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Objectives To examine the efficacy of weekly and bi-weekly heat training to maintain heat acclimatization (HAz) and heat acclimation (HA) for 8 weeks in aerobically trained athletes. Design Randomized, between-group. Methods Twenty-four males (mean [m ± standard deviation [sd]; (age, 34 ± 12 y; body mass, 72.6 ± 8.8 kg, VO2peak, 57.7 ± 6.8 mL·kg-1·min-1) completed five trials (baseline, following HAz, following HA (HAz + HA), four weeks into heat training [HTWK4], and eight weeks into HT [HTWK8] that involved 60 min of steady-state exercise (59.1 ± 1.8% vVO2peak) in an environmental laboratory (wet bulb globe temperature [WBGT], 29.6 ± 1.4 °C) on a motorized treadmill. Throughout exercise, heart rate (HR) and rectal temperature (Trec) were recorded. Following HAz + HA, participants were assigned to three groups: control group (HT0), once per week heat training (HT1), and twice per week heat training (HT2). HT involved heated exercise (WBGT, 33.3 ± 1.3 °C) to achieve hyperthermia (38.5-39.75 °C) for 60 min. Repeated measures ANOVAs were used to determine differences. Results HAz + HA resulted in significant improvements in HR (p Conclusions Bi-weekly HT provided clear evidence for the ability to maintain physiological adaptions for 8 weeks following HA.

Background: The purpose of this study was to investigate effects of heat acclimatization (HAz) followed by heat acclimation (HA), and intermittent heat training (IHT) on time-trial performance. Hypothesis: Time-trial performance will improve after HA and will further improve with twice a week of IHT. Study Design: Interventional study. Level of Evidence: Level 3. Methods: A total of 26 male athletes (mean ± SD; age, 35 ± 12 years; body mass, 72.8 ± 8.9 kg; peak oxygen consumption [VO2peak], 57.3 ± 6.7 mL·kg−1·min−1) completed five 4-km time trials (baseline, post-HAz, post-HA, post-IHT4, post-IHT8) in the heat (ambient temperature, 35.4°C ± 0.3°C; relative humidity, 46.7% ± 1.2%) on a motorized treadmill. After baseline time trial, participants performed HAz (109 ± 10 days) followed by post-HAz time trial. Then, participants completed 5 days of HA, which involved exercising to induce hyperthermia (38.50°C-39.75°C) for 60 minutes. Participants were then divided into 3 groups and completed IHT either twice per week (IHTMAX), once per week (IHTMIN), or not at all (IHTCON) over an 8-week period. The exercise used for the IHT matched the HA. Four-kilometer time trials were performed after 4 weeks (post-IHT4) and 8 weeks of IHT (post-IHT8). Results: Time trial was faster in post-HA (17.98 ± 2.51 minutes) compared with baseline (18.61 ± 3.06 minutes; P = 0.037) and post-HAz (18.66 ± 3.12 minutes; P = 0.023). Percentage change in time trial was faster in IHTMAX (−3.9% ± 5.2%) compared with IHTCON (11.5% ± 16.9%) ( P = 0.020) and approached statistical significance with large effect (effect size = 0.96) compared with IHTMIN (1.6% ± 6.2%; P = 0.059) at post-IHT8. Additionally, IHTMAX (−2.2% ± 4.2%) was faster than IHTCON (3.6% ± 6.9%) ( P = 0.05) at post-IHT4. Conclusion: These results indicate that HA after HAz induces additional improvement in time-trial performance. IHT twice per week shows improvement after 8 weeks, while once per week maintains performance for 8 weeks. No IHT results in a loss of adaptations after 4 weeks and even greater losses after 8 weeks. Clinical Relevance: HA after HAz improves time-trial performance, twice a week of IHT improves performance further, and once a week of IHT maintains performance for at least 8 weeks.

This study used a spina bifida electronic medical record and the National Spina Bifida Patient Registry to explore the relationship between neurosurgical/orthopedic surgeries and other variables on ambulation and transfer ability over time in individuals with spina bifida.This study was an analysis of longitudinal data collected within the National Spina Bifida Patient Registry and spina bifida electronic medical record. Logistic regression models were used to determine which variables were associated with ambulation/transfer ability in the myelomeningocele (MMC) and non-MMC populations.Longitudinal data from 806 individuals were collected. In the MMC group, decreased ambulation ability was associated with higher motor levels, tethered cord releases, spine/scoliosis surgeries, hip orthopedic surgeries, and having supplemental insurance. Increased ambulatory ability was associated with lower motor levels, tibial torsion/related surgeries, ankle/foot surgeries, being female, and being non-Hispanic/Latinx. Decreased transfer ability was associated with being Hispanic/Latinx and having higher motor levels. Lower motor level and ankle/foot surgeries were associated with increased transfer ability. No significant associations were found in the non-MMC group.Motor level is an important predictor of ambulation and transfer ability in MMC. Surgeries distal to the knee were associated with higher levels of function; surgeries proximal to the knee were associated with lower functional levels.

The purpose of this study was to examine the effect of heat acclimation (HA) on thirst levels, sweat rate, and percentage of body mass loss (%BML), and changes in fluid intake factors throughout HA induction. Twenty-eight male endurance athletes (mean ± SD; age, 35 ± 12 years; body mass, 73.0 ± 8.9 kg; maximal oxygen consumption, 57.4 ± 6.8 ml·kg−1·min−1) completed 60 min of exercise in a euhydrated state at 58.9 ± 2.3% velocity of maximal oxygen consumption in the heat (ambient temperature, 35.0 ± 1.3 °C; relative humidity, 48.0 ± 1.3%) prior to and following HA where thirst levels, sweat rate, and %BML were measured. Then, participants performed 5 days of HA while held at hyperthermia (38.50–39.75 °C) for 60 min with fluid provided ad libitum. Sweat volume, %BML, thirst levels, and fluid intake were measured for each session. Thirst levels were significantly lower following HA (pre, 4 ± 1; post, 3 ± 1, p p = .039) and %BML (pre, 2.66 ± 0.53%; post, 2.98 ± 0.83%, p = .049) were significantly greater following HA. During HA, thirst levels decreased (Day 1, 4 ± 1; Day 2, 3 ± 2; Day 3, 3 ± 2; Day 4, 3 ± 1; Day 5, 3 ± 1; p p = .010) and fluid intake (Day 1, 1.20 ± 0.45 L; Day 2, 1.52 ± 0.58 L; Day 3, 1.69 ± 0.63 L; Day 4, 1.65 ± 0.58 L; Day 5, 1.74 ± 0.51 L; p

Background: Multiteam, multi-institution prospective studies of both women’s and men’s sports are essential for collectively investigating injury and primary to the generalization and individualization of injury prevention strategies. Hypothesis: Characteristics of workload, sleep, and contextual factors will be associated with injury risk in collegiate soccer athletes. Study Design: Cohort study; Level of evidence, 2. Methods: Injuries, workload, and sleep characteristics were recorded daily throughout a complete season for 256 athletes from 12 separate National Collegiate Athletic Association Division I men’s and women’s soccer teams. Workload and contextual factors were assessed via multilevel Poisson regression to capture differences in injury incidence rate ratio (IRR). Paired t test and multilevel logistic regressions were used to assess the relationship between sleep behavior and injury. Results: Collegiate soccer athletes had lower rates of noncontact injury in the in-season (IRR, 0.42) and postseason (IRR, 0.48) compared with preseason, lower rates of injury in training (IRR, 0.64) compared with matches, and higher injury rates with only 1 day of rest in the previous week (IRR, 1.58) compared with >1 day. Injury rates peaked when training occurred 4 days before a match (IRR, 2.24) compared with a match. Injury rate increased exponentially with increases in the number of noncontact injuries incurred throughout the season (IRR, 2.23). Lower chronic loading, higher training monotony, and acute spikes and lulls in workload were associated with higher noncontact injury rates. Alterations in previous week sleep quality were associated with injury, while chronic sleep behavior and acute alterations ( .05). Conclusion: Athlete and schedule-specific contextual factors, combined with characteristics of workload and weekly sleep behavior, are significantly associated with injury in collegiate soccer. Multiteam prospective cohort studies involving objective and subjective monitoring allow for the identification of multiple injury risk factors in sports, which can be used to guide injury prevention strategies. Maintaining higher chronic workloads, lowering training monotony, minimizing acute spikes or lulls in workloads, managing workloads during preseason and for athletes with previous injury, integrating more rest and recovery during congested periods, and optimizing sleep quality are all practical considerations for reducing injury risk in collegiate soccer.

