A pilot study proposing an algorithm for pubertal induction in cerebral palsy.

OBJECTIVES: To explore delayed puberty in cerebral palsy (CP) and to test the acceptability of an interventional puberty induction algorithm. METHODS: A two phase cohort study in children and adolescents diagnosed with CP who have delayed puberty. Phase 1: Retrospective review of clinical records and interviews with patients who have been treated with sex-steroids and Phase 2: Prospective interventional trial of pubertal induction with a proposed algorithm of transdermal testosterone (males) or oestrogen (females). Phase 1 examined experiences with sex-steroid treatment. Phase 2 collected data on height adjusted bone mineral density (BMAD), fractures, adverse effects, mobility and quality of life over two years during the induction. RESULTS: Phase 1, treatment was well tolerated in 11/20 treated with sex-steroids; phase 2, using the proposed induction algorithm, 7/10 treated reached Tanner stage 3 by nine months. One participant reached Tanner stage 5 in 24 months. Mean change in BMAD Z-scores was +0.27 % (SD 0.002) in those who could be scanned by dual-energy X-ray absorptiometry (DXA). CONCLUSIONS: Delayed puberty may be diagnosed late. Treatment was beneficial and well tolerated, suggesting all patients with severe pubertal delay or arrest should be considered for sex hormone supplementation.

Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).

PURPOSE: To determine the specific types, durations, and intensities of recreational physical activity associated with the greatest improvements in disease-free survival (DFS) of patients with colon cancer. METHODS: We conducted a prospective cohort study nested within a randomized multicenter trial of stage III colon cancer that compared 3 versus 6 months of fluorouracil, leucovorin, and oxaliplatin with or without celecoxib. We measured recreational physical activity in the first 3 months of chemotherapy and again 6 months after completion of chemotherapy. The primary end point was DFS. RESULTS: During a median follow-up of 5.9 years, 457 of 1,696 patients experienced disease recurrence or death. For total recreational physical activity volume, the 3-year DFS was 76.5% with < 3.0 metabolic equivalent task hours per week (MET-h/wk) and 87.1% with ≥ 18.0 MET-h/wk (risk difference [RD], 10.6%; 95% CI, 4.7 to 19.4; P < .001). For light-intensity to moderate-intensity activities, the 3-year DFS was 65.7% with 0.0 h/wk and 87.1% with ≥ 1.5 h/wk (RD, 21.4%; 95% CI, 9.2 to 37.1; P < .001). For vigorous-intensity activity, the 3-year DFS was 76.0% with 0.0 h/wk and 86.0% with ≥ 1.0 h/wk (RD, 10.0%; 95% CI, 4.5 to 18.9; P < .001). For brisk walking, the 3-year DFS was 81.7% with < 1.0 h/wk and 88.4% with ≥ 3.0 h/wk (RD, 6.7%; 95% CI, 3.0 to 13.8; P < .001). For muscle strengthening activity, the 3-year DFS was 81.8% with 0.0 h/wk and 88.8% for ≥ 0.5 h/wk (RD, 7.0%; 95% CI, 3.1 to 14.2; P = .003). CONCLUSION: Among patients with stage III colon cancer enrolled in a trial of postoperative treatment, larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the greatest improvements in DFS.

Best practices for predictions of radionuclide activity concentrations and total absorbed dose rates to freshwater organisms exposed to uranium mining/milling.

