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Cancer patients often want information from "peers" with the same diagnosis or treatment. To increase access to this valuable resource, we developed a website to deliver written peer support to cancer patients undergoing stem cell transplant. Because little evidence describes how to optimize benefits or reduce potential harms of written peer support, we gathered multiple forms of stakeholder feedback to inform the website's ethical approach, personalization, design, function, and content: a Community Advisory Board; a longitudinal study of patients' written peer support needs and motivations; focus groups; semi-structured interviews; and usability testing. Findings provide a rich foundation for website development.

PURPOSE In this work, we propose that Δ B1+ -induced errors in magnetization transfer (MT) saturation (MTsat ) maps can be corrected with use of an R1 and B1+ map and through numerical simulations of the sequence. THEORY AND METHODS One healthy subject was scanned at 3.0T using a partial quantitative MT protocol to estimate the relationship between observed R1 (R1,obs ) and apparent bound pool size ( M0,appB ) in the brain. MTsat values were simulated for a range of B1+ , R1,obs , and M0,appB . An equation was fit to the simulated MTsat , then a linear relationship between R1,obs and M0,appB was generated. These results were used to generate correction factor maps for the MTsat acquired from single-point data. The proposed correction was compared to an empirical correction factor with different MT-preparation schemes. RESULTS M0,appB was highly correlated with R1,obs (r > 0.96), permitting the use of R1,obs to estimate M0,appB for B1+ correction. All B1+ corrected MTsat maps displayed a decreased correlation with B1+ compared to uncorrected MTsat and MTsat corrected with an empirical factor in the corpus callosum. There was good agreement between the proposed approach and the empirical correction with radiofrequency saturation at 2 kHz, with larger deviations seen when using saturation pulses further off-resonance and in inhomogeneous (ih) MTsat maps. CONCLUSION The proposed correction decreases the dependence of MTsat on B1+ inhomogeneities. Furthermore, this flexible framework permits the use of different saturation protocols, making it useful for correcting B1+ inhomogeneities in ihMT.

Background: As the global outbreak of COVID-19 continues to ravage the world, it is important to understand how frontline clinicians manage ventilatory support and the various limiting factors. / Methods: An online survey composed of 32 questions was developed and validated by an international expert panel. / Results: Overall, 502 respondents from 40 countries across six continents completed the survey. The mean number (±SD) of ICU beds was 64 ± 84. The most popular initial diagnostic tools used for treatment initiation were arterial blood gas (48%) and clinical presentation (37.5%), while the national COVID-19 guidelines were the most used (61.2%). High flow nasal cannula (HFNC) (53.8%), non-invasive ventilation (NIV) (47%), and invasive mechanical ventilation (IMV) (92%) were mostly used for mild, moderate, and severe COVID-19 cases, respectively. However, only 38.8%, 56.6% and 82.9% of the respondents had standard protocols for HFNC, NIV, and IMV, respectively. The most frequently used modes of IMV and NIV were volume control (VC) (36.1%) and continuous positive airway pressure/pressure support (CPAP/PS) (40.6%). About 54% of the respondents did not adhere to the recommended, regular ventilator check interval. The majority of the respondents (85.7%) used proning with IMV, with 48.4% using it for 12– 16 hours, and 46.2% had tried awake proning in combination with HFNC or NIV. Increased staff workload (45.02%), lack of trained staff (44.22%) and shortage of personal protective equipment (PPE) (42.63%) were the main barriers to COVID-19 management. / Conclusion: Our results show that general clinical practices involving ventilatory support were highly heterogeneous, with limited use of standard protocols and most frontline clinicians depending on isolated and varied management guidelines. We found increased staff workload, lack of trained staff and shortage of PPE to be the main limiting factors affecting global COVID-19 ventilatory support management.

Psychosocial functioning in bipolar disorder (BD) persists even during euthymia and has repeatedly been associated with illness progression and cognitive function. Its neurobiological correlates remain largely unexplored. Using a structural covariance approach, we explored whole cortex intracortical myelin (ICM) and psychosocial functioning in 39 BD type I and 58 matched controls.TIn BD only, psychosocial functioning was associated with global efficiency (β = -0.312, pThese results uncovered a novel brain-behaviour relationship between intracortical myelin signal changes and psychosocial functioning in BD.