Objectives To assess the effects of hydration status and ice-water dousing on physiological and performance parameters. Design Randomized, crossover. Methods Twelve athletes (mean[M] ± standard deviation[SD]; age, 20 ± 1 years; height, 174 ± 8 cm; body mass, 72.1 ± 11.0 kg; VO2max 53.9 ± 7.3 mL⋅kg−1⋅min−1) completed four trials (euhydrated without dousing, hypohydrated without dousing, euhydrated with dousing, and hypohydrated with dousing), which involved intermittent treadmill running (five 15-minute bouts) in the heat (M ± SD; ambient temperature, 34.7 ± 2.1 °C; relative humidity, 46 ± 3%; wet-bulb globe temperature, 28.0 ± 0.4 °C). Participants also completed four cognitive, power, agility, reaction time, and repeated sprint performance tests throughout each trial. Heart rate (HR) and rectal temperature (Trec) were measured continuously. Repeated measures ANOVAs were performed to assess differences between physiological and performance variables. Alpha was set at ≤0.05, a priori. Data are reported as mean difference ± standard error (MD ± SE). Results HR was significantly lower in euhydrated trials compared to hypohydrated trials, irrespective of dousing (8 ± 2 bpm; p = 0.001). Dousing did not significantly impact HR (p = 0.455) and there was no interaction between hydration and dousing (p = 0.893). Trec was significantly lower in euhydrated trials compared to hypohydrated trials (0.39 ± 0.05 °C, p Conclusions Athletes should aim to maintain euhydration during exercise in the heat for improved physiological function and cooling with ice-water dousing elicits additional performance benefits.

Assessing the adaptation of rectal temperature (Trec) is critical following heat acclimatization (HAz) and heat acclimation (HA) because it is associated with exercise performance and safety; however, more feasible and valid methods need to be identified. The purpose of this study was to predict adaptations in Trec from heart rate (HR), sweat rate (SR), and thermal sensation (TS) using predictive modeling techniques. Twenty-five male endurance athletes (age, 36 ± 12 y; VO2max, 57.5 ± 7.0 mL⋅kg−1⋅min−1) completed three trials consisting of 60 min running at 59.3 ± 1.7% vVO2max in a hot environment. During trials, the highest HR and TS, SR, and Trec at the end of trials were recorded. Following a baseline trial, participants performed HAz followed by a post-HAz trial and then completed five days HA, followed by a post-HA trial. A decision tree indicated cut-points of HR (0.3 L·h−1), and TS (≤−0.5) to predict lower Trec. When two or three variables met cut-points, the probability of accuracy of showing lower Trec was 95.7%. Greater adaptations in Trec were observed when two or three variables met cut-points (−0.71 ± 0.50 °C) compared to one (−0.13 ± 0.36 °C, p < 0.001) or zero (0.0 3 ± 0.38 °C, p < 0.001). Specificity was 0.96 when two or three variables met cut-points to predict lower Trec. These results suggest using heart rate, sweat rate, and thermal sensation adaptations to indicate that the adaptations in Trec is beneficial following heat adaptations, especially in field settings, as a practical and noninvasive method.

Sekiguchi, Y, Curtis, RM, Huggins, RA, Benjamin, CL, Walker, AJ, Arent, SM, Adams, WM, Anderson, T, and Casa, DJ. The relationships between perceived wellness of, sleep of, and acute: chronic training load on National Collegiate Athletics Association division I male soccer players. J Strength Cond Res XX(X): 000-000, 2021-The purpose of this study was to investigate relationships between perceived wellness, sleep, and acute: chronic workload ratio (ACWR) throughout a collegiate men's soccer season. Sixty male collegiate soccer players (mean[M] ± SD; age, 21±2 year; body mass, 77.6 ± 6.5 kg; height, 180.1 ± 6.4 cm; body fat%, 9.9 ± 3.9% ; and V[Combining Dot Above]O2max, 53.1 ± 5.0 ml·kg-1·min-1) participated in this study. During each session, players used a heart rate and global positioning satellite-enabled chest strap to measure training impulse and ACWR. The ACWR values were trichotomized at the individual level giving an equal number of observations within each ACWR category of low, moderate, and high ACWR (M ± SD; low, 0.658 ± 0.23; moderate, 0.92 ± 0.15; and high, 1.17 ± 0.16). Stress, fatigue, and soreness levels were collected using 1-10 Likert scales and sleep duration, and sleep quality were measured by the Karolinska Sleep Diary. Stress, fatigue, soreness levels, and sleep quality were transformed to corresponding z-scores at the individual level. Fatigue levels were significantly higher when ACWR was high compared with low (mean difference [95% confidence intervals], effect size, p-value; 0.31 [0.21, 0.42], 0.29, p < 0.001) and moderate (0.14 [0.03, 0.24], 0.13, p = 0.01). Fatigue levels were also significantly higher when the ACWR was moderate compared with low (0.18 [0.07, 0.28], 0.16, p = 0.001). Soreness levels were significantly higher when the ACWR was high compared with low (0.25 [0.14, 0.36], 0.23, p < 0.001). Stress levels were significantly greater when the ACWR was high compared with low (0.19, [0.08, 0.29], 0.18, p < 0.001) and compared with moderate (0.15, [0.05, 0.25], 0.14, p = 0.004). There were no differences in sleep duration or sleep quality in different ACWR. The ACWR may be a useful tool to achieve an appropriate balance between training and recovery to manage daily fatigue and soreness levels in athletes.

Clinical Scenario: Exercise in the heat can lead to performance decrements and increase the risk of heat illness. Heat acclimation refers to the systematic and gradual increase in exercise in a controlled, laboratory environment. Increased duration and intensity of exercise in the heat positively affects physiological responses, such as higher sweat rate, plasma volume expansion, decreased heart rate, and lower internal body temperature. Many heat acclimation studies have examined the hydration status of the subjects exercising in the heat. Some of the physiological responses that are desired to elicit heat acclimation (ie, higher heart rate and internal body temperature) are exacerbated in a dehydrated state. Thus, euhydration (optimal hydration) and dehydration trials during heat acclimation induction have been conducted to determine if there are additional benefits to dehydrated exercise trials on physiological adaptations. However, there is still much debate over hydration status and its effect on heat acclimation. Clinical Question: Does dehydration affect the adaptations of plasma volume, heart rate, internal body temperature, skin temperature, and sweat rate during the induction phase of heat acclimation? Summary of Findings: There were no observed differences in plasma volume, internal body temperature, and skin temperature following heat acclimation in this critically appraised topic. One study found an increase in sweat rate and another study indicated greater changes in heart rate following heat acclimation with dehydration. Aside from these findings, all 4 trials did not observe statistically significant differences in euhydrated and dehydrated heat acclimation trials. Clinical Bottom Line: There is minimal evidence to suggest that hydration status affects heat acclimation induction. In the studies that met the inclusion criteria, there were no differences in plasma volume concentrations, internal body temperature, and skin temperature. Strength of Recommendation: Based on the Oxford Centre for Evidence-Based Medicine Scale, Level 2 evidence exists.

Associations between cleaning chemical exposures and asthma have previously been identified in professional cleaners and healthcare workers. Domestic workers, including housecleaners and caregivers, may receive similar exposures but in residential environments with lower ventilation rates. Study objectives were to compare exposures to occupational exposure limits (OELs), to determine relative contributions from individual cleaning tasks to overall exposure, and to evaluate the effects of ventilation and posture on exposure. Airborne chemical concentrations of sprayed cleaning chemicals (acetic acid or ammonia) were measured during typical cleaning tasks in a simulated residential work environment. Whole-house cleaning exposures (18 cleaning tasks) were measured using integrated personal sampling methods. Individual task exposures were measured with a sampling line attached to subjects' breathing zones, with readings recorded by a ppbRAE monitor, equipped with a photoionization detector calibrated for ammonia and acetic acid measurements. Integrated sampling results indicated no exposures above OELs occurred, but 95th percentile air concentrations would require risk management decisions. Exposure reductions were observed with increased source distance, with lower exposures from mopping floors compared to kneeling. Exposure reductions were also observed for most but not all tasks when ventilation was used, with implications that alternative exposure reduction methods may be needed.

The purpose of this study was to assess the effect of two fluid intake protocols on alertness and reaction time before and after fluid intake. Healthy college-age males (n = 12) followed two fluid intake protocols on separate occasions: (1) prescribed fluid (PF) and fluid restricted (FR). In PF, participants were instructed to consume 500 mL of fluid the night prior to and the morning of data collection. In FR, participants were instructed to refrain from the consumption of fluid for 12 h. To assess hydration status, urine specific gravity and urine color were measured. Participants perceived level of thirst and alertness were also recorded. Participants then completed visuomotor reaction time tests using the Dynavision LED board, using both a central visuomotor test and a peripheral visuomotor test (PVRT) prior to (1) and following (2) the ingestion of 100 mL of water. Participants displayed significantly improved PVRT in PF state as compared to FR (PF1 = 1.13 ± 0.16, PF2 = 1.04 ± 0.14; FR1 = 1.27 ± 0.27, FR2 = 1.18 ± 0.20; p = 0.038, ηp2 = 0.363). Both CVRT and PVRT improved over time, following the ingestion of 100 mL of fluid. Participants in the PF state were also significantly more alert than participants in the FR state (PF = 4 ± 2, FR = 5 ± 2; p = 0.019, ES = 0.839). Collectively, perceived alertness and PVRT were negatively impacted by FR.

