Efficacy of thrombopoietin receptor agonists versus rituximab in non-responsive immune thrombocytopenia-A single centre retrospective analysis.

Management of immune thrombocytopenia (ITP) beyond initial glucocorticoid therapy is challenging. In this retrospective single-centre cohort study, we compared all ITP patients relapsed or non-responsive to glucocorticoid therapy treated with either continuous TPO-RAs (n = 35) or rituximab induction (n = 20) between 2015 and 2022. While both groups showed high initial complete response rates (CR, 68.6 vs. 80.0%, ns), the overall rate of progression to the next therapy was higher after time-limited rituximab (75.0 vs. 42.9%), resulting in a lower relapse-free survival (median 16.6 vs. 25.8 months, log-rank; p < 0.05). We conclude that both treatments show similar initial efficacy and their ideal duration of therapy warrants further investigation.

Mutational patterns in therapy-related acute lymphoblastic leukemia subgroups: one step closer to unveiling the genetic odyssey.

There is increasing evidence that therapy-related acute lymphoblastic leukemia (trALL) resulting from chemo- and/or radiotherapy represents a distinct entity. However, apart from KMT2A rearrangements, which have been repeatedly reported in this subgroup, the relevance of other aberrations remains controversial due to divergent study results and sparse molecular analyses. Within our ALL patient cohort, 15% (n = 19/131) met the criteria for trALL with a high proportion of Ph + and KMT2A rearrangements. On the molecular level, the most frequently observed mutation was KMT2D, followed by CDKN2A, KRAS and DNMT3A. No TP53 mutation was detected. Outcome was particularly poor in Ph + trALL compared to Ph+ de novo ALL, which seemed to be mitigated by allogeneic stem cell transplantation. Our findings further define trALL as a distinct entity but highlight the need for further molecular genome sequencing of somatic and germline variants to advance our understanding of trALL.

Quadriceps Strength and Knee Function After Anterior Cruciate Ligament Reconstruction with Quadriceps Tendon Bone Autograft: A Preliminary Report.

Introduction: The purpose of this study was to evaluate quadriceps strength and knee function after anterior cruciate ligament (ACL) reconstruction using a quadriceps tendon bone (QTB) autograft. Methods: Preliminary data were extracted from an ongoing prospective cohort study in which the operative extremity was compared to non-operative extremity. Patients from 14 to 40 years of age who had an ACL reconstruction with QTB autograft volunteered to have knee assessment including quadriceps isokinetic strength measures and functional knee testing at 6 and 12 months post-operatively. Paired t-tests were conducted to compare post-operative strength and function scores on participants who had minimum one-year post-surgical follow-up. Results: Patients had a significant recovery of quadriceps strength as determined by isokinetic testing and single leg hop test. For 31 participants, quadriceps strength of the operative leg measured at 60 deg/sec was 63% of the non-operative leg at six months, increasing to 79% at one year (p < 0.001); when measured at 180 deg/sec, these values were 68% at six months, increasing to 82% at one year (p < 0.001). For 30 participants, single leg hop functional scores of the operative leg were 80% of the non-operative leg at six months, increasing to 91% at one year (p < 0.001). Conclusions: After QTB autograft for ACL reconstruction, there were significant gains in quadriceps strength and knee function from six months to one year post-operative. These findings indicated the QTB is an acceptable ACL reconstruction option.

Clinical Rotation Handbook Promotes Orthopaedic Resident Wellness: A Quality Improvement Study.

Introduction: Transitioning from one clinical rotation to the next may be particularly stressful for orthopaedic residents attempting to navigate new work environments with new faculty mentors and new patients. The purpose of this quality improvement (QI) project was to determine if resident stress could be improved by using a handbook to disseminate key rotation-specific data during quarterly rotation transition periods. Methods: A comprehensive electronic handbook was created by residents to describe each rotation in our orthopaedic training program in terms of: (1) faculty and staff contact data, (2) daily clinic and surgery schedules, (3) resident responsibilities and faculty expectations, and (4) key resources and documents. At rotation transition, a session in the academic schedule was dedicated for outgoing residents to update the handbook and to sign-out to incoming residents. Pre- and post-handbook questionnaires were administered to assess resident perceptions of stress or anxiety, preparedness, and confidence before commencing the new rotation. Nonparametric data derived from the surveys were analyzed using the sign test choosing p < 0.05 for a two-tailed test as the level of statistical significance. Results: Most residents perceived improvements in stress/anxiety, preparedness, and confidence understanding rotation expectations after the handbook was implemented. Changes in these three outcome parameters were statistically significant. Conclusions: This rotation transition QI initiative consisting of a resident-authored, rotation-specific electronic handbook and dedicated verbal sign-out session enhanced resident wellness by decreasing stress, increasing preparedness, and improving confidence among residents starting a new rotation. Similar online resources may be useful for trainees in other specialties.

