The PRO-ACTIVE trial protocol: a randomized study comparing the effectiveness of PROphylACTic swallow InterVEntion for patients receiving radiotherapy for head and neck cancer.

BACKGROUND: Swallowing therapy is commonly provided as a treatment to lessen the risk or severity of dysphagia secondary to radiotherapy (RT) for head and neck cancer (HNC); however, best practice is not yet established. This trial will compare the effectiveness of prophylactic (high and low intensity) versus reactive interventions for swallowing in patients with HNC undergoing RT. METHODS: This multi-site, international randomized clinical trial (RCT) will include 952 adult patients receiving radiotherapy for HNC and who are at high risk for post-RT dysphagia. Participants will be randomized to receive one of three interventions for swallowing during RT: RE-ACTIVE, started promptly if/when dysphagia is identified; PRO-ACTIVE EAT, low intensity prophylactic intervention started before RT commences; or, PRO-ACTIVE EAT+EXERCISE, high intensity prophylactic intervention also started before RT commences. We hypothesize that the PRO-ACTIVE therapies are more effective than late RE-ACTIVE therapy; and, that the more intensive PRO-ACTIVE (EAT + EXERCISE) is superior to the low intensive PRO-ACTIVE (EAT). The primary endpoint of effectiveness is duration of feeding tube dependency one year post radiation therapy, selected as a pragmatic outcome valued equally by diverse stakeholders (e.g., patients, caregivers and clinicians). Secondary outcomes will include objective measures of swallow physiology and function, pneumonia and weight loss, along with various patient-reported swallowing-related outcomes, such as quality of life, symptom burden, and self-efficacy. DISCUSSION: Dysphagia is a common and potentially life-threatening chronic toxicity of radiotherapy, and a priority issue for HNC survivors. Yet, the optimal timing and intensity of swallowing therapy provided by a speech-language pathologist is not known. With no clearly preferred strategy, current practice is fraught with substantial variation. The pragmatic PRO-ACTIVE trial aims to specifically address the decisional dilemma of when swallowing therapy should begin (i.e., before or after a swallowing problem develops). The critical impact of this dilemma is heightened by the growing number of young HNC patients in healthcare systems that need to allocate resources most effectively. The results of the PRO-ACTIVE trial will address the global uncertainty regarding best practice for dysphagia management in HNC patients receiving radiotherapy. TRIAL REGISTRATION: The protocol is registered with the US Patient Centered Outcomes Research Institute, and the PRO-ACTIVE trial was prospectively registered at ClinicalTrials.gov , under the identifier NCT03455608 ; First posted: Mar 6, 2018; Last verified: Jun 17, 2021. Protocol Version: 1.3 (January 27, 2020).

Association between cardiovascular risk-factors and venous thromboembolism in a large longitudinal study of French women.

BACKGROUND: Previous studies have shown conflicting results regarding the influence of cardiovascular risk-factors on venous thromboembolism. This study aimed to determine if these risk-factors, i.e. physical activity, smoking, hypertension, dyslipidaemia, and diabetes, were associated with the risk of venous thromboembolism, and to determine if these associations were confounded by BMI. METHODS: We used data from the E3N cohort study, a French prospective population-based study initiated in 1990, consisting of 98,995 women born between 1925 and 1950. From the women in the study we included those who did not have prevalent arterial disease or venous thromboembolism at baseline; thus 91,707 women were included in the study. Venous thromboembolism cases were self-reported during follow-up, and verified via specific mailings to medical practitioners or via drug reimbursements for anti-thrombotic medications. Hypertension, diabetes and dyslipidaemia were self-reported validated against drug reimbursements or specific questionnaires. Physical activity, and smoking were based on self-reports. Cox-models, adjusted for BMI and other potential risk-factors were used to determine hazard ratios for incident venous thromboembolism. RESULTS: During 1,897,960 person-years (PY), 1, 649 first incident episodes of thrombosis were identified at an incidence rate of 0.9 per 1000 PY. This included 505 cases of pulmonary embolism and 1144 cases of deep vein thrombosis with no evidence of pulmonary embolism. Hypertension, dyslipidaemia, diabetes, smoking and physical activity were not associated with the overall risk of thrombosis after adjustment for BMI. CONCLUSIONS: Traditional cardiovascular risk factors were not associated with the risk of venous thromboembolism after adjustment for BMI. Hypertension, dyslipidaemia and diabetes may not be risk-factors for venous thromboembolism.

Associations between smoking and blood-group, and the risk of dyslipidaemia amongst French women.