Cytomegalovirus (CMV) is the most common viral infection in hematopoietic cell transplantation (HCT) recipients. We performed deep phenotyping of CMV-specific T cells to predict CMV outcomes following allogeneic HCT. By using 13-color flow cytometry, we studied ex vivo CD8+ T-cell cytokine production in response to CMV-pp65 peptides in 3 clinically distinct subgroups of CMV-seropositive HCT patients: (1) Elite Controllers (n = 19): did not have evidence of CMV DNAemia on surveillance testing; (2) Spontaneous Controllers (n = 16): spontaneously resolved low-grade CMV DNAemia without antiviral therapy; and (3) Noncontrollers (NC; n = 21): experienced clinically significant CMV. Two CMV-specific CD8+ T-cell functional subsets were strongly associated with risk of CMV: (i) the nonprotective signature (NPS; IL-2−IFN-γ+TNF-α−MIP-1β+), found at increased levels among NC; and (ii) the protective signature (PS; IL-2+IFN-γ+TNF-α+MIP-1β+) found at low levels among NC. High levels of the NPS and low levels of PS were associated with an increased 100-day cumulative incidence of clinically significant CMV infection (35% vs 5%; P = .02; and 40% vs 12%; P = .05, respectively). The highest predictive value was observed when these signatures were combined into a composite biomarker consisting of low levels of the PS and high levels of the NPS (67% vs 10%; P < .001). After adjusting for steroid use or donor type, this composite biomarker remained associated with a fivefold increase in the risk of clinically significant CMV infection. CMV-specific CD8+ T-cell cytokine signatures with robust predictive value for risk of CMV reactivation should prove useful in guiding clinical decision making in HCT recipients.

The purpose of this study was to assess the effectiveness of heat acclimatization (HAz) followed by heat acclimation (HA) on physiological adaptations. 25 male endurance athletes (age 36 ± 12 y, height 178.8 ± 6.39 cm, body mass 73.03 ± 8.97 kg, and VO2peak 57.5 ± 7.0 mL·kg−1·min−1) completed HAz and HA. HAz was 3 months of self-directed summer training. In the laboratory, a 5-day HA prescribed exercise to target a hyperthermic zone (HZHA) of Trec between 38.50 and 39.75 °C for 60 min. Exercise trials were 60 min of running (59% ± 2% VO2peak) in an environmental chamber (wet bulb globe temperature 29.53 ± 0.63 °C) and administered at: baseline, post-HAz, and post-HAz+HA. Measured variables included internal body temperature (Trec), heart rate (HR), and sweat rate (SR). Repeated measure ANOVAs and post hoc comparisons were used to assess statistically significant (p &lt, 0.05) differences. Trec was lower post-HAz+HA (38.03 ± 0.39 °C) than post-HAz (38.25 ± 0.42 °C, p = 0.009) and baseline (38.29 ± 0.37 °C, p = 0.005). There were no differences between baseline and post-HAz (p = 0.479) in Trec. HR was lower post-HAz (143 ± 12 bpm, p = 0.002) and post-HAz+HA (134 ± 11 bpm, p &lt, 0.001) than baseline (138 ± 14 bpm). HR was lower post-HAz+HA than post-HAz (p = 0.013). SR was higher post-HAz+HA (1.93 ± 0.47 L·h−1) than post-HAz (1.76 ± 0.43 L·h−1, p = 0.027). Combination HAz and HA increased physiological outcomes above HAz. This method can be used to improve performance and safety in addition to HAz alone.

The purpose of this study was to examine the changes in metabolic heat production (Hprod), evaporative heat loss (Hevap), and dry heat loss (Hdry), following heat acclimatization (HAz) and heat acclimation (HA). Twenty-two male endurance athletes (mean ± standard deviation; age, 37 ± 12 y; body mass, 73.4 ± 8.7 kg; height, 178.7 ± 6.8 cm; and VO2max, 57.1 ± 7.2 mL·kg−1·min−1) completed three trials (baseline; post-HAz; and post-HA), which consisted of 60 min steady state exercise at 59 ± 2% velocityVO2max in the heat (ambient temperature [Tamb], 35.2 ± 0.6 °C; relative humidity [%rh] 47.5 ± 0.4%). During the trial, VO2 and RER were collected to calculate Hprod, Hevap, and Hdry. Following the baseline trial, participants completed self-directed outdoor summer training followed by a post-HAz trial. Then, five days of HA were completed over eight days in the heat (Tamb, 38.7 ± 1.1 °C; %rh, 51.2 ± 2.3%). During the HA sessions, participants exercised to maintain hyperthermia (38.50 °C and 39.75 °C) for 60 min. Then, a post-HA trial was performed. There were no differences in Hprod between the baseline (459 ± 59 W·m−2), post-HAz (460 ± 61 W·m−2), and post-HA (464 ± 55 W·m−2, p = 0.866). However, Hevap was significantly increased post-HA (385 ± 84 W·m−2) compared to post-HAz (342 ± 86 W·m−2, p = 0.043) and the baseline (332 ± 77 W·m−2, p = 0.037). Additionally, Hdry was significantly lower at post-HAz (125 ± 8 W·m−2, p = 0.013) and post-HA (121 ± 10 W·m−2, p < 0.001) compared to the baseline (128 ± 7 W·m−2). Hdry at post-HA was also lower than post-HAz (p = 0.049). Hprod did not change following HAz and HA. While Hdry was decreased following HA, the decrease in Hdry was smaller than the increases in Hevap. Adaptations in body heat exchange can occur by HA following HAz.

Huggins, RA, Giersch, GEW, Belval, LN, Benjamin, CL, Curtis, RM, Sekiguchi, Y, Peltonen, J, and Casa, DJ. The validity and reliability of GPS units for measuring distance and velocity during linear and team sport simulated movements. J Strength Cond Res 34(11): 3070-3077, 2020-This experimental study aimed to assess the validity and reliability of shirt-mounted 10-Hz global positioning system (GPS) units (Polar Team Pro) for measuring total distance (TD), constant velocity (VelC), and instantaneous velocity (VelI) during linear running and a team sport simulation circuit (TSSC). Fifteen male soccer athletes completed linear tasks (40 and 100 m) at various velocities: walk (W) (4.8-7.9 km·h), jog (J) (8.0-12.7 km·h), run (R) (12.9-19.9 km·h), and sprint (S) (20.0 km·h) and a 120-m TSSC. Global positioning system validity and reliability for TD, VelC, and VelI were compared with criterion measures using 2 methods (a and b) of GPS raw data extraction. When measuring TD for the Polar Team Pro device, validity and reliability measures were5% error at all velocities during the 40-m (with the exception of the S [%CV = 8.03]) and 100-m linear trial (both extraction methods) and TSSC. The GPS mean difference (±SD) for TD during the TSSC using extraction methods (a) and (b) was 0.2 ± 1.2 and 2.2 ± 2.2 m, respectively. The validity of the device in measuring VelC was significantly different (p0.05) at all velocities during the 40 m (exception W) and the 100 m, with effect sizes ranging from trivial to small (exception of 100 m S). VelI was similar (p0.05) at all velocities, except for the W (p = 0.001). The reliability of the device when measuring VelC during the 40 and 100 m was5% CV; however, during the 100 m, VelI ranged from 1.4 to 12.9%. Despite trivial to large effect sizes for validity of TD, this device demonstrated good reliability5% CV during linear and TSSC movements. Similarly, effect sizes ranged from trivial to large for VelC, and yet VelI reliability was good for VelC, but good to poor for VelI.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited cardiomyopathy characterised by right ventricular dysfunction, ventricular arrhythmias and increased risk of sudden cardiac death. Due to the replacement of myocardium with fibro-fatty and fibrous tissue, patients with ARVC are prone to develop ventricular tachycardia. Histologically, it is often reported as the 'triangle of dysplasia' involving the inflow tract, outflow tract and apex of the right ventricle.2 We describe a 20-years-old patient who collapsed during a futsal match and was subsequently diagnosed to have ARVC with a right ventricular thrombus from cardiac magnetic resonance imaging.

Complete biliary occlusions at different anatomic locations that are not amenable to surgical, endoscopic, or routine percutaneous methods pose a challenge to physicians. Biliary ductal neoanastomosis technique can play a very important role in solving such clinical problems. Between October 2004 and January 2018, six patients were treated in our institution for biliary drainage using biliary ductal neoanastomosis technique via sharp recanalization and a staged approach to achieve internal/external biliary drainage. All procedures were performed in an angiography suite by an interventional radiologist after multidisciplinary discussion. The mean patient age of the cohort was 54 years and 50% of the patients were female (three/six patients). The cause of obstruction was complications or disease progression after Whipple procedure in four patients, partial hepatectomy in one patient and benign biliary stricture after radioembolization in one patient. All patients were treated with percutaneous biliary neoanastomosis. All procedures were successfully performed in all six patients (100% technical success) without any major complications. All patients were successfully managed by capped drainage catheters for the duration of the follow up (one patient was transitioned to endoscopically inserted biliary stent, and in one patient the tube was eventually removed after establishment of patent neoanastomosis). Biliary ductal neoanastomosis is an effective treatment option when the anatomy has been significantly altered in the post-surgical setting and wire cannot be safely passed into target draining organ or the remainder of biliary system. When performed by an experienced operator, this technique is safe and effective with a high technical success rate.