Predictions of radionuclide dose rates to freshwater organisms can be used to evaluate the radiological environmental impacts of releases from uranium mining and milling projects. These predictions help inform decisions on the implementation of mitigation measures. The objective of this study was to identify how dose rate modelling could be improved to reduce uncertainty in predictions to non-human biota. For this purpose, we modelled the activity concentrations of 210Pb, 210Po, 226Ra, 230Th, and 238U downstream of uranium mines and mills in northern Saskatchewan, Canada, together with associated weighted absorbed dose rates for a freshwater food chain using measured activity concentrations in water and sediments. Differences in predictions of radionuclide activity concentrations occurred mainly from the different default partition coefficient and concentration ratio values from one model to another and including all or only some 238U decay daughters in the dose rate assessments. Consequently, we recommend a standardized best-practice approach to calculate weighted absorbed dose rates to freshwater biota whether a facility is at the planning, operating or decommissioned stage. At the initial planning stage, the best-practice approach recommend using conservative site-specific baseline activity concentrations in water, sediments and organisms and predict conservative incremental activity concentrations in these media by selecting concentration ratios based on species similarity and similar water quality conditions to reduce the uncertainty in dose rate calculations. At the operating and decommissioned stages, the best-practice approach recommends relying on measured activity concentrations in water, sediment, fish tissue and whole-body of small organisms to further reduce uncertainty in dose rate estimates. This approach would allow for more realistic but still conservative dose assessments when evaluating impacts from uranium mining projects and making decision on adequate controls of releases.

Scaling of computed tomography body composition to height: relevance of height-normalized indices in patients with colorectal cancer.

BACKGROUND: Body weight scales to height with a power of ≈2 (weight/height2 ), forming the basis of body mass index (BMI). The corresponding scaling of body composition measured by abdominal computed tomography (CT) to height has not been established. The objective of this analysis was to quantify the scaling of body composition measured by a single-slice axial abdominal CT image (skeletal muscle, and visceral, subcutaneous, and total adipose tissue) to height in patients with colorectal cancer (CRC). METHODS: This cross-sectional study included non-Hispanic white males and females, aged 18-80 years, who were diagnosed with stage I-III CRC at an integrated health care system in North America between January 2006 and December 2011. Body composition was measured by a single-slice axial CT image of the third lumbar vertebra and analysed with a semi-automated threshold segmentation procedure. Allometric regression models were used to quantify height scaling powers (ß ± standard error) for each body composition measure, adjusted for age, for males and females. An interaction test was used to determine if height scaling powers were statistically significantly different between males and females. RESULTS: Among 2036 subjects, the mean (standard deviation) age was 64 ± 11 years, 1008 (49.5%) were female, and the mean (standard deviation) BMI was 27.9 ± 5.4 kg/m2 . Powers for skeletal muscle area were 1.06 ± 0.12 for males and 0.80 ± 0.12 for females (P = 0.049). Powers for visceral adipose tissue area were 1.81 ± 0.64 for males and 0.57 ± 0.79 for females (P = 0.16). Powers for subcutaneous adipose tissue area were 2.04 ± 0.42 for males and 0.81 ± 0.45 for females (P = 0.056). Powers for total abdominal adipose tissue area were 1.80 ± 0.46 for males and 0.76 ± 0.50 for females (P = 0.20). CONCLUSIONS: Body composition measured by single-slice axial abdominal CT, particularly muscle area, scales to height with age-adjusted powers that are different than 2 and are distinct between males and females. These observations may have implications for the development of height-adjusted body composition indices in patients with cancer.

Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Body Composition among Patients with Advanced or Metastatic Colorectal Cancer: A Randomized Trial.

Skeletal muscle and adipose tissue express the vitamin D receptor and may be a mechanism through which vitamin D supplementation slows cancer progression and reduces cancer death. In this exploratory analysis of a double-blind, multicenter, randomized phase II clinical trial, 105 patients with advanced or metastatic colorectal cancer who were receiving chemotherapy were randomized to either high-dose vitamin D3 (4000 IU) or standard-dose (400 IU) vitamin D3. Body composition was measured with abdominal computed tomography at enrollment (baseline) and after cycle 8 of chemotherapy (16 weeks). As compared with standard-dose vitamin D3, high-dose vitamin D3 did not significantly change body weight [-0.7 kg; (95% CI: -3.5, 2.0)], body mass index [-0.2 kg/m2; (95% CI: -1.2, 0.7)], muscle area [-1.7 cm2; (95% CI: -9.6, 6.3)], muscle attenuation [-0.4 HU; (95% CI: -4.2, 3.2)], visceral adipose tissue area [-7.5 cm2; (95% CI: -24.5, 9.6)], or subcutaneous adipose tissue area [-8.3 cm2; (95% CI: -35.5, 18.9)] over the first 8 cycles of chemotherapy. Among patients with advanced or metastatic colorectal cancer, the addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy did not result in any changes in body composition.

