer.

Psychooncology 2020 02 26;29(2):280-286. Epub 2019 Dec 26.

Atlantic PATH, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Objective: Prostate cancer (PCa) is the most prevalent form of cancer among men and has one of the most favorable survival rates among all cancers. Here we examine the association between depression and anxiety symptoms in a population-based sample of men.

Methods: A cross-sectional analysis was conducted on a subsample of 6 585 male participants aged 49-69 from 2009 to 2015 survey cycle of the Atlantic PATH. Mild, moderate or severe depression or anxiety indicators were primary outcomes and were assessed using the Generalized Anxiety Disorder (GAD-7) scale and the Patient Health Questionnaire (PHQ-9). The presence of a lifetime history of PCa, other forms of cancer (except PCa) or absence of either was the main predictor variable.

Results: An estimated 3.9% of men self-identified as having had a history of PCa diagnosis, 11.3% of men identified as having had a history of other forms of cancer and 84.9% reported never having had a diagnosis of cancer in their lifetime, respectively. Survivors of PCa had 2.45 or 2.05 statistically significantly higher odds of screening positive for current anxiety or depressive symptoms, respectively, compared with those who identified as without a lifetime history of any form of cancer in controlled analyses (including survivorship time).

Conclusions: Increased rates of anxiety and depression among men with a history of PCa highlight the need for mental health screening among PCa survivors. The findings highlight the importance of a multidisciplinary effort to prioritize and deliver comprehensive mental health support to PCa survivors.
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http://dx.doi.org/10.1002/pon.5244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383500PMC
February 2020

Mini-gastric bypass: Prevention and management of complications in performance and follow-up.

Int J Surg 2019 Nov 23;71:119-123. Epub 2019 Sep 23.

Honorary President of MGB-OAGB International Club, USA. Electronic address:

The mini-gastric bypass (MGB) has proven to be a safe, rapid and effective weight-loss procedure. However, as with all abdominal operations, complications may still occur, and should be prevented if possible and treated appropriately. The authors discuss experience with the MGB.
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http://dx.doi.org/10.1016/j.ijsu.2019.09.003DOI Listing
November 2019

The Role of Response-Shift in Studies Assessing Quality of Life Outcomes Among Cancer Patients: A Systematic Review.

Front Oncol 2019 20;9:783. Epub 2019 Aug 20.

Department of Radiation Oncology, Faculty of Medicine, Dalhousie University, Halifax Regional Municipality, NS, Canada.

Response-shift has been cited as an important measurement consideration when assessing patient reported quality of life (QoL) outcomes over time among patients with severe chronic conditions. Here we report the results of a systematic review of response shift in studies assessing QoL among cancer patients. A systematic review using MEDLINE, EMBASE, and PsychINFO along with a manual search of the cited references of the articles selected, was conducted. A quality review was performed using STROBE criteria and reported according to PRISMA guidelines. A systematic review of 1,487 records published between 1,887 and December 2018 revealed 104 potentially eligible studies, and 35 studies met inclusion criteria for content and quality. The most common cancer patient populations investigated in these studies were breast (18 studies), lung (14 studies), prostate (eight studies), and colorectal (eight studies). Response shift was identified among 34 of the 35 studies reviewed. Effect sizes were reported in 17 studies assessing QoL outcomes among cancer patients; 12 of which had negligible to small effect sizes, four reported medium effect sizes which were related to physical, global QoL, pain, and social (role) functioning and one reported a large effect size (fatigue). The most prevalent method for assessing response shift was the , which is prone to recall bias, followed by the method. Given the heterogeneity among the characteristics of the samples and designs reviewed, as well as the overall small to negligible effect sizes for the effects reported, conclusions stating that changes due to internal cognitive shifts in perceived QoL should account for changes observed in cancer patients' QoL outcomes should be interpreted with caution. Further work is needed in this area of research. Future studies should control for patient characteristics, time elapsed between diagnosis and baseline assessment and evaluate their contribution to the presence of response shift. Time between assessments should include short and longer periods between assessments and evaluate whether the presence of response shift holds over time. Possible avenues for inquiry for future investigation are discussed.
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http://dx.doi.org/10.3389/fonc.2019.00783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710367PMC
August 2019

Traumatic brain injury and hazardous/harmful drinking: Concurrent and single associations with poor mental health and roadway aggression.

