Calibrated transmission and reflection from a multi-qubit microwave package.

We report calibrated microwave transmission and reflection measurements of a qubit sample holder at millikelvin temperatures. The methodology we present extends our previous work on one-port cryogenic short-open-load (SOL) calibration to a two-port SOLT measurement by implementing an unknown thru (T) standard. We report the resulting calibrated transmission and reflection at millikelvin temperatures through a printed circuit board that is installed into the sample holder. Finally, we consider a cascade of components at the end of a qubit drive line that includes (1) a cryogenic attenuator, (2) a coaxial cable, and (3) a qubit sample holder. Using experimentally determined parameters for return losses for all three components, we calculate the negligible state-preparation error in the frequency band of 5-7 GHz due to control pulse distortions arising from reflection at the coaxial launches. Taken together, our results highlight the utility of calibrated cryogenic scattering parameter measurements for the validation of qubit packaging and the wiring in its immediate vicinity.

The association of selected multiple sclerosis symptoms with disability and quality of life: a large Danish self-report survey.

BACKGROUND: People with multiple sclerosis (MS) experience a wide range of unpredictable and variable symptoms. The symptomatology of MS has previously been reported in large sample registry studies; however, some symptoms may be underreported in registries based on clinician-reported outcomes and how the symptoms are associated with quality of life (QoL) are often not addressed. The aim of this study was to comprehensively evaluate the frequency of selected MS related symptoms and their associations with disability and QoL in a large self-report study. METHODS: We conducted a cross-sectional questionnaire survey among all patients at the Danish Multiple Sclerosis Center, Copenhagen University Hospital, Denmark. The questionnaire included information on clinical and sociodemographic characteristics, descriptors of QoL and disability, as well as prevalence and severity of the following MS symptoms: impaired ambulation, spasticity, chronic pain, fatigue, bowel and bladder dysfunction, and sleep disturbances. RESULTS: Questionnaires were returned by 2244/3606 (62%). Participants without MS diagnosis or incomplete questionnaires were excluded, n = 235. A total of 2009 questionnaires were included for analysis (mean age 49.4 years; mean disease duration 11.7 years; and 69% were women). The most frequently reported symptoms were bowel and bladder dysfunction (74%), fatigue (66%), sleep disturbances (59%), spasticity (51%) and impaired ambulation (38%). With exception of fatigue and sleep disturbances, all other symptoms increased in severity with higher disability level. Invisible symptoms (also referred to as hidden symptoms) such as fatigue, pain and sleep disturbances had the strongest associations with the overall QoL. CONCLUSION: We found invisible symptoms highly prevalent, even at mild disability levels. Fatigue, pain and sleep disturbances had the strongest associations with the overall QoL and were more frequently reported in our study compared with previous registry-based studies. These symptoms may be underreported in registries based on clinician reported outcomes, which emphasizes the importance of including standardized patient reported outcomes in nationwide registries to better understand the impact of the symptom burden in MS.

Illegal cannabis use is common among Danes with multiple sclerosis.

BACKGROUND: Use of cannabis to alleviate multiple sclerosis (MS)-related symptoms is increasing. Due to strict regulations, only a minority of MS patients receive cannabis-based prescription drugs. The extent of recreational and medical cannabis use among Danes with MS is unknown. Our aim was to evaluate the prevalence of illegal and legal use of cannabis in MS patients, as well as reasons for use and perceived adverse effects. METHODS: An anonymous questionnaire was sent to all 3606 patients at the Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen. The questionnaire included questions about sociodemographic factors, clinical characteristics and medical or recreational cannabis use. RESULTS: Questionnaires were completed by 2244/3606 (62%), of which 2009 questionnaires from patients with MS or clinical isolated syndrome (CIS) were valid for analysis. Forty-nine percent (980/2009) had used cannabis at least once. Cannabis was used within the past year (current user) by 21%, and only 21% of those received prescribed cannabis-based medicine. Recreational use was reported by 17%. The primary reasons for use were to alleviate pain (61%), spasticity (52%) and sleep disturbances (46%). The most common adverse effects were drowsiness (30%), feeling quiet/subdued (23%) and dizziness (13%). Almost half (44%) of the non-cannabis users would consider use of cannabis to alleviate MS symptoms if the drug was legalized. CONCLUSION: This study shows that illegal cannabis use is common among Danes with MS as only 21% of the current cannabis users received prescribed cannabis-based medicine. Current cannabis users reported high efficacy in relieving pain, spasticity and sleep disturbances. In addition, only mild to moderate severity of adverse effects were reported. To the best of our knowledge, this is the most comprehensive survey of cannabis use among MS patients.