Global consensus on nutritional rickets: Implications for Australia.

In 2016, a global consensus on the prevention, diagnosis and management of nutritional rickets was published. The bone and mineral working group of the Australasian Paediatric Endocrine Group provides a summary and highlights differences to previous Australian and New Zealand (ANZ) guidelines on vitamin D deficiency and their implications for clinicians. Key points are: (i) The International Consensus document is focused on nutritional rickets, whereas the ANZ guidelines were focused on vitamin D deficiency. (ii) Definitions for the interpretation of 25-hydroxy vitamin D (25OHD) levels do not differ between statements. (iii) The global consensus recommends that routine 25OHD screening should not be performed in healthy children and recommendations for vitamin D supplementation are not based solely on 25OHD levels. The Australasian Paediatric Endocrine Group bone and mineral working group supports that screening for vitamin D deficiency should be restricted to populations at risk. (iv) Recommendations from the global consensus for vitamin D dosages for the therapy of nutritional rickets (diagnosed based on history, physical examination, biochemical testing and a confirmation by X-rays) are higher than in ANZ publications. (v) The global consensus recommends the implementation of public health strategies such as universal supplementation with vitamin D from birth to 1 year of age and food fortification. We conclude that updated global recommendations for therapy of nutritional rickets complement previously published position statements for Australia and New Zealand. Screening, management and the implementation of public health strategies need to be further explored for Australia.

A Review of Pathogens, Diseases, and Contaminants of Muskrats (Ondatra zibethicus) in North America.

Over the last 50 years, significant muskrat (Ondatra zibethicus) harvest declines have been observed throughout North America. Several theories for the decline have been proposed, including increased parasite infections and disease within muskrat populations. No existing wholistic review of muskrat exposure to pathogens, contaminants, and diseases exists. To address this knowledge gap, we conducted a thorough review of existing literature on muskrat pathogens, contaminants, and diseases across their natural range. This review is comprised of 131 articles from 1915 to 2019 and from 27 U.S. states and 9 Canadian provinces. A wide diversity of contaminants, toxins, and pathogens were reported in muskrats, with the most common diseases being cysticercosis, tularemia, Tyzzer's disease, and biotoxin poisoning from cyanobacteria. This review provides a summary of muskrat pathogens, contaminants, and diseases over a century that has observed significant population declines throughout the species' range in North America. Such data provide a baseline for understanding the potential role of disease in these declines. In addition, these data highlight critical knowledge gaps that warrant future research efforts.

Body Composition and Cardiovascular Events in Patients With Colorectal Cancer: A Population-Based Retrospective Cohort Study.