Psychiatry Res 2019 02 13;272:458-466. Epub 2018 Dec 13.

Division of Neurosurgery, University of Toronto, Toronto, Canada.

This study describes the association among lifetime traumatic brain injury (TBI) and past year hazardous/harmful drinking, as well as their unique and synergistic effects, on mental health problems and roadway aggression among Canadian adults. A cross-sectional sample of 6074 Ontario adults aged 18 years or older were surveyed between 2011 and 2013. TBI was defined as trauma to the head resulting in loss of consciousness or overnight hospitalization. Past year hazardous/harmful drinking was assessed using the Alcohol Use Disorders Identification Test. An estimated 13.1% (95%CI:12.0,14.2) adults reported a prior TBI (no hazardous/harmful drinking), 2.7% (95%CI:2.2,3.3) reported a prior TBI while concurrently screening positive for past year hazardous/harmful drinking and 9.8% (95%CI:8.9,10.9) screened positive for hazardous/harmful drinking (no TBI). Men had significantly higher odds of exhibiting all three conditions compared to women, especially for the concurrent class. Younger adults had significantly greater odds of hazardous/harmful drinking, or the concurrent class compared to adults 55 years and older. Adults in any of the three conditions had greater odds for mental health problems and roadway aggression. Concordance of both conditions corresponded to a greater than additive effect and greater odds of mild roadway aggression, than either condition alone. Results show that singly and jointly, these conditions are associated with adverse health and behavioral impediments.
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http://dx.doi.org/10.1016/j.psychres.2018.12.069DOI Listing
February 2019

The Mini-Gastric Bypass original technique.

Int J Surg 2019 Jan 24;61:38-41. Epub 2018 Nov 24.

Department of Surgery, Kular Hospital Pvt. Ltd., National Highway 1, Bija, Khanna, Ludhiana, Punjab, 141412, India. Electronic address:

Introduction: Mini-Gastric Bypass (MGB) is becoming more and more popular as shown by the numerous articles published over the past 15 years, supporting the operation as a short and simple procedure with excellent outcomes and low complication rates. There is still confusion amongst surgeons on the technique of the operation. The purpose of this paper is to review and describe the technique of MGB by its originators.

Methods: With 20 years of experience of performing the original MGB, the authors present the details of the MGB.

Results: The MGB consists of a long conduit from below the crow's foot extending up to the left of the angle of His. It is similar to, but importantly, not the same as the pouch of the Sleeve Gastrectomy. MGB has a wide gastro-jejunal anastomosis to an anti-colic loop of jejunum 150-200 cm distal to the ligament of Trietz. The power of MGB comes from the fact that it is both a "Non-Obstructive" restrictive procedure and it also has a significant fatty food intolerance component with minimal malabsorption.

Conclusion: In this article we describe the original Rutledge technique of Mini-Gastric Bypass. Notably this is neither a "Single Anastomosis bypass", nor an "Omega Loop Bypass" and also not the "One Anastomosis Bypass of Carbajo". It is a particular technique first created by Rutledge in 1997 and associated with low risk and excellent outcomes. The goal of this manuscript is to help avoid complications and problems seen when the operation deviates from some of the basic principles of general surgery used in the original operation.
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http://dx.doi.org/10.1016/j.ijsu.2018.10.042DOI Listing
January 2019

Yoga for Young Adults With Noncurative Cancer: A Brief Report.

Glob Adv Health Med 2018 16;7:2164956118763523. Epub 2018 Mar 16.

1School of Health and Human Performance, Dalhousie University, Halifax, Nova Scotia, Canada.

Background: The practice of yoga has been shown to improve disease- and treatment-related side effects in the noncurative cancer patient.

Objective: This user experience study aimed to examine the feasibility and usefulness of a DVD-based yoga program for young adult cancer patients with a noncurative diagnosis.

Methods: Participants were asked to partake in a 7-week DVD-based yoga program and complete measures of program use and usefulness.

Results: Nine patients expressed study interest and 5 consented to participate. Four completed the full study protocol. Participants reported being satisfied with the program and described that it provided an opportunity for self-care. Improvements in functional, physical, and spiritual well-being and overall quality of life were found. Barriers included competing time demands and feeling unwell. No adverse events were reported.

