Feasibility of collecting longitudinal patient-reported outcomes in individuals with relapsed or refractory large B-cell lymphoma who received chimeric antigen receptor T-cell (CART) therapy.

PURPOSE: Chimeric antigen receptor T-cell (CART) therapy has shown clinical efficacy in refractory and relapsed large B-cell lymphomas, but is associated with serious acute and long-term toxicities. To understand the patient perspective, we measured a patient-reported outcome (PRO), specifically, health-related quality of life (HRQoL), at multiple time points over one year. METHODS: This was a prospective feasibility study of a cohort of patients who were eligible for standard of care CART therapy, tisagenlecleucel. Demographic data and disease characteristics were collected. HRQoL was measured using FACT-Lym at baseline, and months 1, 3, 6 and 12. FACT-Lym includes FACT-G (physical, social, emotional and functional well-being domains), plus a lymphoma subscale. RESULTS: Thirty-four of 35 patients approached, consented to participate. Two of them did not receive their infusion due to progressive disease. 50% were female and median age was 62 (23-77). Twenty-nine patients (91%) completed baseline FACT-Lym and 20 of 21 (95%) eligible patients completed 12-month FACT-Lym. 52% completed all 4 post-baseline FACT-Lym measures. Exploratory analyses for changes in FACT-Lym scores are reported. CONCLUSION: It is feasible to measure longitudinal PROs in patients who receive CART therapy. This study will inform future studies in evaluating the patient perspective on CART therapy.

Effect of asthma and six-months high-intensity interval training on heart rate variability during exercise in adolescents.

Little is known regarding the influence of asthma and exercise, and their interaction, on heart rate variability (HRV) in adolescents. Thirty-one adolescents with asthma (13.7±0.9 years; 21.9±3.9 kg·m-2; 19 boys, 12 girls) and thirty-three healthy adolescents (13.8±0.9 years; 20.3±3.2 kg·m-2; 16 boys, 17 girls) completed an incremental ramp test and three heavy-intensity constant-work-rate cycle tests. Thirteen adolescents (7 boys, 6 girls; 6 asthma, 7 control) completed six-months high-intensity interval training (HIIT) and were compared to age- and sex-matched controls. Standard time-domain, frequency-domain and non-linear indices of HRV were derived at baseline, three- and six-months. Asthma did not influence HRV at baseline or following HIIT. Total power, low frequency and normalised low frequency power, and sympathovagal balance increased at three-months in HIIT, subsequently declining towards baseline at six-months. Normalised high frequency power was reduced at three-months in both groups, which was sustained at six-months. No effects of HIIT were observed in the time-domain nor in the non-linear indices. HRV was not influenced by asthma, potentially because such derangements are a function of disease progression, severity or duration. HIIT may be associated with a short-term shift towards greater sympathetic predominance during exercise, perhaps caused by physiological overload and fatigue.

Perceptions of asthma and exercise in adolescents with and without asthma.

OBJECTIVE: To elicit the views of adolescents, with and without asthma, about exercise and asthma, and the perceived benefits of and barriers to participation. The adolescent views elicited would subsequently inform the design of a high-intensity exercise intervention to improve asthma control. METHODS: Fifty-four adolescents (age 13.1 ± 0.9 years; 26 with asthma) participated in twelve semi-structured group interviews. Questions were structured around knowledge, attitudes and beliefs towards asthma and its impact on exercise participation and lifestyle. The interviews were transcribed verbatim, thematically analysed and presented via diagrams of emergent themes. Ethical approval was granted by the institutional research ethics committee. RESULTS: Fear of an asthma attack emerged as the main barrier to exercise, with many adolescents with asthma withdrawing from exercise as a coping strategy; many healthy adolescents perceived this withdrawal as laziness or an excuse. Despite this, the majority (81%) of adolescents with asthma reported exercise to be their most enjoyable activity. Adolescents suggested incorporating mixed activities, such as team games (e.g., rounders, football, netball), for future interventions to ensure adherence. CONCLUSIONS: Whilst exercise is important in the management of asthma, the tendency of those with asthma to withdraw from exercise to avoid adverse events could be addressed through a games-based high-intensity exercise intervention. Furthermore, educating all adolescents on asthma could simultaneously reduce stigmatisation and enhance exercise engagement.

Fetal thoracoamniotic shunting for large macrocystic congenital cystic adenomatoid malformations of the lung.