Real-world outcomes in elderly ALL patients with and without allogeneic hematopoietic stem cell transplantation: a single-center evaluation over 10 years.

Elderly patients (EP) of 60 years and above with acute lymphoblastic leukemia (ALL) have a dismal prognosis, but pediatric-inspired chemotherapy and allogeneic stem cell transplantation (allo HCT) are used reluctantly due to limited data and historical reports of high treatment-related mortality in EP. We analyzed 130 adult ALL patients treated at our center between 2009 and 2019, of which 26 were EP (range 60-76 years). Induction with pediatric-inspired protocols was feasible in 65.2% of EP and resulted in complete remission in 86.7% compared to 88.0% in younger patients (YP) of less than 60 years. Early death occurred in 6.7% of EP. Three-year overall survival (OS) for Ph - B-ALL was significantly worse for EP (n = 16) than YP (n = 64) with 30.0% vs 78.1% (p ≤ 0.001). Forty-nine patients received allo HCT including 8 EP, for which improved 3-year OS of 87.5% was observed, whereas EP without allo HCT died after a median of 9.5 months. In Ph + B-ALL, 3-year OS did not differ between EP (60.0%, n = 7) and YP (70.8%, n = 19). Non-relapse mortality and infection rate were low in EP (14.3% and 12.5%, respectively). Our data indicate that selected EP can be treated effectively and safely with pediatric regimens and might benefit from intensified therapy including allo HCT.

Acute Mild Hypoxic Hypoxia Effects on Cognitive and Simulated Aircraft Pilot Performance.

BACKGROUND: The effects of acute mild hypoxic hypoxia (HH) and physical activity on physiological measures, signs and symptoms, mood, fatigue, cognition, and performance on a simulated flight task were investigated between 8000 (8K; 2438 m) and 14,000 ft (14K; 4267 m). METHOD: In a hypobaric chamber, 16 military helicopter pilots were randomly exposed to 4 altitudes and 3 physical exertion levels. After each exercise period, participants identified targets on a designated flight path on a desktop simulator and completed a cognitive test battery. Cerebral regional and finger pulse oxyhemoglobin saturation levels (rSO2 and Spo2), heart and respiration rates were continuously monitored. Participants indicated their symptoms, mood and fatigue. RESULTS: rSO2 and Spo2 were affected by the increase of altitude and exercise level. Target identification accuracy and latency within the simulated flight task showed decrements at 8K, 10K (3048 m), 12K (3658 m), and 14K. Cognitive performance was degraded at 14K. More than 60% of the participants at 8K and 10K and more than 80% at 12K and 14K reported symptoms. Altitude increased symptoms, negative mood, general fatigue, and physical fatigue. DISCUSSION: Our findings indicate a significant influence of mild HH on a number of outcome measures at altitudes above 10K, where operational restrictions are well established. In contrast, there was no clear influence of HH on performance at lower altitudes (i.e., 8K and 10K). The occurrence of HH symptoms and the decrements in target identification latency and accuracy at 8K and 10K may negatively impact flight performance and require further study.Bouak F, Vartanian O, Hofer K, Cheung B. Acute mild hypoxic hypoxia effects on cognitive and simulated aircraft pilot performance. Aerosp Med Hum Perform. 2018; 89(6):526-535.

Parameters affecting length of stay in a pediatric emergency department: a retrospective observational study.