Interventional radiology is a constantly evolving specialty overlapping with multiple other specialties, including cardiology, vascular surgery, orthopedic surgery, urology, and minimally invasive surgery. Unique ergonomic considerations for interventional radiology include utilization of intraoperative viewing monitors and personal radiation protection equipment. Work-related injuries are common in interventional radiologists,1 often leading to pain while performing procedures or during time away from work. This review article aims to identify the ergonomic challenges related to interventional radiology and provide background, guidelines, and specific recommendations for prevention of musculoskeletal injury.

The aim of this study was to estimate the cost-of-illness associated with completely resected stage IIIB/IIIC melanoma with macroscopic lymph node involvement, overall and by disease phase, in France, Germany and the UK. This retrospective observational study included patients aged older than or equal to 18 years first diagnosed with stage IIIB/IIIC cutaneous melanoma between 1 January 2009 and 31 December 2011. Data were obtained from medical records and a patient survey. Direct costs, indirect costs and patient out-of-pocket expenses were estimated in euros (€) (and British pounds, £) by collecting resource use and multiplying by country-specific unit costs. National annual costs were estimated using national disease prevalence from the European cancer registry and other published data. Forty-nine centres provided data on 558 patients (58.2% aged65 years, 53.6% stage IIIB disease at diagnosis). The mean follow-up duration was 27 months (France), 26 months (Germany) and 22 months (UK). The mean total direct cost per patient during follow-up was €23 582 in France, €32 058 in Germany and €37 970 (£31 123) in the UK. The largest cost drivers were melanoma drugs [mean €14 004, €21 269, €29 750 (£24 385), respectively] and hospitalization/emergency treatment [mean: €6634, €6950, €3449 (£2827), respectively]. The total mean indirect costs per patient were €129 (France), €4,441 (Germany) and €1712 (£1427) (UK). Estimates for annual national direct cost were €13.1 million (France), €30.2 million (Germany) and €27.8 (£22.8) million (UK). The economic burden of stage IIIB/IIIC melanoma with macroscopic lymph node involvement was substantial in all three countries. Total direct costs were the highest during the period with distant metastasis/terminal illness.

Background Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals. Objective To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials. Good Practices for Outcomes Research This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition’s natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient’s perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use. Conclusions This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.

Benjamin, CL, Hosokawa, Y, Curtis, RM, Schaefer, DA, Bergin, RT, Abegg, MR, and Casa, DJ. Environmental conditions, preseason fitness levels, and game workload: Analysis of a female NCAA DI National Championship Soccer Season. J Strength Cond Res 34(4): 988-994, 2020-The purpose of this study was to determine the independent and combined moderating effect of aerobic fitness and environmental conditions on physical workloads during collegiate female soccer matches. Nineteen National Collegiate Athletic Association female soccer athletes were included in this study (mean ± SD: age, 20.6 ± 1.4 years; height, 169 ± 6.1 cm; body mass 64.7 ± 5.3 kg). Maximal oxygen consumption (V[Combining Dot Above]O2max) was estimated from the yo-yo intermittent recovery test before preseason training and wet-bulb globe temperature (WBGT) was recorded onsite for home matches and at the nearest weather station for away matches. Relative distance (TD), relative high-speed running distance (%HSD), and relative high metabolic load (%HML) performance were collected during each match using a global positioning system unit (Viper Pod; STATSports, Chicago, IL). Statistically significant differences were observed in TD between LOW WBGT and MOD WBGT (mean difference [MD] = 7.08 m·min; effect size [ES] = 0.54; p < 0.001), in %HSD between LOW WBGT and MOD WBGT (MD = 1.97%; ES = 0.64; p = 0.01) and between LOW WBGT and HIGH WBGT (MD = 2.71%; ES = 1.01; p < 0.001), and in %HML between LOW WBGT and MOD WBGT (MD = 1.24%; ES = 0.56; p < 0.001) and between LOW WBGT and HIGH WBGT (MD = 1.55%; ES = 0.78; p = 0.01). There was a significant interaction between WBGT and V[Combining Dot Above]O2max for %HSD (p = 0.03). These findings demonstrate that physical performance metrics were affected by increased WBGT. In addition, aerobic fitness seemed to moderate the effect of increasing WBGT on %HSD, meaning maximizing aerobic capacity is important for optimizing running performance in the heat. Coaches and sports medicine staff could alter training time and session length based on environmental conditions as well as potentially use aggressive cooling strategies to mitigate the imposed heat stress and decrements in physical performance.

PURPOSE: To evaluate the influence of recall periods on the assessment of physical function, we compared, in cancer and general population samples, the standard administration of PROMIS Physical Function items without a recall period to administrations with 24-hour and 7-day recall periods. METHODS: We administered 31 items from the PROMIS Physical Function v2.0 item bank to 2400 respondents (n = 1001 with cancer; n = 1399 from the general population). Respondents were randomly assigned to one of three recall conditions (no recall, 24-hours, or 7-days) and one of two “reminder” conditions (with recall periods presented only at the start of the survey or with every item). We assessed items for potential differential item functioning (DIF) by recall time period. We then tested recall and reminder effects with analysis of variance controlling for demographics, English fluency, and co-morbidities. RESULTS: Based on conservative pre-set criteria, no items were flagged for recall time period-related DIF. Using analysis of variance, each condition was compared to the standard PROMIS administration for Physical Function (no recall period). There was no evidence of significant differences among groups in the cancer sample. In the general population sample, only the 24-hour recall condition with reminders was significantly different from the “no recall” PROMIS standard. At the item level, for both samples, the number of items with non-trivial effect size differences across conditions was minimal. CONCLUSIONS: Compared to no recall, the use of a recall period has little to no effect upon PROMIS physical function responses or scores. We recommend that PROMIS Physical Function be administered with the standard PROMIS “no recall” period.

Curtis, RM, Huggins, RA, Benjamin, CL, Sekiguchi, Y, Adams, WM, Arent, SM, Jain, R, Miller, SJ, Walker, AJ, and Casa, DJ. Contextual factors influencing external and internal training loads in collegiate men's soccer. J Strength Cond Res 34(2): 374-381, 2020-This study investigated factors influencing training loads (TL) in collegiate men's soccer. Total distance, high-speed running distance (14.4 km·h), high-intensity heart-rate zone duration (HI HRZ,70% heart rate relative to maximum), and session rating of perceived exertion were assessed daily from 107 male soccer players competing for 5 National Collegiate Athletics Association Division I teams. Differences between athlete role (starter and reserve), position (defender, midfielder, and forward), season phase (preseason, in-season, and postseason), days relative to match (MD-1 to MD-5+), days between matches (4, 4-5,5 days), previous match outcome (win, loss, and draw), and upcoming opponent relative ranking (weaker, trivial, and stronger) were examined. Mean differences (MD) and effect sizes (ESs) with 90% confidence intervals were reported. There were trivial and insignificant differences by player role, position, or upcoming opponent strength, and small-moderate increases in preseason TL compared with in-season (ES [range] = 0.4-0.9). TLs were lower for MD-1 and higher for MD-5+ (ES [range] = 0.4-1.3) when compared with MD-2-4. External loads (ES = -0.40 ± 0.20) were less after wins compared with losses. TLs are increased in the preseason, when training sessions occur greater than 5 days from a match and after losses. Contextualizing factors affecting TLs has implications for developing workload prescription and recovery strategies.

Background: Plastic bronchitis is a dreaded complication of single ventricle physiology occurring following palliation via Fontan procedure. Medical management of plastic bronchitis often fails, requiring heart transplantation. Percutaneous lymphatic embolization is an emerging treatment for plastic bronchitis. Methods: To determine the cost-effectiveness of competing management strategies, a modified Markov model was constructed with patients transiting through treatments—medical management, lymphatic embolization, or heart transplantation from a hospital system perspective. Health state transitions were modeled using an institutional review board–approved retrospective review of the Children’s Hospital of Pennsylvania’s plastic bronchitis cohort. Medication pricing data were obtained from the National Inpatient Sample. Differences in costs and quality-adjusted life years (QALYs) over a five-year horizon for each group were determined. The incremental cost-effectiveness ratio was then calculated. Results: The mean cost of lymphatic embolization from procedure performance was US$340,941, US$385,841 for heart transplantation, and US$594,520 for medical management. The mean quality-adjusted survival of lymphatic embolization yielded an additional 0.66 QALYs ( P < .03) relative to heart transplantation and 1.3 ( P < .0001) relative to medical management. Orthotopic heart transplantation yielded an additional 0.66 QALYs ( P = .06) when comparing heart transplantation to medical management. Compared to medical management, lymphatic embolization generated an incremental cost-effectiveness ratio of US$192,105. Similarly, compared to heart transplantation, lymphatic embolization yielded an incremental cost-effectiveness ratio of US$68,030. Conclusions: Of the available plastic bronchitis treatments, with a willingness to pay of US$150,000, lymphatic embolization produces an incremental cost-effectiveness ratio within the bounds considered to be cost-effective, potentially causing financial benefits to the health system.