OBJECTIVE: To evaluate fetal thoracoamniotic shunting for isolated large macrocystic congenital cystic adenomatoid malformations (CCAM) of the lung. METHODS: This was a retrospective study of 11 fetuses with macrocystic CCAM who underwent thoracoamniotic shunting. This procedure was offered if fetal hydrops or signs of evolving hydrops (such as ascites or polyhydramnios) were present, or when there were very large lesions or lesions rapidly increasing in size. If there were multiple large cysts within the lesion, a single shunt was used, aiming to traverse several cysts. RESULTS: Shunts were inserted at a mean gestational age of 24.6 (range, 17-32) weeks. Marked mediastinal shift was present in all cases. Six fetuses were hydropic and, of the remaining five, one had severe polyhydramnios, three had lesions that were rapidly increasing in size and one had a very large lesion at initial presentation. In total, four cases had polyhydramnios. Shunting one cyst always decompressed the entire lesion and hydrops and/or polyhydramnios resolved in all surviving fetuses. One hydropic fetus that underwent the procedure at 17 weeks died 1 day later. The shunt dislodged in one case and the lesion did not re-expand. No mother went into labor or had ruptured membranes before 35.6 weeks. Mean gestational age at delivery was 38.2 weeks (n = 10). All pregnancies were delivered vaginally, with no maternal complications. All newborns had uneventful lobectomies, and pathology confirmed CCAM in all cases. CONCLUSION: Fetal thoracoamniotic shunting for large macrocystic CCAM is associated with favorable outcome in most cases, and should be considered in severe cases even before hydrops develops.

Fetal sensory-elicited body movements differ in breech compared to cephalic position.

Behavior was examined in 28 near term fetuses in the breech versus cephalic position. Breech fetuses had fewer body movements to a vibroacoustic stimulus and more to an airborne sound. These findings raise the possibility of differential perceptual experience before birth.

A prospective study of Rivaroxaban for central venous catheter associated upper extremity deep vein thrombosis in cancer patients (Catheter 2).

INTRODUCTION: Patients with cancer are at increased risk of thrombosis, particularly those with central venous catheter (CVC) placement, which may predispose to the development of upper extremity deep vein thrombosis (UEDVT). Standard treatment includes low molecular weight heparin (LMWH) or LMWH bridged to warfarin. The direct oral anticoagulants (DOACs) have become standard of care for uncomplicated venous thromboembolism (VTE), but research in patients with cancer is ongoing. OBJECTIVES: To assess rivaroxaban monotherapy in patients with cancer who develop UEDVT due to CVC for preservation of line function, and safety outcomes of VTE recurrence, bleeding risk and death. MATERIALS AND METHODS: Patients ≥18years of age with active malignancy and symptomatic proximal UEDVT with or without pulmonary embolism (PE), associated with a CVC, were eligible. Treatment included rivaroxaban 15mg oral twice daily for 3weeks, followed by 20mg oral daily for 9weeks. Patients were followed clinically for 12weeks to assess for line function, recurrent VTE and bleeding. RESULTS: Seventy patients (47 women) were included, with mean age 54.1years. The most common malignancy was breast cancer (41%). Preservation of line function was 100% at 12weeks. The risk of recurrent VTE at 12weeks was 1.43%, with one episode of fatal PE. 9 patients (12.9%) experienced 11 total bleeding episodes. CONCLUSIONS: Rivaroxaban showed promise in treating CVC-UEDVT in cancer patients, resulting in preserved line function. However, bleeding rates and a fatal pulmonary embolism on treatment are concerning safety outcomes necessitating further study before rivaroxaban can be recommended.

Prion diseases and the gastrointestinal tract.

The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Although they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPsc propagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer's patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPsc in the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies.

Effects of antifungals on the viability of heart valve cusp derived fibroblasts.

Fibroblasts were isolated from fresh porcine aortic cusps and their identity confirmed morphologically and biochemically. The fibroblasts were used to assess the cytotoxicity of nystatin and amphotericin B at room temperature and 4 degrees C, following exposure periods of 4, 24, and 48 h. Except at the highest concentration and the longest exposure period at room temperature, nystatin had little detrimental effect compared with the nystatin free control. In contrast, amphotericin B proved highly cytotoxic. Published protocols for the use of amphotericin B in the disinfection of viable heart valve allografts would result in little residual fibroblast viability. We recommend that amphotericin B is no longer used in this situation.

Normal-pressure hydrocephalus. Is cisternography still useful in selecting patients for a shunt?