Prolonged emergency department (ED) length of stay (LOS) is used as a proxy for ED overcrowding and is associated with adverse outcomes of patients requiring therapy and reduced patient satisfaction. Our aim was to identify and quantify variables which affect ED-LOS. Patients admitted to the pediatric ED of a large regional Swiss hospital during a 1-year period were analyzed for LOS (in minutes). Predictor variables included patient-associated parameters (time of admission and discharge, ED occupancy, triage score, diagnosis, and demographic data) and external factors (weekday, time, and season). A total of 4885 visits were included in a multivariable logistic regression analysis. Median LOS was 124 min. The most important factors associated with prolonged LOS were physician referral (adjusted odds ratio [OR], 1.97; 95% confidence interval [CI], 1.47-2.62); morning admissions, especially before noon (OR, 1.92; 95% CI, 1.23-3.07); and gastrointestinal infections (OR, 1.38; 95% CI, 1.08-1.76). Upper airway infections (OR, 0.37; 95% CI, 0.27-0.49) and triage level 5 (OR, 0.18; 95% CI, 0.06-0.61) were inversely associated with ED-LOS. Together with ED occupancy, these factors did significantly contribute to log LOS in a stepwise backward multiple regression model (p < 0.001). CONCLUSION: Several parameters are associated with prolonged ED-LOS. Notably, morning arrivals represent possible targets for strategies to reduce LOS. What is Known: • Prolonged length of stay (LOS) may affect care delivered to admitted patients in the emergency department (ED) and is well studied in the setting of adult patients with high acuity conditions. • Little is known about parameters which impact LOS in European pediatric EDs. What is New: • Several predictors of prolonged LOS could be identified in a European pediatric setting. • Our results indicate that prolonged LOS is associated with modifiable factors like morning and summer admission, which have the potential to be addressed by modification in staffing, infrastructure, and higher attention to faster processing.

Prevalence of Anti-infliximab Antibodies and Their Associated Co-factors in Children with Refractory Arthritis and/or Uveitis: A Retrospective Longitudinal Cohort Study.

OBJECTIVE: Infliximab (IFX) is a monoclonal tumor necrosis factor-α-inhibiting antibody used in children with refractory arthritis and uveitis. Immunogenicity is associated with a lack of clinical response and infusion reactions in adults; data on immunogenicity in children treated with IFX for rheumatic diseases are scarce. We aimed to describe the prevalence of anti-IFX antibodies and determine co-factors associated with anti-IFX antibodies in children with inflammatory rheumatic and ocular diseases. METHODS: Consecutive children treated between August 2009 and August 2012 with IFX at our department were included. Blood samples were collected every 6 months before IFX infusion and tested for anti-IFX antibodies by radioimmunoassay. Patients' charts were retrospectively reviewed for clinical features and analyzed for associations with anti-IFX antibodies. RESULTS: Anti-IFX antibodies occurred in 14/62 children (23%) and 32/253 blood samples (12.6%) after a mean treatment time of 1084 days (range 73-3498). Infusion reactions occurred in 10/62 (16%) children during the treatment period. With continuation of IFX, anti-IFX antibodies disappeared in 7/14 children. In the bivariate analysis, the occurrence of anti-IFX antibodies was associated with younger age at IFX treatment start (mean age 7.01 vs 9.88 yrs, p = 0.003) and infusion reactions (OR 15.0), while uveitis as treatment indication was protective against development of anti-IFX antibodies (OR 0.17), likely because of higher IFX doses. In the multivariate logistic regression, all 3 covariates remained highly significant. CONCLUSION: Anti-IFX antibodies occurred commonly at any time during IFX treatment. Anti-IFX antibodies were associated with younger age at IFX start, infusion reactions, and arthritis as treatment indication.

Infliximab in pediatric rheumatology patients: a retrospective analysis of infusion reactions and severe adverse events during 2246 infusions over 12 years.