Dyslipidaemia is a major risk factor for cardio-vascular disease, as it promotes atherosclerosis. While cross-sectional studies have identified higher serum cholesterol amongst individuals with the A blood group, there is less evidence from prospective studies whether this translates into a higher risk of dyslipidaemia that requires treatment, nor if this genetic factor interacts with smoking status. This study aimed to prospectively determine potential associations between smoking, ABO blood groups, and risk of incident dyslipidaemia requiring treatment, and to assess associations over strata of blood ABO group. We assessed associations between blood ABO group, smoking and dyslipidaemia in 74,206 women participating in the E3N cohort. We included women who did not have cardiovascular disease at baseline. Logistic regression was used to determine associations between ABO group, smoking and prevalent dyslipidaemia at baseline. Cox proportional hazard models were then used to determine if blood ABO group and smoking were associated with the risk of incident dyslipidaemia, amongst women free of dyslipidaemia at baseline. At baseline 28,281 women with prevalent dyslipidaemia were identified. Compared to the O-blood group, the non-O blood group was associated higher odds of with prevalent dyslipidaemia (ORnon-O = 1.09 [1.06: 1.13]). Amongst the women free of dyslipidaemia at baseline, 6041 incident cases of treated dyslipidaemia were identified during 454,951 person-years of follow-up. The non-O blood groups were associated with an increased risk of dyslipidaemia when compared to the O-group (HRnon-O = 1.16 [1.11: 1.22]), specifically the A blood-group (HRA = 1.18 [1.12: 1.25]). Current smokers were associated with an increased risk of incident dyslipidaemia (HR smokers = 1.27 [1.16: 1.37]), compared to never-smokers. No evidence for effect modification between smoking and ABO blood group was observed (p-effect modification = 0.45), although the highest risk was observed among AB blood group women who smoked (HR = 1.76 [1.22: 2.55]). In conclusion, the non-O blood groups, specifically the A group were associated with an increased risk of dyslipidaemia. Current smokers were associated with a 30% increased risk of dyslipidaemia. These results could aid in personalised approaches to the prevention of cardiovascular risk-factors.

Study of lymph node vascular relationships of the inferior epigastric veins: The solve anatomical study.

INTRODUCTION: Tissue surrounding the superficial inferior epigastric vein (SIEV) can be harvested for vascularised lymph node transfer (vLNT) for the treatment of lymphoedema. The aim of this study is to define the anatomical relationship of lymph nodes surrounding the SIEV. METHODS: Twenty-five fresh-frozen cadaveric groin specimens were harvested en bloc to the level of the deep fascia along the following anatomical boundaries, yielding quadrilateral tissue blocks: pubic tubercle (medial), anterior superior iliac spine (lateral), 5 cm superior and inferior to the inguinal ligament. The SIEV was marked at its entry point with the femoral vein. Specimens were oriented, secured and fixed in formaldehyde and analysed using longitudinal slices at 3 mm intervals. RESULTS: A total of 86 lymph nodes were identified. The average position of lymph nodes examined was 0.4 cm medial and 3.2 cm inferior to the mid-inguinal point. CLINICAL RELEVANCE: An improved understanding of the anatomical locations of lymph nodes surrounding the SIEV will allow a more purposeful harvest during vLNT, allowing a greater number of lymph nodes to be captured whilst limiting donor site morbidity.

Management of ureteropelvic junction obstruction in children-a roundtable discussion.

The investigation, management and follow-up of paediatric ureteropelvic junction obstruction is not standardized. The Young Pediatric Urology Committee of the European Society of Pediatric Urology interviewed five experts in the field on various aspects of management and compared this with published literature.

An observer-blinded randomized controlled pilot trial comparing localized immersion psoralen-ultraviolet A with localized narrowband ultraviolet B for the treatment of palmar hand eczema.