Even though sleep has been shown to be influenced by athletes’ training status, the association with resting heart rate and heart rate variability remains unclear. The purpose of this study was to compare the changes in and relationships between resting heart rate, heart rate variability and sleep characteristics across a female collegiate cross-country season. Ten NCAA Division I collegiate female cross-country athletes (mean ± SD; age, 19 ± 1 year; height, 167.6 ± 7.6 cm; body mass, 57.7 ± 10.2 kg; VO2max, 53.3 ± 5.9 ml kg-1 min-1) participated in this study. Resting heart rate, heart rate variability and the percentage of time in slow wave sleep were captured using a wrist-worn multisensor sleep device throughout the 2016 competitive cross-country season (12 weeks). Linear mixed-effects models and magnitude-based inferences were used to assess differences between each week. Pearson product moment correlations were used to investigate relationships between variables. Resting heart rate at the end of the season, specifically during weeks 10–12 (mean ± SE; week 10, 48 ± 2; week 11, 48 ± 3; week 12, 48 ± 3), showed a practically meaningful increase compared to the beginning of the season, weeks 2–4 (week 2, 44 ± 2; week 3, 45 ± 2; week 4, 44 ± 2). Higher resting heart rate (r = 0.55) and lower heart rate variability (r = -0.62) were largely associated with an increase in percentage of time spent in slow wave sleep. These data suggest that when physiological state was impaired, meaning the physiological restorative demand was higher, the percentage of time in slow wave sleep was increased to ensure recovery. Thus, it is important to implement sleep hygiene strategies to promote adequate slow wave sleep when the body needs physiological restoration.

Euhydration remains a challenge in children due to lack of access and unpalatability of water and to other reasons. The purpose of this study was to determine if the availability/access to a beverage (Creative Roots®) influences hydration in children and, therefore, sleep quality and mood. Using a crossover investigation, 46 participants were randomly assigned to a control group (CON) or an intervention group and received Creative Roots® (INT) for two-week periods. We recorded daily first morning and afternoon urine color (Ucol), thirst perception, and bodyweight of the two groups. Participants reported to the lab once per week and provided first morning urine samples to assess Ucol, urine specific gravity (USG), and urine osmolality (Uosmo). Participants also completed the questionnaires Profile of Mood States-Adolescents (POMS-a) and Pittsburgh Sleep Quality Index (PSQI). Dependent t-tests were used to assess the effects of the intervention on hydration, mood, and sleep quality. Uosmo was greater and Ucol was darker in the control group (mean ± SD) [Uosmo: INT = 828 ± 177 mOsm·kg−1, CON = 879 ± 184 mOsm·kg−1, (p = 0.037], [Ucol:INT = 5 ± 1, CON = 5 ± 1, p = 0.024]. USG, POMS-a, and PSQI were not significant between the groups. At-home daily afternoon Ucol was darker in the control group [INT = 3 ± 1, CON = 3 ± 1, p = 0.022]. Access to Creative Roots® provides a small, potentially meaningful hydration benefit in children. However, children still demonstrated consistent mild dehydration based on Uosmo, despite consuming the beverage.

Objective: To estimate per-event cost and economic burden associated with managing the most common and/or severe metastatic melanoma (MM) treatment-related adverse events (AEs) in Australia, France, Germany, Italy, and the UK. Methods: AEs associated with chemotherapy (dacarbazine, paclitaxel, fotemustine), immunotherapy (ipilimumab), and targeted therapy (vemurafenib) were identified by literature review. Medical resource use data associated with managing AEs were collected through two blinded Delphi panel cycles in each of the five countries. Published costs were used to estimate per-event costs and combined with AEs incidence, treatment usage, and MM prevalence to estimate the economic burden for each country. Results: The costliest AEs were grade 3/4 events due to immunotherapy (Australia/France: colitis; UK: diarrhea) and chemotherapy (Germany/Italy: neutropenia/leukopenia). Treatment of AEs specific to chemotherapy (Australia/Germany/Italy/France: neutropenia/leukopenia) and targeted therapy (UK: squamous cell carcinoma) contributed heavily to country-specific economic burden. Limitations: Economic burden was estimated assuming that each patient experienced an AE only once. In addition, the context of settings was heterogeneous and the number of Delphi panel experts was limited. Conclusions: Management costs for MM treatment-associated AEs can be substantial. Results could be incorporated in economic models that support reimbursement dossiers. With the availability of newer treatments, establishment of a baseline measure of the economic burden of AEs will be crucial for assessing their impact on patients and regional healthcare systems.

Sekiguchi, Y, Huggins, RA, Curtis, RM, Benjamin, CL, Adams, WM, Looney, DP, West, CA, and Casa, DJ. Relationship between heart rate variability and acute:chronic load ratio throughout a season in NCAA D1 men's soccer players. J Strength Cond Res 35(4): 1103-1109, 2021-The purpose of this study was twofold: (a) to examine the relationship between heart rate variability (HRV) and acute:chronic workload ratio (ACWR)-based training load (TL) metrics and (b) to examine relationships across various A:C ratio-based TL metrics. Heart rate variability in 23 male college soccer players (mean ± SD; age, 21 ± 1 years; body mass, 80.3 ± 5.8 kg; height, 181.9 ± 6.5 cm; %body fat, 11.9 ± 2.0%; and V̇o2max, 51.9 ± 5.0 ml·kg-1·min-1) was measured at 5 time points: week(W)1, W3, W7, W12, and W14 during the 2015 NCAA men's soccer season. Heart rate variability was calculated from beat to beat intervals using a heart rate monitor. Players donned a global position satellite-enabled device that measured the following TL metrics: session time (ST), Player Load (PL), PL·min-1, and total distance (TD). Acute:chronic workload ratio was calculated for each TL metric: ACWR-based ST (ACWRST), ACWR-based PL (ACWRPL), ACWR-based PL·min-1 (ACWRPLM), and ACWR-based TD (ACWRTD): ACWR = week average TLs/mo average (30 ± 1 days) TLs. Relationships between HRV and ACWR-based each TL metric were evaluated using mixed effects models. Tukey pairwise comparisons were used to examine differences between types of ACWR-based TL metrics. An increase in ACWRST significantly reduced HRV throughout a season (-7.4 ± 3.6 m·s-1; p = 0.04). There were significant differences between ACWRPLM and ACWRST, ACWRPL and ACWRTD at W1, ACWRPLM and ACWRST at W3 (p0.05). In conclusion, ACWRST, ACWRPL, and ACWRTD were significantly different from ACWRPLM. ACWRST was found to significantly predict HRV; higher ACWRST was significantly associated with lower HRV. Therefore, tracking of the ACWR using ST may help to optimize athlete's physiological state throughout a season.

International audience; Objectives: To inform health-technology assessments of new adjuvant treatments, we describe treatment patterns in patients with complete resection of stage IB-IIIA non-small cell lung cancer (NSCLC) in France, Germany, and the United Kingdom (UK).Materials and methods: Data were collected via medical record abstraction. Patients were aged ≥18 years with completely resected stage IB-IIIA NSCLC, diagnosed between 01 January 2009 and 31 December 2011. Median follow-up was 26 months. Adjuvant treatment patterns and clinical outcomes were summarized descriptively.Results: Among the 831 patients studied, 239 (29%) had stage IB disease, 179 (22%) had stage IIA disease, 165 (20%) had stage IIB disease, and 248 (30%) had stage IIIA disease. Adjuvant systemic therapy was received by 402 patients (48.4%), (France, 61.8%; Germany, 51.9%; UK, 33.4%). Use of adjuvant therapy increased with increasing stage of disease. Cisplatin/vinorelbine and carboplatin/vinorelbine were the most frequently prescribed adjuvant regimens. Median disease-free survival was 48.0 months (95% confidence interval [CI] 42.3-not estimable); the 25th percentile was 13.2 months (95% CI, 11.0-15.3). 204 patients (24%) died during the follow-up period. The median overall survival was not reached, the 25th percentile was 31.2 months (95% CI 26.8-36.0 months). 272 patients (33%) had disease recurrence during the follow-up period. For 86 of those patients, the first recurrence was local or regional with no distant metastasis and 14 had further progression to metastatic disease during the follow-up time. For the other 186 patients, the first recurrence involved distant metastases. A total of 200 patients had metastatic disease at any time during study follow-up.Conclusions: Less than half the patients with stage IB-IIIA NSCLC in this observational study received adjuvant systemic therapy. A high rate of first recurrence with distant metastatic disease was observed, emphasising the need for more effective systemic adjuvant therapies in this population.