OBJECTIVE: To describe infusion reactions (IR) and severe adverse events (SAE) associated with infliximab (IFX) in pediatric patients with rheumatologic and ocular inflammatory diseases in a real-world setting. METHODS: This is a retrospective chart review of all patients treated with IFX at the pediatric rheumatology division of a university hospital between October 2000 and December 2012. RESULTS: A total of 2446 IFX infusions were given to 82 patients (72% female). IR occurred in 46 infusions (2%) of 14 patients (17%) after a mean IFX treatment time of 340 days (range 41-780); 9/14 patients (64%) experienced repeated IR. IR were classified as mild (26%), moderate (74%), or severe (0%). Indications for IFX were arthritis (60%), uveitis (20%), arthritis and uveitis (13%), and other inflammatory diseases (5%). The most common clinical symptoms were respiratory signs (72%), cutaneous manifestations (69%), and malaise (61%). In 6/14 patients (43%) with IR, IFX was discontinued: 4 patients because of repeated IR and 2 patients wished to stop treatment immediately following a mild IR. The other 8/14 patients (57%) received premedication with high-dose antihistamine (100%), corticosteroids (75%), and IFX dose increase (75%) and continued IFX treatment for a mean followup period of 146 weeks (range 26-537) after the first IR. We observed severe infections in 5/82 patients (6%); other SAE were rare. CONCLUSION: Mild and moderate IR occurred in 17% of our patients. Treatment with antihistamines and methylprednisolone, and increasing the IFX dose, allowed continued treatment despite IR in > 50% of patients. Other SAE were infrequent.

Various anti-motion sickness drugs and core body temperature changes.

INTRODUCTION: Blood flow changes and inactivity associated with motion sickness appear to exacerbate the rate of core temperature decrease during subsequent body cooling. We investigated the effects of various classes of anti-motion sickness drugs on core temperature changes. METHODS: There were 12 healthy male and female subjects (20-35 yr old) who were given selected classes of anti-motion sickness drugs prior to vestibular Coriolis cross coupling induced by graded yaw rotation and periodic pitch-forward head movements in the sagittal plane. All subjects were then immersed in water at 18 degrees C for a maximum of 90 min or until their core temperature reached 35 degrees C. Double-blind randomized trials were administered, including a placebo, a non-immersion control with no drug, and six anti-motion sickness drugs: meclizine, dimenhydrinate, chlorpheniramine, promethazine + dexamphetamine, promethazine + caffeine, and scopolamine + dexamphetamine. A 7-d washout period was observed between trials. Core temperature and the severity of sickness were monitored throughout each trial. RESULTS: A repeated measures design was performed on the severity of sickness and core temperature changes prior to motion provocation, immediately after the motion sickness end point, and throughout the period of cold-water immersion. The most effective anti-motion sickness drugs, promethazine + dexamphetamine (with a sickness score/duration of 0.65 +/- 0.17) and scopolamine + dexamphetamine (with a sickness score/duration of 0.79 +/- 0.17), significantly attenuated the decrease in core temperature. The effect of this attenuation was lower in less effective drugs. CONCLUSION: Our results suggest that the two most effective anti-motion sickness drugs are also the most effective in attenuating the rate of core temperature decrease.

Tactile cueing vs. vestibular sensation and nystagmus during yaw rotation.

INTRODUCTION: It has been reported that vibrating electromechanical tactile stimulation on the torso overrides the vestibular sensation of rotation. The purpose of this study is to further examine the influence of tactile cues on real and apparent sensations of self-rotation and corresponding vestibular nystagmus during passive yaw rotation. METHOD: There were 15 healthy subjects (12 men and 3 women, 31 to 49 yr) who were subjected to clockwise yaw rotation at a constant velocity of 120 degrees. s(-1). A tactile vest using electromechanical tactors (8 columns x 3 rows) was activated either in the clockwise or counterclockwise direction in a randomized design. The sequential activation of the tactors around the body matched the velocity of chair rotation. Eye movements were monitored using infrared eye tracking. Since it is difficult to control for mental set (alertness and imagined target distance) during eye tracking, in addition to paying attention to the apparent sensation of self-motion, the sensation of rotation and the induced vestibular nystagmus were investigated separately. RESULTS: ANOVA failed to reveal any significant effect. Our results suggested that tactile cueing did not enhance or suppress the subjective sensation of rotation during actual rotation, nor did it enhance or suppress the false sensation of rotation experienced. Also, tactile cueing had no effect on the gain and time constant of the induced per-rotation and post-rotation nystagmus with repeated exposures. CONCLUSION: It appears that tactile cueing delivered by a tactile garment provides a sense of direction, but it does not affect any concomitant vestibular responses.

Desensitization to strong vestibular stimuli improves tolerance to simulated aircraft motion.