Pain, spasticity and quality of life in individuals with traumatic spinal cord injury in Denmark.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To estimate the prevalence, predictors and impact of self-reported pain and spasticity and examine variables affecting quality of life in individuals with a traumatic spinal cord injury (SCI). SETTING: Nationwide, Denmark. METHODS: An anonymous questionnaire was sent out to individuals with a traumatic SCI. The questionnaire included questions about demographics and SCI characteristics, pain, spasticity and quality of life. RESULTS: In total, 537 questionnaires were completed. Seventy-three percent reported chronic pain of which 60% used descriptors suggestive of neuropathic pain. The average pain intensity and interference were 5.6 (s.d. 2.3) and 5.0 (s.d. 2.8), respectively, on a 0-10 numeric rating scale (NRS), and 28.1% reported severe pain. Seventy-one percent reported spasticity. Average interference of spasticity was 2.9 (s.d. 2.7). Quality of life scores were 6.5 (s.d. 2.5) for life and life situation, 5.5 (s.d. 2.6) for physical health and 6.7 (s.d. 2.6) for mental health on the NRS (0-10). Female gender was associated with lower mental health scores and tetraplegia with lower physical health scores, and high pain interference and shorter time since injury were associated with lower quality-of-life scores for all three parameters. Pain with descriptors suggestive of neuropathic pain was associated with lower quality-of-life scores than pain without such descriptors. CONCLUSION: Chronic pain and spasticity are common problems after SCI, and in particular, high pain interference is associated with lower quality of life.

Association of socioeconomic status with long-term outcomes in 1-year survivors of allogeneic hematopoietic cell transplantation.

The relationship of socioeconomic status (SES) with long-term outcomes in allogeneic hematopoietic cell transplantation (HCT) survivors has not been well described. We studied the association of SES with the outcomes of 283 consecutive allogeneic HCT recipients transplanted between 2003 and 2012 who had survived for at least 1 year in remission. Median annual household income was estimated using Census tract data and from ZIP code of residence. SES categories were determined by recursive partitioning analysis (low SES (<$51 000/year), N=203; high SES (⩾$51 000/year), N=80). In multivariable analyses, low SES patients had higher risks of all-cause mortality (hazard ratio (HR) 1.98, P=0.012) and non-relapse mortality (NRM) (HR 2.22, P=0.028), but similar risks of relapse mortality (HR 1.01, P=0.97) compared with high SES patients. A trend toward better survival and lower NRM for high SES patients with no chronic GVHD was observed; low SES patients without GVHD had similar survival as patients with chronic GVHD. In allogeneic HCT survivors who survive in remission for at least 1 year, SES is associated with long-term survival that is primarily mediated through higher risks of NRM. More research is needed to understand the mechanisms of health-care disparities and interventions to mitigate them.

Risk factors for vancomycin-resistant enterococcus bacteremia and its influence on survival after allogeneic hematopoietic cell transplantation.

Vancomycin-resistant enterococcus (VRE) is a well-known infectious complication among immunocompromised patients. We performed a retrospective analysis to identify risk factors for the development of VRE bacteremia (VRE-B) within 15 months after allogeneic hematopoietic cell transplantation (alloHCT) and to determine its prognostic importance for other post-transplant outcomes. Eight hundred consecutive adult patients who underwent alloHCT for hematologic diseases from 1997 to 2011 were included. Seventy-six (10%) developed VRE-B at a median of 46 days post transplant. Year of transplant, higher HCT comorbidity score, a diagnosis of ALL, unrelated donor and umbilical cord blood donor were all significant risk factors on multivariable analysis for the development of VRE-B. Sixty-seven (88%) died within a median of 1.1 months after VRE-B, but only four (6%) of these deaths were attributable to VRE. VRE-B was significantly associated with worse OS (hazard ratio 4.28, 95% confidence interval 3.23-5.66, P<0.001) in multivariable analysis. We conclude that the incidence of VRE-B after alloHCT has increased over time and is highly associated with mortality, although not usually attributable to VRE infection. Rather than being the cause, this may be a marker for a complicated post-transplant course. Strategies to further enhance immune reconstitution post transplant and strict adherence to infection prevention measures are warranted.

Fludarabine as a risk factor for poor stem cell harvest, treatment-related MDS and AML in follicular lymphoma patients after autologous hematopoietic cell transplantation.