The clinical usefulness of cisternography in selecting patients with presumed normal-pressure hydrocephalus for shunting was investigated in 76 patients. The predictive value of a scale based on combined clinical and computed tomographic criteria was first established, followed by an assessment of the predictive value of cisternography. Predictions based on cisternograms were identical to those of the clinical/computed tomographic scale in 43%, better in 24%, and worse in 33%. Our findings suggest that cisternography does not improve the diagnostic accuracy of combined clinical and computed tomographic criteria in patients with presumed normal-pressure hydrocephalus.

Frame-mounted porcine valve bioprostheses: preparation during aortic-root dilation. Biomechanics and design considerations.

The leaflet geometry and function of frame-mounted porcine bioprostheses prepared with dilation of the aortic root during frame mounting was investigated. The diameter of the porcine aortic root increased by 47% when dilated with a pressure of 120 mm Hg. In the absence of pressure dilation, the ratio of circumferential leaflet length to the radius of the aortic root (S/RA) was 2.7 +/- 0.1, and the angle of inclination of the leaflet to the base of the valve was 17 +/- 4.3 degrees. In this condition, the leaflet geometry was similar to that of some second-generation porcine bioprostheses, which demonstrated high open-leaflet bending strains at the commissures. Dilation of the porcine root with 120 mm Hg reduced the value of S/RA to 1.84 and produced a triangular open-leaflet configuration with minimum open-leaflet bending strains. Open-leaflet bending strains were also reduced in two prototype frame-mounted valves prepared with partial dilation of the aortic root, which had an S/RA ratio of less than 2.3 and a leaflet angle greater than 27 degrees. The study indicates that the next generation of porcine bioprostheses should be prepared with at least 17% dilation of the aortic root during frame mounting and with zero pressure difference across the leaflets during fixation. This can be achieved by applying an equal hydrostatic pressure to both sides of the valve leaflets during fixation and frame mounting.

Biomechanics of glutaraldehyde-treated porcine aortic roots and valves. An investigation of the effect of predilation of the elastic aortic root.

The biomechanics and function of fresh porcine aortic roots and valves have been compared with those of glutaraldehyde-treated roots prepared in a conventional manner without dilation of the elastic aortic root and with glutaraldehyde-treated roots prepared with permanent predilation during fixation. The glutaraldehyde-treated aortic walls were significantly less extensible than fresh walls, with a mean dilation of only 6% compared with 45% for the fresh root at 120 mm Hg pressure. Permanent predilation of the aortic root during fixation allowed the total dilation of the fixed root to be increased to 19% at 120 mm Hg pressure. The effective orifice area of the fresh root and valve was significantly greater than those of the fixed roots and valves, with permanent predilation fixation producing a significantly greater orifice area than conventional fixation. The open-leaflet bending deformations were found to be lower in the valves fixed after permanent predilation than in the standard fixed valves. The glutaraldehyde-treated porcine root and valve does not reproduce the biomechanics and function of the fresh/root, because of the reduced extensibility of the fixed aortic wall. Permanent predilation during fixation helps to partially overcome the shortcomings of the fixed root, producing better function than a standard fixed valve.

Maximal exercise testing in late gestation: fetal responses.

OBJECTIVE: To determine the fetal response to and safety of maximal maternal exercise in the third trimester. METHODS: Twenty-three active women with uncomplicated pregnancies (singleton gestations) underwent maximal exercise testing in late gestation using a progressive maximal cycle ergometer protocol. Fetal heart rate (FHR) responses were monitored and classified using National Institute of Child Health and Human Development guidelines. Statistical analyses involved use of the Student t test, repeated measures analysis of variance with Tukey-Kramer multiple comparisons posttest, and the chi(2) test. RESULTS: There was an increase in baseline FHR in the 20-minute posttest period compared with the 20-minute pretest period. There were significantly fewer accelerations in the second posttest 10-minute segment compared with the second pretest 10-minute segment. Variability was reduced in both posttest periods compared with the first 10-minute pretest period. Time to reactivity increased after testing. Mild tachycardia was noted in two tracings and bradycardia occurred in a fetus with previously undiagnosed growth restriction. There were no abnormal neonatal outcomes. CONCLUSION: Maximal exercise testing in late gestation led to minimal changes in FHR. Fetal bradycardiac responses were not seen in appropriate for gestational age fetuses, suggesting that brief maximal maternal exertion for research or diagnostic purposes is safe in this group.

Maximal exercise testing in late gestation: maternal responses.