Conclusion: The program was viewed as an accessible and useful activity option; however, a desire for greater social support from relatable others was highlighted.
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http://dx.doi.org/10.1177/2164956118763523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871220PMC
March 2018

Intrapatient study comparing 3D printed bolus versus standard vinyl gel sheet bolus for postmastectomy chest wall radiation therapy.

Pract Radiat Oncol 2018 Jul - Aug;8(4):221-229. Epub 2017 Dec 24.

Department of Radiation Oncology, Dalhousie University, Halifax, Canada; Nova Scotia Health Authority, Halifax, Canada.

Purpose: This patient study evaluated the use of 3-dimensional (3D) printed bolus for chest wall radiation therapy compared with standard sheet bolus with regard to accuracy of fit, surface dose measured in vivo, and efficiency of patient setup. By alternating bolus type over the course of therapy, each patient served as her own control.

Methods And Materials: For 16 patients undergoing chest wall radiation therapy, a custom 5.0 mm thick bolus was designed based on the treatment planning computed tomography scan and 3D printed using polylactic acid. Cone beam computed tomography scanning was used to image and quantify the accuracy of fit of the 2 bolus types with regard to air gaps between the bolus and skin. As a quality assurance measure for the 3D printed bolus, optically stimulated luminescent dosimetry provided in vivo comparison of surface dose at 7 points on the chest wall. Durations of patient setup and image guidance were recorded and compared.

Results: In 13 of 16 patients, the bolus was printed without user intervention, and the median print time was 12.6 hours. The accuracy of fit of the bolus to the chest wall was improved significantly relative to standard sheet bolus, with the frequency of air gaps 5 mm or greater reduced from 30% to 13% (P < .001) and maximum air gap dimension diminished from 0.5 ± 0.3 to 0.3 ± 0.3 mm on average. Surface dose was within 3% for both standard sheet and 3D printed bolus. On average, the use of 3D printed bolus reduced the setup time from 104 to 76 seconds.

Conclusions: This study demonstrates 3D printed bolus in postmastectomy radiation therapy improves fit of the bolus and reduces patient setup time marginally compared with standard vinyl gel sheet bolus. The time savings on patient setup must be weighed against the considerable time needed for the 3D printing process.
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http://dx.doi.org/10.1016/j.prro.2017.12.008DOI Listing
December 2018

Testosterone Suppression with Luteinizing Hormone-Releasing Hormone (LHRH) Agonists in Patients Receiving Radiotherapy for Prostate Cancer.

Pharmacotherapy 2018 03 7;38(3):327-333. Epub 2018 Feb 7.

Department of Radiation Oncology, QE II Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia.

Objectives: To characterize the probability of testosterone escape during a course of radiotherapy and androgen deprivation (ADT) in patients with prostate cancer, and examine predictors of testosterone escape, the prostate specific antigen (PSA) levels during testosterone escape, and the impact of testosterone escape on outcome.

Patients And Methods: To participate in the database review, necessary data included: (i) type of luteinizing hormone-releasing hormone agonist (LHRHa) administered, date of initiation, and date of cessation or duration of therapy, (ii) radiotherapy information (start date and dose) with at least 6 months of follow-up after radiotherapy, (iii) radiotherapy to the prostate or prostate bed, and (iv) at least one serum testosterone and PSA measurement.

Results: Five hundred sixty patients in the database were identified as being treated with radiotherapy and ADT. Three hundred seventy-five patients had at least one measurement of testosterone and PSA, and the type of LHRHa used could be determined in 361 patients. Median follow-up of patients still living was 4.7 years. The median number of testosterone measurements per patient was six. The incidence of testosterone escape per patient course of treatment was buserelin, 9.3%; goserelin, 10.5%; intramuscular leuprolide, 11.5%; leuprolide subcutaneous, 23.9%; and triptorelin, 6.7% (p = 0.02). There was no difference in either biochemical failure-free survival or overall survival in patients stratified by testosterone escape. The modal PSA level during a testosterone escape was an undetectable PSA.

Conclusions: An undetectable PSA does not rule out the presence of higher than desired levels of testosterone during ADT. In this cohort of patients, there appears to be no impact of testosterone escape on either biochemical relapse-free survival or overall survival.
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http://dx.doi.org/10.1002/phar.2084DOI Listing
March 2018

Regarding Liver Function 1 Year After Omega Loop Gastric Bypass.