IMPORTANCE: Patients with colorectal cancer (CRC) are up to 4-fold more likely than individuals without a history of cancer to develop cardiovascular disease. Clinical care guidelines recommend that physicians counsel patients with CRC regarding the association between obesity (defined using body mass index [BMI] calculated as weight in kilograms divided by height in meters squared) and cardiovascular disease risk; however, this recommendation is based on expert opinion. OBJECTIVE: To determine which measures of body composition are associated with major adverse cardiovascular events (MACEs) in patients with CRC. DESIGN, SETTING, AND PARTICIPANTS: Population-based retrospective cohort study of 2839 patients with stage I to III CRC diagnosed between January 2006 and December 2011 at an integrated health care system in North America. EXPOSURES: The primary exposures were BMI and computed tomography-derived body composition measurements (eg, adipose tissue compartments and muscle characteristics) obtained at the diagnosis of CRC. MAIN OUTCOMES AND MEASURES: The primary outcome was time to the first occurrence of MACE after diagnosis of CRC, including myocardial infarction, stroke, and cardiovascular death. RESULTS: In this population-based cohort study of 2839 participants with CRC (1384 men and 1455 women), the average age (SD) was 61.9 (11.5) years (range, 19-80 years). A substantial number of patients were former (1127; 40%) or current smokers (340; 12%), with hypertension (1150; 55%), hyperlipidemia (1389; 49%), and type 2 diabetes (573; 20%). The cumulative incidence of MACE 10 years after diagnosis of CRC was 19.1%. Body mass index was positively correlated with some computed tomography-derived measures of body composition. However, BMI was not associated with MACE; contrasting BMI categories of greater than or equal to 35 vs 18.5 to 24.9, the hazard ratio (HR) was 1.23 (95% CI, 0.85-1.77; P = .50 for trend). Visceral adipose tissue area was associated with MACE; contrasting the highest vs lowest quintile, the HR was 1.54 (95% CI, 1.02-2.31; P = .04 for trend). Subcutaneous adipose tissue area was not associated with MACE; contrasting the highest vs lowest quintile, the HR was 1.15 (95% CI, 0.78-1.69; P = .65 for trend). Muscle mass was not associated with MACE; contrasting the highest vs lowest quintile, the HR was 0.96 (95% CI, 0.57-1.61; P = .92 for trend). Muscle radiodensity was associated with MACE; contrasting the highest (ie, less lipid stored in the muscle) vs lowest quintile, the HR was 0.67 (95% CI, 0.44-1.03; P = .02 for trend). CONCLUSIONS AND RELEVANCE: Visceral adiposity and muscle radiodensity appear to be risk factors for MACE. Body mass index may have limited use for determining cardiovascular risk in this patient population.

Factors Affecting Vitamin D Status in Infants.

Vitamin D is critical to children's skeletal development and health. Despite this, the factors which determine vitamin D concentrations during infancy remain incompletely understood. This article reviews the literature assessing the factors which can affect vitamin D status in infancy, including antenatal and postnatal vitamin D supplementation. Observational data supports that dietary intake of vitamin D, UV exposure, and geographic factors contribute significantly to infants' vitamin D status, but the relationship is unclear regarding genetic variation, ethnicity, and maternal vitamin D status. Randomised controlled trials have compared higher versus lower doses of infant vitamin D supplementation, but no studies have compared infant vitamin D supplementation to placebo and eliminated external sources of vitamin D to fully quantify its effect on vitamin D status. Knowledge gaps remain regarding the factors associated with optimal vitamin D concentrations in infants-including key factors such as ethnicity and genetic variation-and further studies are needed.

Dose-response Effects of Aerobic Exercise Among Colon Cancer Survivors: A Randomized Phase II Trial.

BACKGROUND: Observational studies suggest that higher volumes of physical activity are associated with a lower risk of disease recurrence among survivors of colon cancer. However, the feasibility and safety of prescribing higher volumes of physical activity to survivors of colon cancer are unknown. Furthermore, the pathways through which exercise may reduce disease recurrence are unknown. PATIENTS AND METHODS: Survivors of stage I to III colon cancer were randomized to usual-care control, 150 minutes per week of aerobic exercise (low-dose), or 300 minutes per week of aerobic exercise (high-dose). Changes in soluble intercellular adhesion molecule-1 and vascular adhesion molecule-1 prognostic biomarkers were examined. RESULTS: From January 2015 to February 2016, 39 patients were enrolled (n = 13 usual-care control; n = 14 low-dose; n = 12 high-dose), and 38 participants completed the study (97% follow-up). Over 6 months, the low-dose group completed 142 minutes per week (92.8% adherence), and the high-dose group completed 247 minutes per week (89.0% adherence) of exercise. Compared with the control group, changes in soluble intercellular adhesion molecule-1 were -134.9 ng/mL (95% confidence interval, -238.1 to -31.6 ng/mL) in the low-dose group and -114.8 ng/mL (95% confidence interval, -222.5 to -7.1 ng/mL) in the high-dose group (linear Ptrend = .023; nonlinear Ptrend = .044). No changes were observed for soluable vascular adhesion molecule-1 (linear Ptrend = .791; nonlinear Ptrend = .604). Non-serious adverse events occurred at similar rates among randomized groups. No serious adverse events occurred. CONCLUSION: Higher volumes of moderate-intensity aerobic exercise, up to 300 minutes per week, are feasible, safe, and elicit favorable changes in prognostic biomarkers among patients recently treated for stage I to III colon cancer. These data can be used to guide clinical recommendations for patients, and inform future trials.