OBJECTIVE: To study the effects of human pregnancy on metabolic and respiratory responses to maximal cycle ergometer testing and to test the hypothesis that the respiratory exchange ratio at maximal exercise and peak postexercise lactate concentration are lower in the pregnant compared with the nonpregnant state and that these effects are associated with lower excess postexercise oxygen consumption during pregnancy. METHODS: The pregnant (n = 14, mean gestational age 34.7 +/- 0.4 weeks) and nonpregnant control group (n = 14) included healthy, physically active women. Groups were matched for age, height, parity, prepregnant body mass and body mass index (BMI), and aerobic fitness. Breath-by-breath gas exchange was measured at rest, during exercise, and 15 minutes after exercise. The minimum sample size to detect a statistically significant result for a reasonable difference (0.25 L/min) in the ventilatory threshold was calculated to be ten subjects per group; thus, 14 was considered adequate. RESULTS: Maximal oxygen uptake, the ventilatory threshold, the point of respiratory compensation, and calculated work efficiency did not differ significantly between groups. However, the respiratory exchange ratio at maximal exercise, peak postexercise lactate, and excess postexercise oxygen consumption were significantly lower in the pregnant group. Peak lactate was significantly correlated with the respiratory exchange ratio and excess postexercise oxygen consumption. CONCLUSION: The capacity for weight-supported work is preserved in late gestation, and work efficiency is unchanged. However, carbohydrate utilization might be blunted at high levels of exertion. Blunted respiratory responses were attributed to reduced lactate production and/or dilution of lactate in an expanded blood volume.

Effects of human pregnancy on cardiac autonomic function above and below the ventilatory threshold.

This study examined the effects of human pregnancy on heart rate variability (HRV), spontaneous baroreflex (SBR) sensitivity, and plasma catecholamines at rest and during exercise. Subjects were 14 healthy, physically active pregnant women (PG; mean gestational age = 33.9 +/- 1.0 wk). Results were compared with an age-matched nonpregnant control group (NPG; n = 14) with similar characteristics. The electrocardiographic R-wave-R-wave interval and systolic blood pressure (via finger plethysmograph) were measured on a beat-to-beat basis at rest and during upright cycling at 60 and 110% of the ventilatory threshold (T(vent)). Parasympathetic nervous system (PNS) modulation (as reflected by HRV high-frequency/total power and SBR slope) was significantly reduced at rest in the PG vs. the NPG. During exercise, PNS modulation decreased significantly in both groups, but the magnitude of PNS withdrawal from rest to 110% T(vent) was smaller in the PG vs. NPG. Sympathetic nervous system (SNS) modulation (reflected by the low-frequency power-to-high-frequency power ratio) increased above resting values at 60 and 110% T(vent) in the NPG. SNS modulation at 110% T(vent) was significantly lower in the PG compared with the NPG. Plasma norepinephrine and epinephrine levels were also lower at 110% T(vent) in the PG. It was concluded that healthy pregnant women exhibit lower PNS modulation at rest and blunted SNS modulation during exercise above T(vent) in late gestation.

Comparative study of the hydrodynamic function of the CarboMedics valve.

The hydrodynamic function of each size of the CarboMedics valve was assessed in a pulsatile flow simulator. The mean pressure difference with respect to forward flow, regurgitant volumes, and total energy loss across each valve were analyzed. The results for the 23-mm aortic and 29-mm mitral CarboMedics valves were compared with those for the St. Jude Medical and Björk-Shiley Monostrut valves. Results showed good hydrodynamic function for each CarboMedics valve, although the pressure difference and total energy loss across the 19-mm aortic valve was high. The hydrodynamic function of the CarboMedics valve was comparable with that of the St. Jude Medical valve. Both valves showed similar leakage volumes, which were significantly larger than that for the Björk-Shiley Monostrut valve. On account of this the total energy loss in the Björk-Shiley valve was significantly less than that for the bileaflet valves in the aortic position. Concern remains for the continuing presence of high closed-valve regurgitation in the bileaflet valves.

Geometry of homograft valve leaflets: effect of dilation of the aorta and the aortic root.