INTRODUCTION: The extent to which tolerance acquired in one motion environment can be transferred to another has not been fully elucidated. This study compares three provocative motion stimuli and whether tolerance acquired from cross-coupled motion and torso rotation can be transferred to simulated aircraft motion. METHOD: There were 18 healthy subjects (9 men and 9 women), 18-44 yr of age, who were divided into 3 groups. Each group was exposed to the following desensitization procedure in a pseudo-random repeated measures design. In condition D1, subjects were exposed to 4 consecutive days of cross-coupling and on the 5th d they were exposed to simulated aircraft motion. In D2, subjects were exposed to 4 consecutive days of torso rotation and on the 5th day they were exposed to the simulated aircraft motion as in D1. In D3, subjects were exposed to 5 consecutive days of simulated aircraft motion. Based on Graybiel's diagnostic criteria, severity of motion sickness on the 1st and 5th day in D1, D2, and D3 were compared. RESULTS: Cross-coupled motion was the most provocative stimulus followed by torso rotation and simulated aircraft motion. Within each motion stimulus, there was evidence of desensitization (p < 0.001) within 4 d. There were no significant differences in the severity of motion sickness observed on the 5th day regardless of the desensitization stimuli. CONCLUSION: Our results suggest that desensitization to one provocative motion could be transferred to a less severe motion stimulus. This result could be used in the refinement of desensitization programs for aircrew.

Physiological and behavioral responses to an exposure of pitch illusion in the simulator.

BACKGROUND: It has been suggested that a pilot's physiological and behavioral responses during disorientation can provide a real-time model of pilot state in order to optimize performance. We investigated whether there were consistent behavioral or physiological "markers" that can be monitored during a single episode of disorientation. METHODS: An Integrated Physiological Trainer with a closed loop interactive aircraft control and point of gaze/eye-tracking device was employed. There were 16 subjects proficient in maintaining straight and level flight and with procedures in changing attitude who were exposed to yaw rotation and a brief head roll to 35 +/- 2 degrees. On return to upright head position, subjects were required to initiate either an ascent or descent to a prescribed attitude. BP, HR, skin conductance, eye movements, and point of gaze were monitored throughout the onset, duration, and immediately after the disorientation insult. Simultaneously, airspeed and power settings were recorded. RESULTS: Compared with the control condition, a significant increase (p < 0.01) in HR, HR variability, and mean arterial BP was observed during the disorientation. Flight performance decrement was reflected by a significant delay in setting power for attitude change and deviation in maintaining airspeed (p < 0.01). CONCLUSION: Changes in cardiovascular responses appear to be correlated with the onset of disorientation. The correlation of changing eye-tracking behavior and flight performance decrement is consistent with our previous findings. Further study is required to determine whether these findings can be extrapolated to repeated exposures and to other disorientation scenarios.

Acceleration effects on pupil size with control of mental and environmental factors.

BACKGROUND: Using still photography and cinematography, early studies reported that pupils dilate immediately on exposure to acceleration and the dilation persists during sustained +Gz. Due to the lack of control for mental and environmental factors and poor sampling rate in early techniques, we re-examined the effects of increased acceleration on pupil size in the human centrifuge. METHODS: Eight volunteers were dark adapted for 20 min by fixating on a 2.5 mm LED disk, 1 m away in otherwise complete darkness. Pupil diameters and horizontal and vertical eye movements were recorded binocularly in real time using an eye-tracking and pupillometry system. The recording sequence consisted of 1 min at +1 Gz, followed by transition to +3 Gz at 0.1 G x s(-1) 2 min at sustained +3 Gz, return to +1 Gz at 1 G x s(-1), and finally maintained at +1 Gz for another minute. During this sequence, the subject's heart rate was also monitored and the subject was instructed to subtract 2 from 1000 to maintain mental alertness. RESULTS: All subjects showed a significant decrease in pupil diameter (p < 0.05) and increase in heart rate (p = 0.02) during +3 Gz and regained the baseline level on sustained acceleration ranged from 0.6 to 3.3 mm. CONCLUSION: Our findings suggest that pupils constrict during hypergravity. It appears that the reflex regulation of pupil size is attributed to parasympathetic action through fibers originating in Edinger-Westphal's nucleus in the mesencephalon, which receives direct input from the otoliths.

