Penelope M. A. Brasher

A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer

Localized prostate cancer can be treated several different ways, but head‐to‐head comparisons of treatments are infrequent. The authors of this report conducted a randomized, unblinded, noninferiority trial to compare cryoablation with external beam radiotherapy in these patients.

Enhancing a somatic maturity prediction model

PURPOSE Assessing biological maturity in studies of children is challenging. Sex-specific regression equations developed using anthropometric measures are widely used to predict somatic maturity. However, prediction accuracy was not established in external samples. Thus, we aimed to evaluate the fit of these equations, assess for overfitting (adjusting as necessary), and calibrate using external samples. METHODS We evaluated potential overfitting using the original Pediatric Bone Mineral Accrual Study (PBMAS; 79 boys and 72 girls; 7.5-17.5 yr). We assessed change in R and standard error of the estimate (SEE) with the addition of predictor variables. We determined the effect of within-subject correlation using cluster-robust variance and fivefold random splitting followed by forward-stepwise regression. We used dominant predictors from these splits to assess predictive abilities of various models. We calibrated using participants from the Healthy Bones Study III (HBS-III; 42 boys and 39 girls; 8.9-18.9 yr) and Harpenden Growth Study (HGS; 38 boys and 32 girls; 6.5-19.1 yr). RESULTS Change in R and SEE was negligible when later predictors were added during step-by-step refitting of the original equations, suggesting overfitting. After redevelopment, new models included age × sitting height for boys (R, 0.91; SEE, 0.51) and age × height for girls (R, 0.90; SEE, 0.52). These models calibrated well in external samples; HBS boys: b0, 0.04 (0.05); b1, 0.98 (0.03); RMSE, 0.89; HBS girls: b0, 0.35 (0.04); b1, 1.01 (0.02); RMSE, 0.65; HGS boys: b0, -0.20 (0.02); b1, 1.02 (0.01); RMSE, 0.85; HGS girls: b0, -0.02 (0.03); b1, 0.97 (0.02); RMSE, 0.70; where b0 equals calibration intercept (standard error (SE)) and b1 equals calibration slope (SE), and RMSE equals root mean squared error (of prediction). We subsequently developed an age × height alternate for boys, allowing for predictions without sitting height. CONCLUSION Our equations provided good fits in external samples and provide an alternative to commonly used models. Original prediction equations were simplified with no meaningful increase in estimation error.

Botulinum toxin injection for management of thoracic outlet syndrome: A double-blind, randomized, controlled trial

Summary Botulinum toxin injections to the scalene muscles did not reduce pain in subjects with thoracic outlet syndrome in this double‐blind, randomized, controlled trial. ABSTRACT We studied the effect of botulinum toxin type A (BTX‐A) injections to the scalene muscles on pain in subjects with thoracic outlet syndrome (TOS) in this double‐blind, randomized, parallel group trial with follow‐up at 6 weeks, 3 months, and 6 months. Thirty‐eight patients referred to physiatrists for management of TOS with BTX‐A injection were included. One subject was lost to follow‐up and all other subjects completed the trial. A 75‐unit dose of BTX‐A reconstituted with 0.75 cc of normal saline was injected to the anterior scalene (37.5 units) and middle scalene (37.5 units) muscles using electromyographic guidance. The primary outcome measure was pain as measured on a horizontal visual analog scale (VAS) 6 weeks‐post‐injection. Secondary outcomes were paresthesias measured on a VAS and function measured with the Disabilities of the Arm, Shoulder and Hand (DASH) and Short‐form 36 (SF‐36) questionnaires. For the primary outcome measure of VAS scores for pain at 6 weeks, the difference in the means adjusted for baseline VAS scores between placebo and BTX‐A was 5.03 mm in favor of BTX‐A (95% confidence interval −15.7 to 5.7, P = .36). Changes in secondary outcome measures were also not statistically significant. We conclude that BTX‐A injections to the scalene muscles did not result in clinically or statistically significant improvements in pain, paresthesias, or function in this population of subjects with TOS.