With the increasing interest in aortic homografts as either a free-sewn valve or whole-root replacement, the effect of internal pressure and dilation of the aorta and aortic root on valve leaflet geometry has been studied. Seven aortic homograft roots were studied, six that had been stored in antibiotics and one that had been cryopreserved. The diameter of the aorta was determined as a function of internal pressure and correlated with the stress-strain characteristics of the aortic wall. Three-dimensional leaflet surface geometry was measured in the "neutral" position, and the leaflet was characterized by its radius of curvature and angle of inclination, using a cylindrical model. The diameter of the aorta increased by between 30% and 50% as the dilation pressure increased from 0 to 120 mm Hg. This was consistent with the stress-strain data obtained from strips of the aortic wall in the circumferential direction. The angle of inclination of the leaflet increased from 20 to 80 degrees and the radius of curvature increased from 4 to 17 mm as the internal pressure increased from 0 to 80 mm Hg. The open leaflet configuration showed a triangular orifice with low bending strains for a dilated root, but increased bending strains with reduced dilation pressure. These are important considerations when implanting a free-sewn homograft into the aortic root.

Leaflet geometry and function in porcine bioprostheses.

The leaflet geometry and hydrodynamic function of five porcine bioprostheses have been studied and compared to a fresh tissue porcine valve. The neutral leaflet geometries in two high pressure fixed valves (Carpentier Edwards and Hancock) and two low pressure fixed valves (Carpentier Edwards Supra-Annular and Hancock 2) had been modified during fixation and mounting. The leaflets were extended or displaced downwards towards the base of the valve, producing a higher ratio of circumferential leaflet length to inter-commissural spacing than in the fresh tissue valve. This produced high bending strains in the commissural area of the open leaflet in hydrodynamic tests. The leaflet geometry of the fresh tissue porcine valve studied was defined by a cylindrical shell inclined at approximately 27 degrees to the base of the valve and showed reduced open leaflet bending strains. Leaflet opening at low flows was dependent on leaflet geometry. Geometrical changes which are induced during mounting and fixation produced higher bending strains in the commissural area of the open leaflets. These may be contributing factors to tissue degeneration and calcification in this area.

The hydrodynamic function and leaflet dynamics of aortic and pulmonary roots and valves: an in vitro study.

Fresh homograft aortic and pulmonary roots were tested in a pulsatile flow simulator to assess their hydrodynamic function and leaflet opening characteristics. Simultaneous flow and pressure measurements were obtained for a range of cardiac outputs. The effective orifice area and regurgitant volumes were calculated. The mean pressure difference across the pulmonary roots was obtained under both left and right side pressures. A video recording of valve leaflet function was also obtained for each valve. A comparison was made with four porcine bioprosthetic heart valves (21 and 23 mm). The mean pressure difference with respect to flow for the 21 mm Hancock II and Intact porcine bioprostheses was significantly higher than that for all aortic roots tested. The 24 mm aortic root showed significantly lower pressure drop compared to all porcine valves tested. The mean pressure difference across each pulmonary root at pulmonary pressures was significantly greater than at systemic pressures. At systemic pressures the fully open leaflets had a triangular orifice with low leaflet open bending strains at the commissures. At the lower internal pressures, with reduced dilation of the root, higher bending strains were noted. These were not as severe as seen in porcine valves.

Mitral valve replacement with the Carpentier-Edwards standard bioprosthesis: performance into the second decade.

From March 1978, 196 Carpentier-Edwards standard bioprostheses (stCE) were implanted in 194 patients. There were 154 isolated mitral valve replacements (MVR) and 42 aortic plus mitral valve replacements (AVR/MVR) with a mean follow-up of 7.05 (range 0-15.2) years and 7.15 (range 0-13.8) years, respectively. Freedom from structural valve failure at 10 years was 70.8% +/- 4.9% (MVR) and 59.6% +/- 11.1% (AVR/MVR). The incidence of structural valve failure increased sharply after 7 years. Freedom from thromboembolism was 83.0% +/- 3.8% (MVR) and 89.0 +/- 6.0% (AVR/MVR). Thromboembolic events were related to the presence of atrial fibrillation in patients not receiving anticoagulation. Anticoagulant-related haemorrhage was rare. Freedom from mitral valve prosthetic endocarditis at 10 years was 90.9% +/- 3.1% (MVR) and 86.1% +/- 8.4% (AVR/MVR). Prosthetic valve endocarditis was associated with more than 60% mortality. The probability of event-free survival at 10 years follow-up was 43.6% +/- 4.6% (MVR) and 33.3% +/- 8.6% (AVR/MVR). The performance of the stCE in the mitral position shows a low rate of thromboembolic events and anticoagulant-related haemorrhage, but the long-term performance of the prosthesis is unsatisfactory due to a high rate of structural valve failure. This confirms earlier reports.