Objectives: To investigate the roles that training load and environmental conditions have on fluid balance during a collegiate men’s soccer preseason. Design: Observational study. Methods: Twenty-eight male collegiate soccer players (mean ± SD; age, 20 ± 1.7 y; body mass (BM), 79.9 ± 7.3 kg; height, 180.9 ± 6.8 cm; body fat, 12.7 ± 3.1%; VO2max, 50.7 ± 4.3 ml·kg-1·min-1) participated in this study. Prior to (PRE) and following (POST) each team session, BM, percent BM loss (%BML) and hydration status was measured. Participants donned a heart rate and GPS enabled monitor to measure training load. For all team activities, ambient temperature (TAMB) and relative humidity (RH) were obtained from the nearest local weather station. Participants consumed 500 mL of water as part of the team-based hydration strategy before and after training session. Stepwise linear regression was used to identify the variables that predicted %BML. Significance was set a-priori p < 0.05. Results: Total distance covered predicted %BML during all preseason activities (r2 = 0.253, p < 0.001), with TAMB and RH further adding to the model (r2 = 0.302, p < 0.001). %BML never exceeded 2% of BM during any one session and daily variation in BM was

Background Patient characteristics and survival outcomes in randomized trials may be different from those in real-life clinical practice. The objective of this study was to describe treatment pathways, safety, drug costs and survival in patients with metastatic Renal Cell Carcinoma (mRCC) in a real world setting. Methods A retrospective analysis was performed using IQVIA real world oncology cross-sectional survey data, a retrospective treatment database collecting anonymized patient-level data in Europe. Data on treatment naïve patients with mRCC who received a first-line targeted therapy in France were extracted for the period 2005–2015. Descriptive analyses were performed on treatment patterns, patient characteristics and safety profiles. Progression Free Survival (PFS) was determined using Kaplan-Meier survival analysis. Results One thousand three hundred thirty-one patients with mRCC who received a first-line targeted therapy were included. The male/female sex ratio was 2.5 and 66% of patients were aged > 60 years. 83% of patients had clear cell adenocarcinoma. 83% of patients underwent a surgical procedure, 10% had radiotherapy. In patients who received a first-line targeted therapy, 73% received sunitinib. The mean time from diagnosis to first-line treatment by targeted therapies in patients initially diagnosed with metastatic disease was 3.3 months [95% CI:2.5–4.1]. In patients who received second-line targeted therapy n = 257 (19%), the most frequently observed treatment sequences were sunitinib-everolimus (33%) and sunitinib-sorafenib (27%). Adverse events data were available for 501 patients and adverse events were documented in 70% of patients, most frequently diarrhoea. The overall median PFS was 13 months [95% CI:11.5–16]. Conclusion Patient characteristics were consistent with the literature. Treatment patterns appeared to follow current practice guidelines. Despite some variations, PFS in our study seems to be consistent with findings from other real world studies. Nevertheless, PFS results were higher than those observed in clinical trials. Due to the use of cross-sectional data, PFS in our study should be interpreted with caution. Electronic supplementary material The online version of this article (10.1186/s12885-018-4117-z) contains supplementary material, which is available to authorized users.

Introduction A preliminary study done by a National Dental Practice-Based Research Network precursor observed that 44% of general dentists (GDs) reported always using a rubber dam (RD) during root canal treatment (RCT). This full-scale study quantified the use of all isolation techniques, including RD use. Methods Network practitioners completed a questionnaire about isolation techniques used during RCT. Network enrollment questionnaire data provided practitioner characteristics. Results One thousand four hundred ninety of 1716 eligible GDs participated (87%); 697 (47%) reported always using an RD. This percentage varied by tooth type. These GDs were more likely to always use an RD, do not own a private practice, perform less than 10 RCTs/month, and have postgraduate training. Conclusions Most GDs do not use an RD all the time. Ironically, RDs are used more frequently by GDs who do not perform molar RCT. RD use varies with tooth type and certain dentist, practice, and patient characteristics.

The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150 IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV350 IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P = .02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV350 IU/mL and those who started at CMV350 IU/mL (44% versus 57%; P = .42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P = .001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P = .02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P .0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150 IU/mL is associated with a80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350 IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.

Methylsulfonylmethane (MSM) has become a popular dietary supplement used for a variety of purposes, including its most common use as an anti-inflammatory agent. It has been well-investigated in animal models, as well as in human clinical trials and experiments. A variety of health-specific outcome measures are improved with MSM supplementation, including inflammation, joint/muscle pain, oxidative stress, and antioxidant capacity. Initial evidence is available regarding the dose of MSM needed to provide benefit, although additional work is underway to determine the precise dose and time course of treatment needed to provide optimal benefits. As a Generally Recognized As Safe (GRAS) approved substance, MSM is well-tolerated by most individuals at dosages of up to four grams daily, with few known and mild side effects. This review provides an overview of MSM, with details regarding its common uses and applications as a dietary supplement, as well as its safety for consumption.

Objective Following a successful 2005–2012 phase with three regional practice-based research networks (PBRNs), a single, unified national network called “The National Dental PBRN” was created in 2012 in the United States to improve oral health by conducting practice-based research and serving dental professionals through education and collegiality. Methods Central administration is based in Alabama. Regional centres are based in Alabama, Florida, Minnesota, Oregon, New York and Texas, with a Coordinating Centre in Maryland. Ideas for studies are prioritized by the Executive Committee, comprised mostly of full-time clinicians. Results To date, 2763 persons have enrolled, from all six network regions; enrollment continues to expand. They represent a broad range of practitioners, practice types, and patient populations. Practitioners are actively improving every step of the research process, from idea generation, to study development, field testing, data collection, and presentation and publication. Conclusions Practitioners from diverse settings are partnering with fellow practitioners and academics to improve clinical practice and meet the needs of clinicians and their patients. Clinical significance This “nation's network” aims to serve as a precious national resource to improve the scientific basis for clinical decision-making and foster movement of the latest evidence into routine practice.

Training within a proficiency-based virtual reality (VR) curriculum may reduce errors during real surgical procedures. This study used a scientific methodology to develop a VR training curriculum for phacoemulsification surgery (PS).Ten novice-(n) (performed10 cataract operations), 10 intermediate-(i) (50-200), and 10 experienced-(e) (500) surgeons were recruited. Construct validity was defined as the ability to differentiate between the three levels of experience, based on the simulator-derived metrics for two abstract modules (four tasks) and three procedural modules (five tasks) on a high-fidelity VR simulator. Proficiency measures were based on the performance of experienced surgeons.Abstract modules demonstrated a 'ceiling effect' with construct validity established between groups (n) and (i) but not between groups (i) and (e)-Forceps 1 (46, 87, and 95; P0.001). Increasing difficulty of task showed significantly reduced performance in (n) but minimal difference for (i) and (e)-Anti-tremor 4 (0, 51, and 59; P0.001), Forceps 4 (11, 73, and 94; P0.001). Procedural modules were found to be construct valid between groups (n) and (i) and between groups (i) and (e)-Lens-cracking (0, 22, and 51; P0.05) and Phaco-quadrants (16, 53, and 87; P0.05). This was also the case with Capsulorhexis (0, 19, and 63; P0.05) with the performance decreasing in the (n) and (i) group but improving in the (e) group (0, 55, and 73; P0.05) and (0, 48, and 76; P0.05) as task difficulty increased.Experienced/intermediate benchmark skill levels are defined allowing the development of a proficiency-based VR training curriculum for PS for novices using a structured scientific methodology.

Neurogenesis is a highly-regulated process occurring in the dentate gyrus that has been linked to learning, memory, and antidepressant efficacy. MicroRNAs (miRNAs) have been previously shown to play an important role in the regulation of neuronal development and neurogenesis in the dentate gyrus via modulation of gene expression. However, this mode of regulation is both incompletely described in the literature thus far and highly multifactorial. In this study, we designed sensors and detected relative levels of expression of 10 different miRNAs and found miR-338-3p was most highly expressed in the dentate gyrus. Comparison of miR-338-3p expression with neuronal markers of maturity indicates miR-338-3p is expressed most highly in the mature neuron. We also designed a viral “sponge” to knock down in vivo expression of miR-338-3p. When miR-338-3p is knocked down, neurons sprout multiple primary dendrites that branch off of the soma in a disorganized manner, cellular proliferation is upregulated, and neoplasms form spontaneously in vivo. Additionally, miR-338-3p overexpression in glioblastoma cell lines slows their proliferation in vitro. Further, low miR-338-3p expression is associated with increased mortality and disease progression in patients with glioblastoma. These data identify miR-338-3p as a clinically relevant tumor suppressor in glioblastoma.