Aerobic exercise and vascular cognitive impairment A randomized controlled trial

Objective: To assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). Methods: This was a proof-of-concept single-blind randomized controlled trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Primary outcomes assessed were general cognitive function (Alzheimers Disease Assessment Scale–Cognitive subscale [ADAS-Cog]), executive functions (Executive Interview [EXIT-25]), and activities of daily living (Alzheimers Disease Cooperative Study–Activities of Daily Living [ADCS-ADL]). Results: Seventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses (mean age 74 years, 51% female, n = 35 per group). At the end of the intervention, the aerobic exercise training group had significantly improved ADAS-Cog performance compared with the usual care plus education group (−1.71 point difference, 95% confidence interval [CI] −3.15 to −0.26, p = 0.02); however, this difference was not significant at the 6-month follow-up (−0.63 point difference, 95% CI −2.34 to 1.07, p = 0.46). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter difference, 95% CI 5.82 to 54.86, p = 0.02) and in diastolic blood pressure (−6.89 mm Hg difference, 95% CI −12.52 to −1.26, p = 0.02). Conclusions: This study provides preliminary evidence for the efficacy of 6 months of thrice-weekly progressive aerobic training in community-dwelling adults with mild SIVCI, relative to usual care plus education. ClinicalTrials.gov identifier: NCT01027858. Classification of evidence: This study provides Class II evidence that for adults with mild SIVCI, an aerobic exercise program for 6 months results in a small, significant improvement in ADAS-Cog performance.

Phase II study of hypofractionated image-guided radiotherapy for localized prostate cancer: Outcomes of 55 Gy in 16 fractions at 3.4 Gy per fraction ☆

PURPOSE To estimate the late morbidity of a novel, hypofractionated external beam radiotherapy schedule of 55 Gy in 16 fractions (4 fractions/week, 3.4 Gy per fraction) for localized prostate cancer. METHODS AND MATERIALS A multi-center phase 2 study enrolled seventy-three patients between September 2004 and June 2006. After insertion of fiducial gold markers, they were treated with image-guidance (IGRT) using conformal techniques with intensity-modulation, if necessary, and then followed every 6 months for toxicity rating and PSA. Patient reported outcomes were collected yearly. Median follow up was 4.6 years. RESULTS At 4 years post-radiotherapy, the cumulative incidence of combined urinary and bowel grade 3 toxicity was 7% (95% CI 3-16%) and grade 2+ was 33% (95% CI 24-46%). All except two patients recovered from their grade 3 events. Patient-reported reduction of function was most pronounced at year two for urinary function (mean -7, SD 16), and at year one for bowel function (mean -7, SD 21). The cumulative incidence of biochemical (PSA nadir+2) or biopsy-proven relapse at 4 years was 9% (95% CI 4-18%). CONCLUSIONS Hypofractionated radiotherapy is clinically feasible and more convenient than conventional schedules for patients with localized prostate cancer. Phase 3 multicenter studies are on-going (NCT00126165).

Using the relationship between brain tissue regional saturation of oxygen and mean arterial pressure to determine the optimal mean arterial pressure in patients following cardiac arrest: A pilot proof-of-concept study☆

INTRODUCTION Prospectively assess cerebral autoregulation and optimal mean arterial pressure (MAPOPT) using the dynamic relationship between MAP and regional saturation of oxygen (rSO2) using near-infrared spectroscopy. METHODS Feasibility study of twenty patients admitted to the intensive care unit following a cardiac arrest. All patients underwent continuous rSO2 monitoring using the INVOS(®) cerebral oximeter. ICM+(®) brain monitoring software calculates the cerebral oximetry index (COx) in real-time which is a moving Pearson correlation coefficient between 30 consecutive, 10-s averaged values of MAP and correspond rSO2 signals. When rSO2 increases with increasing MAP (COx ≥0.3), cerebral autoregulation is dysfunctional. Conversely, when rSO2 remains constant or decreases with increasing MAP (COx <0.3), autoregulation is preserved. ICM+(®) fits a U-shaped curve through the COx values plotted vs. MAP. The MAPOPT is nadir of this curve. RESULTS The median age was 59 years (IQR 54-67) and 7 of 20 were female. The cardiac arrest was caused by myocardial infarction in 12 (60%) patients. Nineteen arrests were witnessed and return of spontaneous circulation occurred in a median of 15.5min (IQR 8-33). Patients underwent a median of 30h (IQR 23-46) of monitoring. COx curves and MAPOPT were generated in all patients. The mean overall MAP and MAPOPT were 76mmHg (SD 10) and 76mmHg (SD 7), respectively. MAP was outside of 5mmHg from MAPOPT in 50% (SD 15) of the time. Out of the 7672 5-min averaged COx measurements, 1182 (15%) were at 0.3 or above, indicating absence of autoregulation. Multivariable polynomial fractional regression demonstrated an increase in COx with increasing temperature (P=0.008). CONCLUSIONS We demonstrated the feasibility to determine a MAPOPT using cerebral oximetry in patients after cardiac arrest.