Patients with high-risk multiple myeloma (hrMM) relapse after autologous stem cell transplantation (ASCT) with a median progression free survival (PFS) of 8-14 months without lenalidomide maintenance and 24-39 months with lenalidomide maintenance. We hypothesized that Pembro-Rd will prolong PFS post-ASCT in patients with hrMM compared to historical controls. This Phase II study enrolled hrMM patients with primary objective to assess the efficacy of the combination of Pembro-Rd for a total of 2 cycles and then an additional 2 cycles without dexamethasone. There were 12 evaluable subjects, as enrollment was stopped after an FDA hold. With a median follow-up of 50.7 months, the median PFS was 27.7 months. The PFS rates at years 1 and 2 are 90.9% and 63.6%, respectively. The most common adverse events were neutropenia (grade 1-3), cough, diarrhea and constipation, all grade 1 or 2. The PFS rate with fixed duration therapy was comparable to that seen with continuous dose lenalidomide, potentially offering a new post-ASCT therapeutic strategy. This article is protected by copyright. All rights reserved.

A regimen of escalating doses of thalidomide, in combination with bortezomib and high-dose melphalan (mel/vel/thal), was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients with a prior transplant who had relapsed or achieved less than a complete remission following a prior ASCT. Thalidomide was dose escalated starting from 600 mg to 1000 mg on days −5 to −1 in a 3 × 3 design, bortezomib was administered at 1.6 mg/m2 intravenously on days −4 and −1 and melphalan 200 mg/m2 was administered on day −2. No dose-limiting toxicity was seen in the phase I portion of the trial. An additional 20 patients were enrolled at the maximum tolerated dose of thalidomide of 1000 mg daily. The overall response rate was 69% with 38% complete remission. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. The most common grade 3–4 adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and diarrhea (6.9%). Serious AEs included somnolence (13.8%) and tumor lysis syndrome (3.4%). The addition of high-dose thalidomide to bortezomib and melphalan as conditioning for salvage ASCT was well tolerated and was an effective conditioning regimen.

Background KIR B(x) haplotype donors have been reported to improve outcomes in patients (pts) receiving unrelated donors (URD) for myeloid malignancies, non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Donors are categorized as KIR “Best” or “Better”. Our center performs donor KIR genotyping and haplotype assignment routinely as part of our URD evaluation for pts undergoing transplantation for myeloid disorders, NHL and MM. When presented with multiple equivalently HLA matched URDs, our physicians will prioritize KIR B(X) donors over KIR A/A donors. Weisdorf et. al. (BBMT 2018) suggested that pre-search donor KIR genotyping would accelerate/optimize donor selection. Since 2015, donor KIR genotyping data for > 3 million donors from the DKMS registry is available. We investigated our ability to enhance KIR-favorable donor selections using the DKMS pre-search KIR. Methods In 2018 we requested access to individual KIR donor typing through the National Marrow Donor Program (NMDP) Scientific Services for donors registered by DKMS Germany, DKMS Poland and obtained access to the DKMS Donor Navigator website. Pts with multiple suitable donors were sorted for KIR, if registered by DKMS. Up to 6 donors per patient were selected from the pre-search KIR B(x) donors who ranked KIR “Best”, “Better” and “Neutral”. For pts whose pre-search screen did not identify an adequate number of KIR B(x) informative donors we selected additional donors (KIR unknown) for confirmatory typing. Results Thirty-five pts had informative KIR B(x) pre-search donors identified. There were 1-27 KIR B(x) available donors per pt. The online KIR B Content Calculator ranked these donors as KIR “Best”, “Better”, or “Neutral”. Donors were selected by the physicians, who were unaware of the pre-search ranking. As of Oct 2019, 23 pts were transplanted, 4 are pending. Of these 27 donors selected, 18 were identified in the pre-search group. Six donors (33%) were ranked KIR B “Best”, 10 (55%) “Better”, and 2 (11%) “Neutral”. Nine pts used donors without a pre-search. Five pts did not proceed to an URD transplant, and 3 pts have ongoing searches. Using the pre-search information, 66% of pts received a KIR B(x) donor and we were able to enrich KIR B(x) “Best” and “Better” donor options. Based on registry data, approximately 11%, 20% and 69% of donors randomly selected from a donor registry will be ranked KIR “Best”, “Better” and “Neutral “respectively. For our pt population, we were able to more than double the selection of KIR “Best” and “Better” donors for transplantation. Conclusion The inclusion of KIR donor genotyping on donor registries enriches the number of preferred KIR B (x) donors available and allows a more efficient selection of KIR “Best” and “Better” donors.