The prescription or proscription of exercise in colorectal cancer care.

PURPOSE: Clinical guidelines recommend that oncologists prescribe exercise to their patients with colorectal cancer (CRC). However, 84% of oncologists do not prescribe exercise, citing concerns of safety and feasibility. Data are inadequate regarding the proportion of CRC survivors that could be safely prescribed with the dose of exercise recommended by the American College of Sports Medicine (ACSM), American Cancer Society (ACS), or National Comprehensive Cancer Network (NCCN) in an unsupervised setting. METHODS: We reviewed published guidelines for exercise prescription among cancer survivors and extracted health factors that may necessitate referral to trained personnel (physical therapist or exercise professional) for an individualized exercise program or supervision of exercise as recommended by the ACSM/ACS/NCCN. We applied these health factors to a cohort of nonmetastatic CRC survivors 6 months after completing curative care. The primary outcome was the proportion of CRC survivors to whom oncologists could prescribe unsupervised exercise at the dose recommended by the ACSM/ACS/NCCN. RESULTS: Among 351 CRC survivors, 6 months after curative care, 21%-42% of patients could be prescribed with the dose of exercise recommended by the ACSM/ACS/NCCN. Estimates varied as a function of the inclusion or exclusion of several prevalent comorbid health conditions including hypertension, diabetes, arthritis, obesity, and hyperlipidemia. CONCLUSIONS: Our data are consistent with the clinical observation that a large proportion of CRC survivors may be unable to participate in unsupervised exercise 6 months after curative care. These data underscore the need for continued research to clarify the safety and feasibility of prescribing exercise to CRC survivors.

A hybrid effectiveness-implementation trial of an evidence-based exercise intervention for breast cancer survivors.

BACKGROUND: The primary aims of this hybrid Type 1 effectiveness-implementation trial were to quantitatively assess whether an evidence-based exercise intervention for breast cancer survivors, Strength After Breast Cancer, was safe and effective in a new setting and to qualitatively assess barriers to implementation. METHODS: A cohort of 84 survivors completed measurements related to limb volume, muscle strength, and body image at baseline, 67 survivors completed measurements 12 months later. Qualitative methods were used to understand barriers to implementation experienced by referring oncology clinicians and physical therapists who delivered the program. RESULTS: Similar to the efficacy trial, the revised intervention demonstrated safety with regard to lymphedema, and led to improvements in lymphedema symptoms, muscular strength, and body image. Comparison of effects in the effectiveness trial to effects in the efficacy trial revealed larger strength increases in the efficacy trial than in the effectiveness trial (P < .04), but few other differences were found. Qualitative implementation data suggested significant barriers around intervention characteristics, payment, eligibility criteria, the referral process, the need for champions (ie, advocates), and the need to adapt during implementation of the intervention, which should be considered in future dissemination and implementation efforts. CONCLUSIONS: This trial successfully demonstrated that a physical therapy led strength training program for breast cancer survivors can be implemented in a community setting while retaining the effectiveness and safety of the clinical trial. However, during the translation process, strategies to reduce barriers to implementation are required. This new program can inform larger scale dissemination and implementation efforts.

Synthesis and characterization of biomimetic citrate-based biodegradable composites.