Reexamining the Surfaces of Bone in Boys and Girls During Adolescent Growth: A 12-Year Mixed Longitudinal pQCT Study.

We revisit Stanley Garns theory related to sex differences in endocortical and periosteal apposition during adolescence using a 12‐year mixed longitudinal study design. We used peripheral quantitative computed tomography to examine bone parameters in 230 participants (110 boys, 120 girls; aged 11.0 years at baseline). We assessed total (Tt.Ar, mm2), cortical (Ct.Ar, mm2), and medullary canal area (Me.Ar, mm2), Ct.Ar/Tt.Ar, cortical bone mineral density (Ct.BMD, mg/cm3), and polar strength‐strain index (SSIp, mm3) at the tibial midshaft (50% site). We used annual measures of height and chronological age to identify age at peak height velocity (APHV) for each participant. We compared annual accrual rates of bone parameters between boys and girls, aligned on APHV using a linear mixed effects model. At APHV, boys demonstrated greater Tt.Ar (ratio = 1.27; 95% confidence interval [CI] 1.21, 1.32), Ct.Ar (1.24 [1.18, 1.30]), Me.Ar (1.31 [1.22, 1.40]), and SSIp (1.36 [1.28, 1.45]) and less Ct.Ar/Tt.Ar (0.98 [0.96, 1.00]) and Ct.BMD (0.97 [0.96, 0.97]) compared with girls. Boys and girls demonstrated periosteal bone formation and net bone loss at the endocortical surface. Compared with girls, boys demonstrated greater annual accrual rates pre‐APHV for Tt.Ar (1.18 [1.02, 1.34]) and Me.Ar (1.34 [1.11, 1.57]), lower annual accrual rates pre‐APHV for Ct.Ar/Tt.Ar (0.56 [0.29, 0.83]) and Ct.BMD (–0.07 [–0.17, 0.04]), and similar annual accrual rates pre‐APHV for Ct.Ar (1.10 [0.94, 1.26]) and SSIp (1.14 [0.98, 1.30]). Post‐APHV, boys demonstrated similar annual accrual rates for Ct.Ar/Tt.Ar (1.01 [0.71, 1.31]) and greater annual accrual rates for all other bone parameters compared with girls (ratio = 1.23 to 2.63; 95% CI 1.11 to 3.45). Our findings support those of Garn and others of accelerated periosteal apposition during adolescence, more evident in boys than girls. However, our findings challenge the notion of greater endocortical apposition in girls, suggesting instead that girls experience diminished endocortical resorption compared with boys.

Problems of multiplicity

RésuméNous avons présenté le pour et le contre de plusieurs procédures qui pourraient soigner la «maladie» des comparaisons multiples. Ces approches y parviennent néanmoins au prix d’une puissance réduite ou d’une taille d’échantillon accrue. La prévention dès la phase de conception d’une étude demeure, lorsqu’elle est possible, la meilleure tactique. Les objectifs primaires et secondaires devraient être soigneusement définis. En ce qui concerne les résultats mesurés à plusieurs points dans le temps, les aspects les plus pertinents des trajectoires de réponses (par exemple, l’aire sous la courbe) devraient être clairement identifiés. Dans les plans d’analyse statistique, il faudrait se concentrer davantage sur la description des caractéristiques clés des données en termes de pertinence clinique. Enfin, les chercheurs devraient résister à la tentation de coller l’étiquette du «statistiquement significatif» à chaque comparaison possible.