Anxiety disorders are common in youth (e.g., Bernstein & Borchardt, 1991) and adults, based on 12-month prevalence estimates from the general population (Kessler, Chui, Demler, & Walters, 2005) and across the lifespan (28.8%; Kessler, Berglund, Demler, Jin, & Walters, 2005). Approximately 10 to 20% of children in the general population and primary care settings report distressing levels of anxiety (Chavira, Stein, Bailey, & Stein, 2004; Costello, Mustillo, Keeler, & Angold, 2004). Research suggests that most anxiety disorders do not abate over time (e.g., Pine, Cohen, Gurley, Brook, & Ma, 1998). Indeed, retrospective reports demonstrate that adults with anxiety disorders report having experienced disturbing anxiety as children (e.g., Ost, 1987; Sheehan, Sheehan, & Minichiello, 1981) and older youth report higher levels of anxiety and depression compared to younger children, suggesting untreated anxiety symptoms worsen over time. Anxiety disorders in youth have important long-term implications in terms of their association with later depressive disorders (Alpert, Maddocks, Rosenbaum, & Fava, 1994; Angold, Costello, & Erkanli, 1999; Biederman, Faraone, Mick, & Lelon, 1995; Strauss, Lease, Last, & Francis, 1988), suicidal attempts and ideation (Brent et al., 1986; Rudd, Joiner, & Rumzek, 2004), and substance use (Costello, Mustillo, Erkanli, Keeler, & Angold, 2003; Lopez, Turner, & Saavadra, 2005). As age increases, the presence of an anxiety disorder has an associated increase in the likelihood of a depressive disorder (Beesdo et al., 2007, Pine et al., 1998), and anxiety disorders typically precede the onset of substance use disorders (SUDs; Merikangas et al., 1998). Given the high lifetime co-occurrence of anxiety and SUDs (35% to 45%; Kessler et al., 1996) and the deleterious outcomes associated with substance dependence (Toumbourou et al., 2007), this primacy warrants further investigation. Indeed, there is evidence that effective short-term treatment for adolescent depression is associated with reduced SUDs (Curry et al., 2012). Initial data suggested that CBT for child anxiety may allay later substance use (e.g., Kendall, Safford, Flannery-Schroeder, & Webb, 2004), but that evaluation was undertaken before participants reached the age of greatest risk for associated disorders. Several studies have examined CBT for childhood anxiety and literature reviews support its utility: CBT can be considered an efficacious treatment (based on the criteria proposed by Chambless & Hollon, 1998; see Hollon & Beck, 2013; Kazdin & Weisz, 1998; Ollendick & King, 2012; Silverman, Pina, & Viswesvaran, 2008). Several randomized clinical trials (RCTs) reported the efficacy of one version of CBT for anxious youth, the Coping Cat program (Kendall & Hedtke, 2006), when compared to alternate psychological treatments (e.g., Kendall, Hudson, Gosch, Flannery-Schroeder, & Suveg, 2008) and to medications and pill placebo (e.g., Walkup et al., 2008). Although multiple research groups have advanced the treatment of anxiety disorders in children (see also Barrett, Dadds, & Rapee, 1996; Beidel et al., 2007; Silverman et al., 2008), limited evidence exists with respect to sequelae at the time in adulthood when such disorders are likely to emerge. Several one-year follow-ups have been conducted (e.g., Kendall et al., 1997; Kolko, Loar, & Sturnick, 1990), as well as a 3-year (Beidel, Turner, Young, & Paulson, 2005), 5-year (Beidel, Turner, & Young, 2006), 6-year (Barrett, Duffy, Dadds, & Rapee, 2001) and 7.4-year follow-ups (Kendall et al., 2004). Longer follow-ups are uncommon and those that are available lack appropriate methodological rigor (e.g., do not follow a RCT). A review by Nevo and Manassis (2009) highlighted the dearth of long-term outcome studies of anxious youth and the lack of evidence for the role early anxiety treatment might play in healthy development into adulthood (see also Hirshfeld-Becker, Micco, Simoes, & Henin, 2008). The present study evaluated outcomes associated with treatment for childhood anxiety by comparing (a) successfully treated and (b) unsuccessfully treated participants a mean of 16.24 years after the completion of treatment. The primary aim examined whether participants treated successfully during childhood differ from those for whom treatment was less successful on diagnoses of (a) adult anxiety, (b) depression, and (c) SUDs in young adulthood. A second aim examined whether the two treatment outcome groups differed from the general population on diagnoses of anxiety, depression, and SUDs in early adulthood. It was hypothesized that effective treatment for an anxiety disorder in childhood would reduce the occurrences of anxiety and related disorders in young adulthood. Further, it was hypothesized that successfully treated participants would be no more likely to meet criteria for an anxiety, mood, or SUD diagnosis than individuals in the community, whereas unsuccessfully treated participants would be more likely to meet criteria for a diagnosis than community individuals.

A randomized clinical trial of 100 children (52 boys, 48 girls) ages 2 months to 7 years was conducted to evaluate the effect of vibration therapy without cold analgesia on pain. A convenience sample was recruited at two sites: a publicly funded, free immunization clinic and a private group pediatric practice. Participants were randomly assigned to receive vibration therapy via a specialized vibrating device or standard care. All children regardless of intervention group were allowed to be distracted and soothed by the parent. Pain was evaluated using the FLACC score, which two nurses assessed at three points in time: prior to, during, and after the injection(s). Data were analyzed using a two-independent samples-paired t-test. Results show that vibration therapy had no effect on pain scores in the younger age groups studied (2 months ≤ 1 year,1 year ≤ 4 years). In the oldest age group (4 to 7 years of age), a heightened pain reading was found in the period from preinjection to post-injection periods (p = 0.045). These results indicate that the addition of vibration therapy (without cold analgesia) to standard soothing techniques is no more effective in reducing immunization pain than standard soothing techniques alone, and thus, is not indicated for use with immunization pain. Recommendations include further evaluation of interventions.

Syndrome of inappropriate anti-diuretic hormone (SIADH) has been reported to be associated with systemic Strongyloides stercoralis. Here, we report a case of a stem cell transplant (SCT) recipient who developed severe SIADH secondary to systemic S Stercoralis. The SIADH resolved quickly after treating the systemic S Stercoralis with ivermectin. A systematic review of the literature was performed by PubMed, Scopus, and Cochrane database search. Only eight cases of S Stercoralis in allogeneic SCT recipients have been previously reported. To our knowledge, ours is the first reported case of SIADH secondary to S Stercoralis infection in an allogeneic SCT recipient. Prior to transplantation, even if asymptomatic, patients from endemic regions should be screened with strongyloides immunoglobulin (Ig)G serology. Pretransplantation eosinophilia should be evaluated by screening multiple stool samples for ova and parasites. Transplant candidates with positive serology or stool tests can be treated pretransplantation to eradicate infection. Patients at risk for S Stercoralis who develop nonspecific gastrointestinal complaints, rash, pulmonary infiltrates, or gram-negative bacteremia or meningitis may have S Stercoralis hyperinfection syndrome. Our case indicates that the development of SIADH may be an additional clue to this diagnosis. Appropriate diagnostic studies, including repeat stool and other body fluid sampling, should be expedited and ivermectin therapy initiated rapidly to prevent significant morbidity and mortality.

SummaryA major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate

Two anti-cancer drugs are currently approved for the treatment of HER2-positive metastatic breast cancer (MBC): trastuzumab-based therapy (TBT) administered intravenously as first line therapy until disease progression and lapatinib, an oral self-administered dual therapy with capecitabine (L+C) as second intention for patients who continue to progress despite TBT. In current practice, TBT is still prescribed beyond disease progression. In addition to medical reasons, the difficulty to switch eligible patients to oral drugs may also be explained by economic reasons. Thus, we aimed at comparing the budgetary impact of TBT and L+C for progressing HER2+MBC after TBT from the French Health Insurance perspective.A budget impact analysis was performed on a 3-year time horizon (2012-2014) to simulate a dynamic cohort of 4182 HER2-positive patients with a progressing MBC treated with TBT (73%) and L + C (27%). The model was adjusted on progression-free survival (PFS). Office visits, clinical evaluations, drug acquisition, administration costs, and transportation costs obtained from the literature and published databases were considered.In the base case analysis (2012), the annual treatment cost per patient for TBT (€36,077) was 2-times higher than that of L + C (€17,165). Using L + C for all patients (n = 4182) would avoid €34.8 million of drug administration and transportation costs. Hospital costs represented 1% vs 88%, while community costs represented 99% vs 12% of L + C and TBT treatment costs, respectively. The lack of direct comparison PFS and treatment dosage modification data were the main limitations. However, no major changes from baseline results were observed from sensitivity analyses.Despite a slightly higher acquisition cost, the treatment cost of L + C remains lower than that of TBT, and it is the only approved anti-HER2 treatment for HER2-positive patients with progressing MBC. Based on this, it seems important to consider the potential savings for Health Insurance with the use of oral drug due to the reduction of outpatient hospitalizations. Such reductions may result in a subsequent budget reduction for hospitals, but may also provide those facing acute medical activity with opportunities to better manage other diseases whose treatment cannot be externalized.