Fludarabine is an effective treatment for follicular lymphoma (FL), but exposure to it negatively impacts stem cell mobilization and may increase the risk of subsequent myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML). We hypothesized that the risk that fludarabine imparts to stem cell mobilization and t-MDS/AML would be affected by dose or timing. All patients with FL treated at Cleveland Clinic from 1991 to 2007 with autologous hematopoietic cell transplantation were evaluated. Recursive partitioning analysis was used to explore associations of fludarabine and mitoxantrone dose and timing with poor stem cell harvest and t-MDS/AML. We identified 171 patients, of whom 52 previously received fludarabine. Patients exposed to fludarabine prior to auto-HCT were more likely to require >5 days of leukapheresis (P<0.001) and second stem cell mobilization (P<0.001), especially at a cumulative dose >150 mg/m(2). Univariable risk factors for t-MDS/AML included the number of chemotherapy regimens before auto-HCT, the need for >5 days of leukapheresis to collect CD34+ cells and fludarabine exposure in a dose-dependent manner, particularly when >500 mg/m(2). A cumulative dose of fludarabine >150 mg/m(2) increases the risk for poor stem cell harvests and any exposure increases the risk of t-MDS/AML, with the greatest risk being at doses >500 mg/m(2).

Etoposide plus G-CSF priming compared with G-CSF alone in patients with lymphoma improves mobilization without an increased risk of secondary myelodysplasia and leukemia.

The use of etoposide (VP-16) for stem cell mobilization has been reported as a significant risk factor for the development of therapy-related myelodysplasia/therapy-related AML (tMDS/tAML) after transplantation. We compared the safety and effectiveness of VP-16+G-CSF (VP+G) to G-CSF alone for PBPC mobilization in patients with non-Hodgkin's lymphoma and Hodgkin's lymphoma who underwent autologous transplantation at the Cleveland Clinic and Ohio State University. In the VP+G group, median total CD34+ cells collected were 9.34 × 10(6) per kg (range 0.97-180.89), with 42% of all patients having adequate (2 × 10(6) cells per kg) CD 34+ collection after 2 days of apheresis compared with a median in the G-CSF group of 3.83 × 10(6) per kg (range, 0.72-50.38), with only 16% patients having adequate collection after 2 days (P<0.001). tMDS/tAML occurred in 15 patients (2.3%) in the VP+G and in 12 patients (3.8%) receiving G-CSF alone. (P=0.62). Increased number of days of apheresis was associated with the risk of tMDS/tAML (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.08-1.30, P<0.001). Priming regimen was not a significant variable for relapse-free survival or OS. The addition of etoposide significantly improves the effectiveness of mobilization at the cost of an increased incidence of neutropenic fever though with no mortalities. There is no evidence of increased incidence of tMDS/tAML in patients receiving VP+G compared with those mobilized with G-CSF alone.

Intravenous compared with oral busulfan as preparation for allogeneic hematopoietic progenitor cell transplantation for AML and MDS.

BU and CY is a common conditioning regimen for allogeneic hematopoietic progenitor cell transplantation (HPCT). I.v. BU is increasingly used in place of the oral formulation for conditioning. We compared the outcomes of 135 consecutively treated AML and myelodysplastic syndrome patients who underwent allogeneic HPCT at our institution with BUCY2 using oral (n=93) or i.v. (n=42) BU, without dose adjustment. The i.v. BU patients had a lower incidence of any severity of oral mucositis (3 versus 55%, P=0.002) and severe mucositis (3 versus 24%, P=0.005). Other post transplant outcomes were comparable between the groups. In all 26 i.v. BU and 33 oral BU patients are alive; however, the median follow-up was significantly longer for the oral BU group. One- and two-year non-relapse mortality for the i.v. BU patients was 21% for both, and for the oral BU group was 23% and 29%, respectively. One- and two-year relapse mortality for the i.v. BU patients was 21% for both, and for the oral BU group was 24% and 29%, respectively. Substituting i.v. for oral BU reduces variability in drug exposure and potentially improves toxicity as suggested by our finding of significantly less oral mucositis and decreased severity with i.v. BU.

Apheresis days required for harvesting CD34+ cells predicts hematopoietic recovery and survival following autologous transplantation.

We sought to determine whether patients requiring more aphereses to obtain adequate numbers of CD34+ cells had delayed hematopoietic recovery following autologous transplantation. We identified 496 consecutive individuals with lymphoma who underwent hematopoietic stem cell mobilization using etoposide and G-CSF and first autologous transplantation. In multivariate analysis, increased apheresis days as a continuous and as a categorical variable at ≥5/<5 days significantly predicted neutrophil recovery. Apheresis days fell just short of significance (P=0.06) as a predictor of platelet recovery in multivariate analysis. Increased apheresis days (as both continuous and categorical variables) were also predictive of treatment-related myelodysplastic syndrome/AML. Patients who underwent ≥5 days of pheresis had significantly worse survival (P=0.001) than patients with less pheresis days owing to significantly higher relapse mortality (P=0.001).

BU- vs TBI-based conditioning for adult patients with ALL.