Obes Surg 2016 10;26(10):2483-4

Kular Medical Education and Research Society, National Highway 1, Bija, Khanna, Ludhiana, Punjab, 141412, India.

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http://dx.doi.org/10.1007/s11695-016-2289-7DOI Listing
October 2016

What a Mini/One Anastomosis Gastric Bypass (MGB/OAGB) Is.

Obes Surg 2016 06;26(6):1322-3

Bariatric Surgery, Center of Laparoscopic Obesity Surgery, 1000 North Green Valley Parkway, Suite 440 box 492, Henderson, NV, 89074, USA.

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http://dx.doi.org/10.1007/s11695-016-2168-2DOI Listing
June 2016

Postirradiation pseudosclerodermatous panniculitis with involvement of breast parenchyma: a dramatic example of a rare entity and a pitfall in diagnosis.

J Cutan Pathol 2016 May 31;43(5):444-50. Epub 2016 Mar 31.

Department of Pathology and Laboratory Medicine, Nova Scotia Health Authority and Dalhousie University, Halifax, Canada.

Postirradiation pseudosclerodermatous panniculitis is a rare complication of external beam radiotherapy. This inflammatory process typically presents as an erythematous indurated plaque in a previously irradiated region of skin. To date, 13 cases have been reported worldwide. We present a case of a 70-year-old female who received breast irradiation following conservation surgery for invasive breast carcinoma. In her third year of follow-up, she developed an enlarging mass, involving the subcutis and underlying breast tissue, associated with mammographically detected coarse calcifications and density, at the surgical site. This was deemed highly suspicious of recurrent malignancy. Following several benign needle core biopsies, she had an excision of the mass. This revealed a lobular panniculitis and irradiation-induced vascular changes affecting subcutaneous fat and underlying breast tissue. This is the 14th reported case of this rare entity. It is unique in the degree of involvement, affecting breast parenchyma as well as subcutaneous fat, and in its corresponding dramatic clinical and radiographic manifestations.
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http://dx.doi.org/10.1111/cup.12683DOI Listing
May 2016

Naming the mini-gastric bypass.

Authors:
Robert Rutledge

Obes Surg 2014 Dec;24(12):2173

Center of Laparoscopic Obesity Surgery, 1000 North Green Valley Parkway, Suite 440 box 492, Henderson, NV, 89074, USA,

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http://dx.doi.org/10.1007/s11695-014-1417-5DOI Listing
December 2014

Potential link between biotic defense activation and recalcitrance to induction of somatic embryogenesis in shoot primordia from adult trees of white spruce (Picea glauca).

BMC Plant Biol 2013 Aug 12;13:116. Epub 2013 Aug 12.

Natural Resources Canada, Canadian Forest Service, Laurentian Forestry Centre, 1055 du PEPS, Québec, QC G1V 4C7, Canada.

Background: Among the many commercial opportunities afforded by somatic embryogenesis (SE), it is the ability to clonally propagate individual plants with rare or elite traits that has some of the most significant implications. This is particularly true for many long-lived species, such as conifers, but whose long generation times pose substantive challenges, including increased recalcitrance for SE as plants age. Identification of a clonal line of somatic embryo-derived trees whose shoot primordia have remained responsive to SE induction for over a decade, provided a unique opportunity to examine the molecular aspects underpinning SE within shoot tissues of adult white spruce trees.

Results: Microarray analysis was used to conduct transcriptome-wide expression profiling of shoot explants taken from this responsive genotype following one week of SE induction, which when compared with that of a nonresponsive genotype, led to the identification of four of the most differentially expressed genes within each genotype. Using absolute qPCR to expand the analysis to three weeks of induction revealed that differential expression of all eight candidate genes was maintained to the end of the induction treatment, albeit to differing degrees. Most striking was that both the magnitude and duration of candidate gene expression within the nonresponsive genotype was indicative of an intense physiological response. Examining their putative identities further revealed that all four encoded for proteins with similarity to angiosperm proteins known to play prominent roles in biotic defense, and that their high-level induction over an extended period is consistent with activation of a biotic defense response. In contrast, the more temperate response within the responsive genotype, including induction of a conifer-specific dehydrin, is more consistent with elicitation of an adaptive stress response.