Natural bone apatite crystals, which mediate the development and regulate the load-bearing function of bone, have recently been associated with strongly bound citrate molecules. However, such understanding has not been translated into bone biomaterial design and osteoblast cell culture. In this work, we have developed a new class of biodegradable, mechanically strong, and biocompatible citrate-based polymer blends (CBPBs), which offer enhanced hydroxyapatite binding to produce more biomimetic composites (CBPBHAs) for orthopedic applications. CBPBHAs consist of the newly developed osteoconductive citrate-presenting biodegradable polymers, crosslinked urethane-doped polyester and poly (octanediol citrate), which can be composited with up to 65 wt % hydroxyapatite. CBPBHA networks produced materials with a compressive strength of 116.23 ± 5.37 MPa comparable to human cortical bone (100-230 MPa), and increased C2C12 osterix gene and alkaline phosphatase gene expression in vitro. The promising results above prompted an investigation on the role of citrate supplementation in culture medium for osteoblast culture, which showed that exogenous citrate supplemented into media accelerated the in vitro phenotype progression of MG-63 osteoblasts. After 6 weeks of implantation in a rabbit lateral femoral condyle defect model, CBPBHA composites elicited minimal fibrous tissue encapsulation and were well integrated with the surrounding bone tissues. The development of citrate-presenting CBPBHA biomaterials and preliminary studies revealing the effects of free exogenous citrate on osteoblast culture shows the potential of citrate biomaterials to bridge the gap in orthopedic biomaterial design and osteoblast cell culture in that the role of citrate molecules has previously been overlooked.

From contemporary rehabilitation to restorative neurology.

Recent years have witnessed significant advances in the treatment of neurological injuries such as stroke, traumatic brain injuries (TBI), and spinal cord injuries (SCI). The current approach includes acute intervention to curb the primary insult, prevention of secondary complications and early rehabilitation to optimize residual function to ultimately enhance quality of life and independence. While this is effective in providing a degree of independence to many patients, we believe that further functional gains are possible for many patients who have plateaued followed a contemporary rehabilitation program. Complementary methods are available today that are not widely used, but have demonstrated great promise in augmenting function and quality of life in patients who cannot benefit further from currently available treatment options.

Reinnervation of urethral and anal sphincters with femoral motor nerve to pudendal nerve transfer.

AIMS: Lower motor neuron damage to sacral roots or nerves can result in incontinence and a flaccid urinary bladder. We showed bladder reinnervation after transfer of coccygeal to sacral ventral roots, and genitofemoral nerves (L1, 2 origin) to pelvic nerves. This study assesses the feasibility of urethral and anal sphincter reinnervation using transfer of motor branches of the femoral nerve (L2-4 origin) to pudendal nerves (S1, 2 origin) that innervate the urethral and anal sphincters in a canine model. METHODS: Sacral ventral roots were selected by their ability to stimulate bladder, urethral sphincter, and anal sphincter contraction and transected. Bilaterally, branches of the femoral nerve, specifically, nervus saphenous pars muscularis [Evans HE. Miller's anatomy of the dog. Philadelphia: W.B. Saunders; 1993], were transferred and end-to-end anastomosed to transected pudendal nerve branches in the perineum, then enclosed in unipolar nerve cuff electrodes with leads to implanted RF micro-stimulators. RESULTS: Nerve stimulation induced increased anal and urethral sphincter pressures in five of six transferred nerves. Retrograde neurotracing from the bladder, urethral sphincter, and anal sphincter using fluorogold, fast blue, and fluororuby, demonstrated urethral and anal sphincter labeled neurons in L2-4 cord segments (but not S1-3) in nerve transfer canines, consistent with reinnervation by the transferred femoral nerve motor branches. Controls had labeled neurons only in S1-3 segments. Postmortem DiI and DiO labeling confirmed axonal regrowth across the nerve repair site. CONCLUSIONS: These results show spinal cord reinnervation of urethral and anal sphincter targets after sacral ventral root transection and femoral nerve transfer (NT) to the denervated pudendal nerve. These surgical procedures may allow patients to regain continence.