Evidence suggests an advantage for TBI over BU as a component of conditioning regimens for allogeneic hematopoietic cell transplant in patients with ALL. We have employed both TBI and BU for conditioning in ALL and reviewed our experience to compare outcomes. From July 1989 to June 2008, we identified 86-adult ALL patients treated with either a TBI- or BU-based regimen and transplanted with either a well-matched sibling or unrelated donor. Data including demographics, immunophenotype, disease status and cytogenetic risk were examined by Cox proportional hazards analysis. Patients treated with TBI were older (median age 40 vs 33 years; P=0.018), had a higher-risk cytogenetic profile (P=0.010), were more often transplanted using an unrelated donor (P=0.038) and were treated more recently (P<0.001). There was a significant improvement in EFS (P=0.046), and a trend to improved OS (P=0.08) in patients treated with TBI compared with those treated with BU. However, the advantage for TBI could not be confirmed by multivariable analysis where only disease status retained statistical significance.

Comparison of donor chimerism following myeloablative and nonmyeloablative allogeneic hematopoietic SCT.

Surveillance of hematopoietic chimerism following hematopoietic SCT (HSCT) with nonmyeloablative (NMA) preparative regimens is standard to assess the need for clinical intervention. Monitoring of donor chimerism following HSCT with myeloablative (MA) preparative regimens is, however, not considered useful because engraftment is thought to occur rapidly and consistently. This study compares the timing of donor hematopoietic cell engraftment in patients undergoing NMA conditioning with fludarabine and TBI with those receiving MA conditioning with BU- or TBI-based regimens. Achievement of ≥ 90% donor leukocyte chimerism occurred rapidly and consistently in all three groups and time to achievement of ≥ 90% donor T cells was similar among the three groups (P = 0.57). Achievement of ≥ 90% donor leukocyte chimerism was not associated with risk of acute or chronic GVHD, graft rejection, relapse or all cause mortality in multivariate analyses. Donor T-cell chimerism of ≥ 90% was significantly associated with development of extensive chronic GVHD. The value of routine surveillance of chimerism following any of the preparative regimens used in this study should be reevaluated.

Are backup BM harvests worthwhile in unrelated donor allogeneic transplants?

The Cleveland Clinic blood and marrow transplant program has routinely performed 'backup' autologous harvests in unrelated recipients with hematological malignancies in remission, lymphoma without marrow involvement and CML in chronic phase. We reviewed all adult or cord unrelated donor (URD) transplants performed from January 1995 through September 2008 to evaluate the value of this procedure. Of 130 patients who had backup harvests, 15 (11%) had their backup harvests re-infused, all for graft failure. No patients undergoing fully ablative preparation and unmanipulated or T-depleted grafts from well-matched adult donors required infusion of backup marrow. Nine of 42 patients who underwent T cell grafts from partially matched or mismatched donors, five patients undergoing partially matched ablative transplants from adult donors or cord blood, and one patient undergoing non-myeloablative transplant required infusion of their back-up harvest. Five of 15 patients who received their backup marrow are alive in CR 2-11.6 (median 7.6) years from infusion. Two of these five were bridged to a second URD transplant; the other three showed durable disease-free survival without a second allogeneic transplant. Backup harvest is unnecessary for HLA well-matched myeloablative transplants, but may be useful in patients at higher risk of graft failure.

A randomized trial of etoposide and G-CSF with or without rituximab for PBSC mobilization in B-cell non-Hodgkin's lymphoma.

Some reports have suggested that rituximab administration before PBSC mobilization may adversely affect PBSC yield. We conducted a prospective randomized trial of PBSC mobilization using etoposide and G-CSF with or without rituximab to determine whether its addition would adversely affect CD34+ cell yield in patients with non-Hodgkin's lymphoma. Twenty seven patients were mobilized with etoposide and G-CSF and 28 with etoposide, G-CSF and rituximab. There were no adverse consequences of rituximab on CD34+ cell yield, or hematopoietic recovery or immunoglobulin levels after transplantation.

400 cGy TBI with fludarabine for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation.

Fludarabine and 200 cGy TBI are commonly used for reduced-intensity conditioning preceding allogeneic hematopoietic SCT (HSCT). However, graft rejection and disease relapse are significant causes of treatment failure with this regimen. We modified this regimen by escalating the TBI dose to 400 cGy in 40 patients with hematologic malignancies. Thirty-four patients achieved complete donor T-cell chimerism at a median of 40 days following HSCT. The incidences of grades II-IV and III-IV acute GVHD were 40 and 15%, respectively, whereas that of limited and extensive chronic GVHD were 12 and 20%, respectively. Two patients rejected their grafts and 12 relapsed. The 100-day mortality was 18%, 2-year transplant-related mortality 20% and overall survival was 58% at a median follow-up of 16 months. There were no significant survival differences between patients with lymphoid compared to myeloid malignancies. A dose of 400 cGy TBI administered with fludarabine is well tolerated and further study is needed to determine whether outcomes are superior to those with 200 cGy TBI.