Conclusions: While additional evidence is required to definitively establish an association between SE responsiveness and a specific physiological response, these results suggest that biotic defense activation may be antagonistic, likely related to the massive transcriptional and metabolic reprogramming that it elicits. A major issue for future work will be to determine how and if suppressing biotic defense activation could be used to promote a physiological state more conducive to SE induction.
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http://dx.doi.org/10.1186/1471-2229-13-116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765131PMC
August 2013

Evaluation of qPCR curve analysis methods for reliable biomarker discovery: bias, resolution, precision, and implications.

Methods 2013 Jan 3;59(1):32-46. Epub 2012 Sep 3.

Department of Anatomy, Embryology & Physiology, Academic Medical Center, Meibergdreef 15, 1100AZ Amsterdam, The Netherlands.

RNA transcripts such as mRNA or microRNA are frequently used as biomarkers to determine disease state or response to therapy. Reverse transcription (RT) in combination with quantitative PCR (qPCR) has become the method of choice to quantify small amounts of such RNA molecules. In parallel with the democratization of RT-qPCR and its increasing use in biomedical research or biomarker discovery, we witnessed a growth in the number of gene expression data analysis methods. Most of these methods are based on the principle that the position of the amplification curve with respect to the cycle-axis is a measure for the initial target quantity: the later the curve, the lower the target quantity. However, most methods differ in the mathematical algorithms used to determine this position, as well as in the way the efficiency of the PCR reaction (the fold increase of product per cycle) is determined and applied in the calculations. Moreover, there is dispute about whether the PCR efficiency is constant or continuously decreasing. Together this has lead to the development of different methods to analyze amplification curves. In published comparisons of these methods, available algorithms were typically applied in a restricted or outdated way, which does not do them justice. Therefore, we aimed at development of a framework for robust and unbiased assessment of curve analysis performance whereby various publicly available curve analysis methods were thoroughly compared using a previously published large clinical data set (Vermeulen et al., 2009) [11]. The original developers of these methods applied their algorithms and are co-author on this study. We assessed the curve analysis methods' impact on transcriptional biomarker identification in terms of expression level, statistical significance, and patient-classification accuracy. The concentration series per gene, together with data sets from unpublished technical performance experiments, were analyzed in order to assess the algorithms' precision, bias, and resolution. While large differences exist between methods when considering the technical performance experiments, most methods perform relatively well on the biomarker data. The data and the analysis results per method are made available to serve as benchmark for further development and evaluation of qPCR curve analysis methods (http://qPCRDataMethods.hfrc.nl).
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http://dx.doi.org/10.1016/j.ymeth.2012.08.011DOI Listing
January 2013

A Java program for LRE-based real-time qPCR that enables large-scale absolute quantification.

PLoS One 2011 Mar 2;6(3):e17636. Epub 2011 Mar 2.

Natural Resources Canada, Canadian Forest Service, Quebec, Canada.

Background: Linear regression of efficiency (LRE) introduced a new paradigm for real-time qPCR that enables large-scale absolute quantification by eliminating the need for standard curves. Developed through the application of sigmoidal mathematics to SYBR Green I-based assays, target quantity is derived directly from fluorescence readings within the central region of an amplification profile. However, a major challenge of implementing LRE quantification is the labor intensive nature of the analysis.

Findings: Utilizing the extensive resources that are available for developing Java-based software, the LRE Analyzer was written using the NetBeans IDE, and is built on top of the modular architecture and windowing system provided by the NetBeans Platform. This fully featured desktop application determines the number of target molecules within a sample with little or no intervention by the user, in addition to providing extensive database capabilities. MS Excel is used to import data, allowing LRE quantification to be conducted with any real-time PCR instrument that provides access to the raw fluorescence readings. An extensive help set also provides an in-depth introduction to LRE, in addition to guidelines on how to implement LRE quantification.

Conclusions: The LRE Analyzer provides the automated analysis and data storage capabilities required by large-scale qPCR projects wanting to exploit the many advantages of absolute quantification. Foremost is the universal perspective afforded by absolute quantification, which among other attributes, provides the ability to directly compare quantitative data produced by different assays and/or instruments. Furthermore, absolute quantification has important implications for gene expression profiling in that it provides the foundation for comparing transcript quantities produced by any gene with any other gene, within and between samples.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017636PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047581PMC
March 2011

Initiation of somatic embryos and regeneration of plants from primordial shoots of 10-year-old somatic white spruce and expression profiles of 11 genes followed during the tissue culture process.