Post-discharge management following hip fracture - get you back to B4: A parallel group, randomized controlled trial study protocol

BackgroundFall-related hip fractures result in significant personal and societal consequences; importantly, up to half of older adults with hip fracture never regain their previous level of mobility. Strategies of follow-up care for older adults after fracture have improved investigation for osteoporosis; but managing bone health alone is not enough. Prevention of fractures requires management of both bone health and falls risk factors (including the contributing role of cognition, balance and continence) to improve outcomes.Methods/DesignThis is a parallel group, pragmatic randomized controlled trial to test the effectiveness of a post-fracture clinic compared with usual care on mobility for older adults following their hospitalization for hip fracture. Participants randomized to the intervention will attend a fracture follow-up clinic where a geriatrician and physiotherapist will assess and manage their mobility and other health issues. Depending on needs identified at the clinical assessment, participants may receive individualized and group-based outpatient physiotherapy, and a home exercise program. Our primary objective is to assess the effectiveness of a novel post-discharge fracture management strategy on the mobility of older adults after hip fracture.We will enrol 130 older adults (65 years+) who have sustained a hip fracture in the previous three months, and were admitted to hospital from home and are expected to be discharged home. We will exclude older adults who prior to the fracture were: unable to walk 10 meters; diagnosed with dementia and/or significant comorbidities that would preclude their participation in the clinical service.Eligible participants will be randomly assigned to the Intervention or Usual Care groups by remote allocation. Treatment allocation will be concealed; investigators, measurement team and primary data analysts will be blinded to group allocation. Our primary outcome is mobility, operationalized as the Short Physical Performance Battery at 12 months. Secondary outcomes include frailty, rehospitalizations, falls risk factors, quality of life, as well as physical activity and sedentary behaviour. We will conduct an economic evaluation to determine health related costs in the first year, and a process evaluation to ascertain the acceptance of the program by older adults, as well as clinicians and staff within the clinic.Trial registration numberClinicalTrials.gov: NCT01254942

Physical Activity Correlates with Arterial Stiffness in Community-dwelling Individuals with Stroke

BACKGROUND Physical inactivity contributes to atherosclerotic processes, which manifest as increased arterial stiffness. Arterial stiffness is associated with myocardial demand and coronary perfusion and is a risk factor for stroke and other adverse cardiac outcomes. Poststroke mobility limitations often lead to physical inactivity and sedentary behaviors. This exploratory study aimed to identify functional correlates, reflective of daily physical activity levels, with arterial stiffness in community-dwelling individuals >1 year poststroke. METHODS Carotid-femoral pulse wave velocity (cfPWV) was measured in 35 participants (65% men; mean ± SD age 66.9 ± 6.9 years; median time poststroke 3.7 years). Multivariable regression analyses examined the relationships between cfPWV and factors associated with daily physical activity: aerobic capacity (VO2 peak), gait speed, and balance ability (Berg Balance Scale). Age and the use of antihypertensive medications, known to be associated with pulse wave velocity, were also included in the model. RESULTS Mean cfPWV was 11.2 ± 2.4 m/s. VO2 peak and age were correlated with cfPWV (r = -0.45 [P = .006] and r = 0.46 [P = .004], respectively). In the multivariable regression analyses, age and the use of antihypertensive medication accounted for 20.4% of the variance of cfPWV, and the addition of VO2 peak explained an additional 4.5% of the variance (R2 = 0.249). CONCLUSIONS We found that arterial stiffness is elevated in community-dwelling, ambulatory individuals with stroke relative to healthy people. Multivariable regression analysis suggests that aerobic capacity (VO2 peak) may contribute to the variance of cfPWV after accounting for the effects of age and medication use. Whether intense risk modification and augmented physical activity will improve arterial stiffness in this population remains to be determined.