Failure of cetirizine and fexofenadine to prevent motion sickness.

OBJECTIVE: To determine the effectiveness of 2 second-generation antihistamines in modulating motion sickness induced by Coriolis vestibular cross-coupling stimulation. METHODS: This prospective, randomized, double-blind, crossover, placebo-controlled study was conducted in 18 healthy adults. Subjects were exposed to Coriolis vestibular cross-coupling in the laboratory using the Staircase Profile Test for baseline susceptibility and when under the influence of cetizirine, fexofenadine, and placebo. Subjective evaluation of sickness symptoms was based on the Graybiel diagnostic criteria of acute motion sickness, Golding's scale, and the Coriolis Sickness Susceptibility Index. RESULTS: Repeated measures ANOVA and Friedman nonparametric ANOVA of rank tests revealed that there were significant differences in symptom assessments based on Graybiel's diagnostic criteria (p < or = 0.001), subjective symptoms of motion sickness (p < or = 0.001), and state-anxiety (p < or = 0.001) before and after motion exposure. However, there are no significant differences between the baseline susceptibility to motion sickness and treatment with placebo, cetirizine, or fexofenadine. CONCLUSIONS: The failure of the second-generation antihistamines cetirizine and fexofenadine to prevent motion sickness suggests that the therapeutic actions of this class of antihistamines against motion sickness may be mediated through central versus peripheral receptors. The sedative effect of other antihistamines, such as hydroxyzine, may play a more significant role in alleviating motion sickness than previously thought.

Eye tracking, point of gaze, and performance degradation during disorientation.

BACKGROUND: The cognitive cockpit concept has been proposed as a potential disorientation countermeasure. It involves monitoring the pilot's physiological, behavioral and subjective responses during disorientation. This data is combined to provide a real time model of pilot state, which is used as a basis for optimizing pilot performance. This study attempts to investigate whether there are consistent behavioral or physiological "markers" that can be monitored during a specific disorientation scenario. METHODS: An Integrated Physiological Trainer with interactive aircraft controls and an eye-tracking device was employed. Fourteen subjects proficient in maintaining straight-and-level flight and who have acquired the skills in changing attitude participated in the study. They were exposed to a flight profile consisting of straight-and-level flying and change in attitude without exposure to a head roll (control condition) and a profile with exposure to a head roll (experimental conditions) during constant yaw rotation. Flight performance parameters and subjects' eye movements and point of gaze behavior were monitored continuously. RESULTS: Immediately on the return to upright head position, all subjects reported a strong apparent pitch displacement that lasted < or = 20 s and a lesser sensation of lateral movement. Significant differences (p < 0.01) were noted on a number of scanning behaviors between the control and the experimental conditions. The appearance of nystagmus was apparent as indicated by the number of involuntary saccades during disorientation. Flight performance decrement in the experimental conditions was reflected by a significant deviation in maintaining airspeed (p < 0.01). CONCLUSION: It appears that the pitch illusion consistently affects visual scanning behavior and is responsible for the decrement in flight performance observed in the simulator.

Lack of gender difference in motion sickness induced by vestibular Coriolis cross-coupling.

It has been reported that females are more susceptible to motion sickness than males. Supporting evidence is primarily based on retrospective survey questionnaires and self-reporting. We investigated if there is a gender difference in motion sickness susceptibility using objective and subjective measurements under controlled laboratory conditions. Thirty healthy subjects (14 males and 16 females) between the ages of 18-46 years were exposed to Coriolis cross-coupling stimulation, induced by 120 degrees /s yaw rotation and a simultaneous 45 degrees pitch forward head movement in the sagittal plane every 12 seconds. Cutaneous forearm and calf blood flow, blood pressure, and heart rate were monitored. Graybiel's diagnostic criteria were used to assess sickness susceptibility before and after motion exposure. Golding and Kerguelen's scale was used to assess the severity of symptoms during motion exposure. A significant (p<0.01) increase of forearm and calf blood flow during cross-coupling stimulation was observed in both sexes. However, the subjective symptoms rating and blood flow measurements indicate that there was no significant difference between male and female subjects. Our data also suggests that females may be more inclined to admit discomfort as indicated by their responses to a survey of motion sickness history prior to the experiment.