BACKGROUND: Hand eczema is a common inflammatory dermatosis that causes significant patient morbidity. Previous studies comparing psoralen-ultraviolet A (PUVA) with narrowband ultraviolet B (NB-UVB) have been small, nonrandomized and retrospective. OBJECTIVES: To conduct an observer-blinded randomized controlled pilot study using validated scoring criteria to compare immersion PUVA with NB-UVB for the treatment of chronic hand eczema unresponsive to topical steroids. METHODS: Sixty patients with hand eczema unresponsive to clobetasol propionate 0·05% were randomized to receive either immersion PUVA or NB-UVB twice weekly for 12 weeks with assessments at intervals of 4 weeks. The primary outcome measure was the proportion of patients achieving 'clear' or 'almost clear' Physician's Global Assessment (PGA) response at 12 weeks. Secondary outcome measures included assessment of the modified Total Lesion and Symptom Score (mTLSS) and the Dermatology Life Quality index (DLQI). RESULTS: In both treatment arms, 23 patients completed the 12-week assessment for the primary outcome measure. In the PUVA group, five patients achieved 'clear' and eight 'almost clear' [intention-to-treat (ITT) response rate 43%]. In the NB-UVB group, two achieved 'clear' and five 'almost clear' (ITT response rate 23%). For the secondary outcomes, median mTLSS scores were similar between groups at baseline (PUVA 9·5, NB-UVB 9) and at 12 weeks (PUVA 3, NB-UVB 4). Changes in DLQI were similar, with improvements in both groups. CONCLUSIONS: In this randomized pilot trial recruitment was challenging. After randomization, there were acceptable levels of compliance and safety in each treatment schedule, but lower levels of retention. Using validated scoring systems - PGA, mTLSS and DLQI - as measures of treatment response, the trial demonstrated that both PUVA and NB-UVB reduced the severity of chronic palmar hand eczema.

Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis.

OBJECTIVES: To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities. METHODS: An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×106, 3×106 or 10×106 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood. RESULTS: There were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×106 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high. CONCLUSION: IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×106 tolDC but no systemic clinical or immunomodulatory effects were detectable. TRIAL REGISTRATION NUMBER: NCT01352858.

Peri-implant bony overgrowth as a cause of revision surgery in auditory osseointegrated implantation.

Implantation of auditory osseointegrated implants, also known as bone-anchored hearing systems (BAHS), represents a surgical option for select pediatric patients aged 5 years or older with hearing loss. Functional indications in this patient population include conductive or mixed hearing loss. Common complications of implantation include skin infections, chronic skin irritation, hypertrophic skin overgrowth, and loose abutments. In a case series of 15 pediatric patients, we discovered an unexpectedly high skin-related complication rate requiring surgical revision of 53%. During revision surgery, we discovered 5 patients who exhibited significant bony overgrowth at the abutment site, a complication infrequently noted in past literature.

Cadmium and other elements in tissues from four ungulate species from the Mackenzie Mountain region of the Northwest Territories, Canada.

Tissue samples from four ungulate species from the south Mackenzie Mountain region of the Northwest Territories (NT), Canada, were analysed for stable and radioactive elements and (15)N and (13)C stable isotopes. Elevated Cd concentrations in moose (Alces americanus) kidney have been observed in the region and are a health care concern for consumers of traditional foods. This study examined the factors associated with, and potential renal effects from, the accumulation of cadmium, and interactions with other elements in four sympatric ungulate species. Mean renal Cd concentration was highest in moose (48.3mg/kg ww), followed by mountain caribou (Rangifer tarandus caribou) (13.9mg/kg ww) and mountain goat (Oreamnos americanus) (5.78mg/kg ww). No local sources of Cd were evident and the elevated levels in moose are considered to be natural in origin. Conversely, total Hg concentration was significantly higher in mountain caribou kidney (0.21mg/kg ww) than in moose (0.011mg/kg ww). (134)Cs (t½=2.1 y) in mountain goat and Dall's sheep (Ovis dalli) muscle is evidence of deposition from the Fukushima reactor accident in 2011. (137)Cs (t½=30.2 y) in all four ungulates is primarily a remnant of the nuclear weapons tests of the 1960s. The levels of both nuclides are low and the risk to the animals and people consuming them is negligible. Stable isotope δ(15)N and δ(13)C signatures in muscle showed a separation between the mountain caribou, with a lichen-dominated diet, and moose, which browse shrubs and forbs. Isotope signatures for mountain goat and Dall's sheep showed generalist feeding patterns. Differences in elemental and radionuclide levels between species were attributed to relative levels of metal accumulation in the different food items in the diets of the respective species. Kidneys from each species showed minor histological changes in the proximal tubule and glomerulus, although glomerular changes were rare and all changes were rare in mountain goat kidney. Kidney function was not expected to be affected in any species. Provisional Monthly Intake recommendations from the WHO indicate that Cd in moose organs will continue to be a public health care concern. However, traditional foods continue to be an important nutritional component of northern diets, particularly in consideration of the shift towards store-bought food.

Is post-pneumonia chest X-ray for lung malignancy useful? Results of an audit of current practice.