Patients with Crohn's disease (CD) have an intestinal dysbiosis with components of the microbiota exerting differential immune effects. Smoking is associated with an increased incidence of CD, more frequent relapse, and greater burden of surgery. This study aimed to investigate the association between smoking and the intestinal microbiota in patients with active CD.Patients with active CD (n = 103) and healthy controls (n = 66) were recruited and demographic and clinical data recorded including current smoking behavior. Fecal samples were collected and analyzed by fluorescent in situ hybridization using probes targeting 16S rRNA of bacteria previously shown to be altered in active CD (bifidobacteria, bacteroides, Clostridium coccoides-Eubacterium rectale, Escherichia coli, and Faecalibacterium prausnitzii).In total, 29/101 (29%) patients with CD and 8/58 (14%) controls were current smokers (P = 0.032). Following multivariate analysis, smoking was found to have a significant and independent effect on the microbiota of patients with CD, with higher Bacteroides-Prevotella in smokers (38.4%) compared with nonsmokers (28.1%) (F((1,93)) = 12.6, P = 0.001). Healthy controls who smoked also had higher Bacteroides-Prevotella (34.8%) than nonsmokers (24.1%) (F((1,55)) = 4.5, P = 0.038). In the pooled multivariate analysis, patients with CD had higher bifidobacteria (F((1,156)) = 30.5, P0.001), higher Bacteroides-Prevotella (F((1,156)) = 6.5, P = 0.012), and lower F. prausnitzii (F((1,156)) = 3.8, P = 0.052) compared with healthy controls.Smokers have luminal microbiota that consist of significantly higher bacteroides. Investigation of whether this is one mechanism through which the negative effects of smoking on CD are mediated is warranted.

SummaryHemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.

Incidence of breast cancer with brain metastases (BCBM) is increasing, especially among patients over-expressing HER2. Epidemiology on this sub-type of cancer is scarce, since cancer registries carry no information on the HER2 status. A retrospective database analysis was conducted to estimate the burden of BCBM, especially among HER2-positive patients in a secondary objective.Patients with a new diagnosis of BCBM carried out between January and December 2008 were identified from the national hospital database using the International Disease Classification. Patients receiving a targeted anti-HER2 therapy were identified from the national pharmacy database. Hospital and pharmacy claims were linked to estimate the burden of HER2-positive patients. Data on hospitalizations were extracted to describe treatment patterns and healthcare costs during a 1-year follow-up. Predictors of treatment cost were analyzed through multi-linear regression analysis.Two thousand and ninety-nine BCBM patients were identified (mean age (SD) = 57.8 (13.6)), of whom 12.2% received a targeted anti-HER2 therapy; 79% of patients had brain metastases associated with extracranial metastases, and the attrition rate reached 82%. Patients received mostly palliative care (47.4%), general medical care (40.6%), and chemotherapy (35.0%). The total annual hospital cost of treatment was 8,426,392€, representing a mean cost of 22,591€ (±14,726) per patient, mainly influenced by extracranial metastases, surgical acts, and HER2-overexpression (p 0.0001).The database linkage of hospital and pharmacy claims is a relevant approach to identify sub-type of cancer. Chemotherapy was widely used as a systemic treatment for breast cancer rather than for local treatment of brain metastases whose morbi-mortality remains high. The variability of treatment costs suggests clinical heterogeneity and, thus, extensive individualization of protocols.

Altered intestinal dendritic cell (DC) function underlies dysregulated T-cell responses to bacteria in Crohn's disease (CD) but it is unclear whether composition of the intestinal microbiota impacts local DC function. We assessed the relationship between DC function with disease activity and intestinal microbiota in patients with CD.Surface expression of Toll-like receptor (TLR)-2, TLR-4, and spontaneous intracellular interleukin (IL)-10, IL-12p40, IL-6 production by freshly isolated DC were analyzed by multicolor flow cytometry of cells extracted from rectal tissue of 10 controls and 28 CD patients. Myeloid DC were identified as CD11c(+) HLA-DR(+lin-/dim) cells (lin = anti-CD3, CD14, CD16, CD19, CD34). Intestinal microbiota were analyzed by fluorescent in situ hybridization of fecal samples with oligonucleotide probes targeting 16S rRNA of bifidobacteria, bacteroides-prevotella, C. coccoides-E. rectale, and Faecalibacterium prausnitzii.DC from CD produced higher amounts of IL-12p40 and IL-6 than control DC. IL-6(+) DC were associated with the CD Activity Index (r = 0.425; P = 0.024) and serum C-reactive protein (CRP) (r = 0.643; P = 0.004). DC expression of TLR-4 correlated with disease activity. IL-12p40(+) DC correlated with ratio of bacteroides: bifidobacteria (r = 0.535, P = 0.003). IL-10(+) DC correlated with bifidobacteria, and IL-6(+) DC correlated negatively with F. prausnitzii (r = -0.50; P = 0.008). The amount of TLR-4 on DC correlated negatively with the concentration of F. prausnitzii.IL-6 production by intestinal DC is increased in CD and correlates with disease activity and CRP. Bacterially driven local IL-6 production by intestinal DC may overcome regulatory activity, resulting in unopposed effector function and tissue damage. Intestinal DC function may be influenced by the composition of the commensal microbiota.

A previous report suggested that successful cognitive behavioral therapy (CBT) for child anxiety reduced substance use problems at 7.4-year follow-up, but that report did not include predictors of: (a) substance use disorder (SUD; e.g., attention deficit-hyperactivity disorder symptoms, negative life events, family substance abuse, additional treatment), or (b) treatment outcome (e.g., severity of internalizing pathology, age). Analyses incorporating these factors tested previously reported findings in 72 participants (ages 15–22 at follow-up; 84% of the 7.4-year follow-up sample), using parent and youth diagnostic interviews and report measures. The majority of previously reported associations between less successful treatment and later substance use problems remained significant after controlling for known predictors of SUD and treatment outcome. Our findings bolster previous conclusions that effective CBT for child anxiety may have ameliorative effects on the target disorder and later substance use problems.

Effectively addressing challenges of conducting research in nonacademic settings is crucial to its success. A dental practice-based research network called The Dental Practice-Based Research Network (DPBRN) is comprised of practitioner- investigators in two health maintenance organizations, several universities, many U.S. states, and three Scandinavian countries. Our objective in this article is to describe lessons learned from conducting studies in this research context; the studies are con- ducted by clinicians in community settings who may be doing their first research study. To date, twenty-one studies have been completed or are in implementation. These include a broad range of topic areas, enrollment sizes, and study designs. A total of 1,126 practitioner-investigators have participated in at least one study. After excluding one study because it involved electronic records queries only, these studies included more than 70,000 patient/participant units. Because the DPBRN is committed to being both practitioner- and patient-driven, all studies must be approved by its Executive Committee and a formal study section of academic clinical scientists. As a result of interacting with a diverse range of institutional and regulatory entities, funding agen- cies, practitioners, clinic staff, patients, academic scientists, and geographic areas, twenty-three key lessons have been learned. Patients' acceptance of these studies has been very high, judging from high participation rates and their completion of data forms. Early studies substantially informed later studies with regard to study design, practicality, forms design, informed consent process, and training and monitoring methods. Although time-intensive and complex, these solutions improved acceptability of practice-based research to patients, practitioners, and university researchers.

The commensal intestinal microbiota drive the inflammation associated with Crohn's disease. However, bacteria such as bifidobacteria and Faecalibacterium prausnitzii appear to be immunoregulatory. In healthy subjects the intestinal microbiota are influenced by prebiotic carbohydrates such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS increase faecal bifidobacteria, induce immunoregulatory dendritic cell (DC) responses and reduce disease activity in patients with Crohn's disease.To assess the impact of FOS in patients with active Crohn's disease using an adequately powered randomised double-blind placebo-controlled trial with predefined clinical, microbiological and immunological end points. Patients with active Crohn's disease were randomised to 15 g/day FOS or non-prebiotic placebo for 4 weeks. The primary end point was clinical response at week 4 (fall in Crohn's Disease Activity Index of ≥ 70 points) in the intention-to-treat (ITT) population.103 patients were randomised to receive FOS (n = 54) or placebo (n = 49). More patients receiving FOS (14 (26%) vs 4 (8%); p = 0.018) withdrew before the 4-week end point. There was no significant difference in the number of patients achieving a clinical response between the FOS and placebo groups in the ITT analysis (12 (22%) vs 19 (39%), p = 0.067). Patients receiving FOS had reduced proportions of interleukin (IL)-6-positive lamina propria DC and increased DC staining of IL-10 (p0.05) but no change in IL-12p40 production. There were no significant differences in the faecal concentration of bifidobacteria and F prausnitzii between the groups at baseline or after the 4-week intervention.An adequately powered placebo-controlled trial of FOS showed no clinical benefit in patients with active Crohn's disease, despite impacting on DC function. ISRCTN50422530.