Planta 2011 Mar 7;233(3):635-47. Epub 2010 Dec 7.

Natural Resources Canada, Canadian Forest Service, Laurentian Forestry Centre, 1055 du P.E.P.S, P.O. Box 10380, Stn. Sainte-Foy, Quebec, QC, G1V 4C7, Canada.

Adult conifers are notoriously recalcitrant in vegetative propagation and micropropagation that would result in the regeneration of juvenile propagules through somatic embryogenesis (SE) has not been demonstrated to date. Because SE-derived material is more amenable in subsequent tissue culture experiments compared with seed-derived material, a multi-year study was conducted to investigate induction of SE from primordial shoot (PS) explants that were excised from shoot buds of somatic embryo-derived white spruce. The SE induction experiments were carried out first with greenhouse-grown and later with field-grown trees each year from 2002 (2-year-old) to 2010 (10-year-old). Of the four genotypes tested, 893-2 and 893-12 never responded, 893-1 responded up to year 4 and 893-6 consistently responded every year. In 2010, for the first time, three of the 17 893-6 clonal trees produced male strobili as well as SE from cultured PS explants. SE induction was associated with formation of a nodule on the surface of an elongated needle primordium or in callus. Early somatic embryos were detectable after about 3 weeks of culture. Of 11 genes whose expression profiles were followed during the PS cultures, CHAP3A, VP1, WOX2 and SAP2C were expressed exclusively in the early stages of SE, and could potentially be used as markers of embryogenecity. Mature somatic embryos and plants were produced from the explants of responding genotype. Implication of these results for future research on adult conifer recalcitrance in micropropagation is discussed.
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http://dx.doi.org/10.1007/s00425-010-1325-4DOI Listing
March 2011

Toward understanding the mechanism of action of the yeast multidrug resistance transporter Pdr5p: a molecular modeling study.

J Struct Biol 2011 Feb 27;173(2):333-44. Epub 2010 Oct 27.

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Pleotropic drug resistant protein 5 (Pdr5p) is a plasma membrane ATP-binding cassette (ABC) transporter and the major drug efflux pump in Saccharomyces cerevisiae. The Pdr5p family of fungal transporters possesses a number of structural features significantly different from other modeled or crystallized ABC transporters, which include a reverse topology, an atypical ATP-binding site, a very low sequence similarity in the transmembrane section and long linkers between domains. These features present a considerable hurdle in molecular modeling studies of these important transporters. Here, we report the creation of an atomic model of Pdr5p based on a combination of homology modeling and ab initio methods, incorporating information from consensus transmembrane segment prediction, residue lipophilicity, and sequence entropy. Reported mutations in the transmembrane substrate-binding pocket that altered drug-resistance were used to validate the model, and one mutation that changed the communication pattern between transmembrane and nucleotide-binding domains was used in model improvement. The predictive power of the model was demonstrated experimentally by the increased sensitivity of yeast mutants to clotrimazole having alanine substitutions for Thr1213 and Gln1253, which are predicted to be in the substrate-binding pocket, without reducing the amount of Pdr5p in the plasma membrane. The quality and reliability of our model are discussed in the context of various approaches used for modeling different parts of the structure.
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http://dx.doi.org/10.1016/j.jsb.2010.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026082PMC
February 2011

The signaling interface of the yeast multidrug transporter Pdr5 adopts a cis conformation, and there are functional overlap and equivalence of the deviant and canonical Q-loop residues.

Biochemistry 2010 Jun;49(21):4440-9

Department of Biology, The Catholic University of America, Washington, DC 20064, USA.