BACKGROUND/AIM: Patients with community-acquired pneumonia (CAP) are often screened with repeat chest X-ray within 6-12 weeks following an admission. This practice is aimed to detect underlying lung malignancy, which can be difficult to identify initially when an acute infiltrate is present on X-ray. We conducted a study on the use of follow-up chest X-rays after an admission with CAP to determine the yield of suspected or diagnosed cancer. METHODS: During the 2-year period, January 2010-January 2012, we evaluated all patients over the age of 50 who had no previous history of lung cancer and were admitted to Hutt Hospital with CAP. RESULTS: A total of 302 patients was included. Of these, 53% received a follow-up chest X-ray within 6-12 weeks after admission. A total of six patients (2.0%) was diagnosed with lung cancer based on a chest X-ray within 6-12 weeks after admission. After a median period of follow up of 19.5 months, a further five patients who had normal chest X-ray were diagnosed with lung malignancy. CONCLUSION: The majority of patients were screened with follow-up X-rays. The yield from a 6- to 12-week chest X-ray following CAP is low, which is consistent with previous studies. The development of clear guidelines to ensure identification of patient groups at significantly high risk of lung cancer is important to increase the sensitivity of screening. High yielding strategies, such as low-dose computed tomography, should be considered as an alternative.

Measurements and simulations of focused beam for orthovoltage therapy.

PURPOSE: Megavoltage photon beams are typically used for therapy because of their skin-sparing effect. However, a focused low-energy x-ray beam would also be skin sparing, and would have a higher dose concentration at the focal spot. Such a beam can be produced with polycapillary optics. MCNP5 was used to model dose profiles for a scanned focused beam, using measured beam parameters. The potential of low energy focused x-ray beams for radiation therapy was assessed. METHODS: A polycapillary optic was used to focus the x-ray beam from a tungsten source. The optic was characterized and measurements were performed at 50 kV. PMMA blocks of varying thicknesses were placed between optic and the focal spot to observe any variation in the focusing of the beam after passing through the tissue-equivalent material. The measured energy spectrum was used to model the focused beam in MCNP5. A source card (SDEF) in MCNP5 was used to simulate the converging x-ray beam. Dose calculations were performed inside a breast tissue phantom. RESULTS: The measured focal spot size for the polycapillary optic was 0.2 mm with a depth of field of 5 mm. The measured focal spot remained unchanged through 40 mm of phantom thickness. The calculated depth dose curve inside the breast tissue showed a dose peak several centimeters below the skin with a sharp dose fall off around the focus. The percent dose falls below 10% within 5 mm of the focus. It was shown that rotating the optic during scanning would preserve the skin-sparing effect of the focused beam. CONCLUSIONS: Low energy focused x-ray beams could be used to irradiate tumors inside soft tissue within 5 cm of the surface.

MO-A-213AB-01: Potential for Focused Low Energy X-Ray Beam for Therapy.

PURPOSE: Megavoltage photon beams are typically used for therapy because of their skin sparing effect. However, a focused low-energy x-ray beam would also be skin sparing, and would have a higher dose concentration at the focal spot. Such a beam can be produced with polycapillary optics. MCNP5 was used to model dose profiles for a scanned focused beam, using measured beam parameters. The potential of low energy focused x-ray beams for radiation therapy was assessed. METHODS: A polycapillary optic was used to focus the x-ray beam from a tungsten source. The optic was characterized and measurements were performed at 50 KV. PMMA blocks of varying thicknesses were placed between optic and the focal spot to observe any variation in the focusing of the beam after passing through the tissue-equivalent material. The measured energy spectrum was used to model the focused beam in MCNP5. A source card (SDEF) in MCNP5 was used to simulate the converging x-ray beam. Dose calculations were performed inside a breast tissue phantom. RESULTS: The measured focal spot size for the polycapillary optic was 0.2 mm with a depth of field of 5 mm. Focusing was found to remain unchanged through 40 mm of phantom thickness. The calculated depth dose curve inside the breast tissue showed a dose peak several centimeters below the skin with a sharp dose fall off around the focus. The percent dose falls below 10% within 5 mm of the focus. Rotating the optic during scanning preserves the skin-sparing effect of the focused beam. CONCLUSIONS: Low energy focused x-ray beams could be used to irradiate tumors inside soft tissue within 5 cm of the surface.

Mathematical analysis of antigen selection in somatically mutated immunoglobulin genes associated with autoimmunity.