ABC transporters are polytopic proteins. ATP hydrolysis and substrate transport take place in separate domains, and these activities must be coordinated through a signal interface. We previously characterized a mutation (S558Y) in the yeast multidrug transporter Pdr5 that uncouples ATP hydrolysis and drug transport. To characterize the transmission interface, we used a genetic screen to isolate second-site mutations of S558Y that restore drug transport. We recovered suppressors that restore drug resistance; their locations provide functional evidence for an interface in the cis rather than the trans configuration indicated by structural and cross-linking studies of bacterial and eukaryotic efflux transporters. One mutation, E244G, defines the Q-loop of the deviant portion of NBD1, which is the hallmark of this group of fungal transporters. When moved to an otherwise wild-type background, this mutation and its counterpart in the canonical ATP-binding site Q951G show a similar reduction in drug resistance and in the very high basal-level ATP hydrolysis characteristic of Pdr5. A double E244G, Q951G mutant is considerably more drug sensitive than either of the single mutations. Surprisingly, then, the deviant and canonical Q-loop residues are functionally overlapping and equivalent in a strikingly asymmetric ABC transporter.
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http://dx.doi.org/10.1021/bi100394jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954458PMC
June 2010

Hormonally regulated overexpression of Arabidopsis WUS and conifer LEC1 (CHAP3A) in transgenic white spruce: implications for somatic embryo development and somatic seedling growth.

Plant Cell Rep 2010 Jul 28;29(7):723-34. Epub 2010 Apr 28.

Natural Resources Canada, Canadian Forest Service, Laurentian Forestry Centre, Quebec, QC, Canada.

Adult conifers are still recalcitrant in clonal propagation despite significant advances in forest tree biotechnology. Plant regeneration through somatic embryogenesis from explants older than mature zygotic embryos is either difficult or impossible to achieve. To investigate if ectopic expression of transcription factors involved in the induction of the embryogenic process would induce somatic embryogenesis in Picea glauca (white spruce) somatic plants, we used the LEAFY-COTYLEDON1 homolog cloned from Picea mariana, CHAP3A, and Arabidopsis thaliana WUS to transform embryonal mass of P. glauca. Ectopic gene expression was induced by 17-beta-estradiol during stages of somatic embryogenesis (early embryogenesis and late embryogenesis) and somatic seedling growth in the transgenics. Of the two transcription factors, only WUS produced severe phenotypes by disrupting the development of somatic embryos on the maturation medium and inhibiting germination. However, none of the transgenes induced ectopic somatic embryogenesis even in the presence of plant growth regulators. Absolute quantitative PCR confirmed the expression of both CHAP3A and WUS in transgenic embryonal mass and in all parts of somatic seedlings. A high expression of the transgenes did not influence expression profiles of any of the ten other transcription factors tested, some of which have been known to be involved in the process of embryogenesis. Implications of these results for further work are discussed.
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http://dx.doi.org/10.1007/s00299-010-0859-zDOI Listing
July 2010

Assessing the performance capabilities of LRE-based assays for absolute quantitative real-time PCR.

PLoS One 2010 Mar 17;5(3):e9731. Epub 2010 Mar 17.

Canadian Forest Service, Natural Resources Canada, Quebec, Quebec, Canada.

Background: Linear regression of efficiency or LRE introduced a new paradigm for conducting absolute quantification, which does not require standard curves, can generate absolute accuracies of +/-25% and has single molecule sensitivity. Derived from adapting the classic Boltzmann sigmoidal function to PCR, target quantity is calculated directly from the fluorescence readings within the central region of an amplification profile, generating 4-8 determinations from each amplification reaction.

Findings: Based on generating a linear representation of PCR amplification, the highly visual nature of LRE analysis is illustrated by varying reaction volume and amplification efficiency, which also demonstrates how LRE can be used to model PCR. Examining the dynamic range of LRE further demonstrates that quantitative accuracy can be maintained down to a single target molecule, and that target quantification below ten molecules conforms to that predicted by Poisson distribution. Essential to the universality of optical calibration, the fluorescence intensity generated by SYBR Green I (FU/bp) is shown to be independent of GC content and amplicon size, further verifying that absolute scale can be established using a single quantitative standard. Two high-performance lambda amplicons are also introduced that in addition to producing highly precise optical calibrations, can be used as benchmarks for performance testing. The utility of limiting dilution assay for conducting platform-independent absolute quantification is also discussed, along with the utility of defining assay performance in terms of absolute accuracy.

Conclusions: Founded on the ability to exploit lambda gDNA as a universal quantitative standard, LRE provides the ability to conduct absolute quantification using few resources beyond those needed for sample preparation and amplification. Combined with the quantitative and quality control capabilities of LRE, this kinetic-based approach has the potential to fundamentally transform how real-time qPCR is conducted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009731PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840021PMC
March 2010
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