Affinity maturation is a process by which low-affinity antibodies are transformed into highly specific antibodies in germinal centres. This process occurs by hypermutation of immunoglobulin heavy chain variable (IgH V) region genes followed by selection for high-affinity variants. It has been proposed that statistical tests can identify affinity maturation and antigen selection by analysing the frequency of replacement and silent mutations in the complementarity determining regions (CDRs) that contact antigen and the framework regions (FRs) that encode structural integrity. In this study three different methods that have been proposed for detecting selection: the binomial test, the multinomial test and the focused binomial test, have been assessed for their reliability and ability to detect selection in human IgH V genes. We observe first that no statistical test is able to identify selection in the CDR antigen-binding sites, second that tests can reliably detect selection in the FR and third that antibodies from nasal biopsies from patients with Wegener's granulomatosis and pathogenic antibodies from systemic lupus erythematosus do not appear to be as stringently selected for structural integrity as other groups of functional sequences.

Mobility and survival of Salmonella Typhimurium and human adenovirus from spiked sewage sludge applied to soil columns.

AIMS: This study investigated the survival and transport of sewage sludge-borne pathogenic organisms in soils. METHODS AND RESULTS: Undisturbed soil cores were treated with Salmonella enterica ssp. enterica serovar Typhimurium-lux (STM-lux) and human adenovirus (HAdV)-spiked sewage sludge. Following an artificial rainfall event, these pathogens were analysed in the leachate and soil sampled from different depths (0-5 cm, 5-10 cm and 10-20 cm) after 24 h, 1 and 2 months. Significantly more STM-lux and HAdV leached through the soil cores when sewage sludge was present. Significantly more STM-lux were found at all soil depths, at all time periods in the sewage sludge treatments, compared to the controls. The rate of decline of STM-lux in the controls was more rapid than in the sewage sludge treatments. Survival and transport of HAdV were minimal. CONCLUSIONS: The presence of sewage sludge can significantly influence the transport and survival of bacterial pathogens in soils, probably because of the presence of organic matter. Environmental contamination by virus is unlikely because of strong soil adsorption. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests that groundwater contamination from vertical movement of pathogens is a potential risk and that it highlights the importance of the treatment requirements for biosolids prior to their application to land.

Curved crystal x-ray optics for monochromatic imaging with a clinical source.

Monochromatic x-ray imaging has been shown to increase contrast and reduce dose relative to conventional broadband imaging. However, clinical sources with very narrow energy bandwidth tend to have limited intensity and field of view. In this study, focused fan beam monochromatic radiation was obtained using doubly curved monochromator crystals. While these optics have been in use for microanalysis at synchrotron facilities for some time, this work is the first investigation of the potential application of curved crystal optics to clinical sources for medical imaging. The optics could be used with a variety of clinical sources for monochromatic slot scan imaging. The intensity was assessed and the resolution of the focused beam was measured using a knife-edge technique. A simulation model was developed and comparisons to the measured resolution were performed to verify the accuracy of the simulation to predict resolution for different conventional sources. A simple geometrical calculation was also developed. The measured, simulated, and calculated resolutions agreed well. Adequate resolution and intensity for mammography were predicted for appropriate source/optic combinations.

E-learning education solutions for caregivers in long-term care (LTC) facilities: new possibilities.

CONTEXT: Online learning (referred to as e-learning throughout this article) has proved to be a useful tool for delivering accessible and convenient education to busy clinical healthcare workers. The ABS Management Company specifically designed a program to provide nurses and caregivers with the necessary knowledge and skills to improve the quality of care and the quality of life for the geriatric population in long-term care (LTC) facilities. OBJECTIVES: The purpose of the "Online Solutions: Quality Education for Quality Care in Long-Term Care" program is to use new educational pedagogies and innovative ways to conceptualise and deliver healthcare education to meet the complex issues and concerns of caregivers in LTC facilities. METHODS: During the one-year period that data were collected for this study, 881 caregivers completed the eight (one-hour) modules in the program. Of these, 753 (85%) completed the optional assessment (both the pre and post tests) for one or more of the eight modules. Therefore, of the 881 employees who reviewed all eight modules (881x8 = 7048 modules), 1046 modules (15%) had both pre-post test data upon which to build the analysis. FINDINGS: Information from the evaluation revealed learner improvement in pre-post test scores in excess of 10%, suggesting an increase in new and relevant skills and knowledge related to abuse and neglect, elopement, infection control, nutrition and hydration, pressure ulcers, provision of basic care and restraints. Moreover, the data indicated a reduction in the use of restraints and occurrence of pressure ulcers, suggesting that learners applied new knowledge and skills in the workplace. Finally, staff turnover rates decreased more than 20% suggesting greater job satisfaction after participating in the program. CONCLUSIONS: The research findings point to an urgent and unmet need to provide more accessible just-in-time, just-for-you education programs for caregivers in LTC facilities to ensure quality and efficient services to residents and their families.