Escalating doses of bortezomib with high-dose melphalan was evaluated as as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory multiple myeloma (MM). MM patients with less than a partial remission (PR) (or 50% reduction) compared to their pretransplantation paraprotein parameters after a prior ASCT with melphalan conditioning, or who were in relapse after a prior autologous transplantation, were eligible for study. Bortezomib was dose escalated in steps of 1, 1.3, and 1.6 mg/m2 (3 × 3 design) on days −4 and −1 before transplantation with melphalan 200 mg/m2 given on day −2. Thirty-two patients were enrolled: 12 in the phase I dose escalation phase and an additional 20 in phase II to gain additional experience with the regimen. Twenty-four (75%) patients were Durie Salmon stage III, and 12 (37.5%) had >2 prior lines of therapy. The overall response rate (≥PR) was 44% with 22% complete remission. Two-year overall survival and progression-free survival were 76% and 39%, respectively, with a median follow-up of 31.7 months. The most common grade 3 and 4 nonhematologic adverse events were neutropenic fever (25%), nausea (18.8%), and mucositis (9.4%). Serious adverse events included intensive care unit admission (9.4%), seizure (3.1%), prolonged diarrhea (3.1%), and Guillain-Barre syndrome (3.1%). Two patients (6%) died of sepsis. There was no emergent peripheral neuropathy nor increase in any pre-existing peripheral neuropathy. The addition of bortezomib to melphalan as conditioning for salvage ASCT was well tolerated. More importantly, it can provide durable remission for patients who have a suboptimal response to prior single-agent melphalan conditioning for ASCT, without requiring a reduction in the dose of melphalan. Larger randomized prospective studies to determine the effect of combination conditioning are being conducted.

Most patients eligible for allogeneic hematopoietic stem cell transplantation will require identification of an alternate (unrelated or mismatched related) donor. We explored the transplantation outcomes for a sequential series of 54 patients undergoing haploidentical donor transplantation (HAPLO) compared to those from a control group of patients receiving cells from matched or mismatched unrelated donors (URD) selected by diagnosis and stem cell source. Patients undergoing HAPLO transplantations received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (Cy). Day 15 neutrophil recovery was lower after HAPLO than in URD recipients (43% versus 77%, P .001), as was day 30 platelet recovery (67% versus 84%, P = .043). HAPLO patients receiving bone marrow achieved neutrophil engraftment at a median of 17 days and platelet engraftment at a median of 29 days, compared with 16 days and 24 days, respectively, for recipients of peripheral blood stem cells. The incidence of graft failure was similar for both HAPLO and URD recipients (P = .42). HAPLO recipients were more likely to reach donor CD3 chimerism95% by day 28 after transplantation (88% versus 62%, P = .003). The cumulative incidence of grades II to IV acute GVHD (aGVHD) at 6 months after transplantation did not differ for these 2 groups (63% for HAPLO and 53% for URD recipients; P = .269), nor did the cumulative incidence of severe grade III/IV aGVHD (13% for HAPLO and 8% for URD recipients; P = .44). The cumulative incidence of moderate or severe chronic GVHD at 2 years did not differ, with probabilities of 24% for HAPLO and 18% for URD recipients (P = .43). The cumulative incidence of cytomegalovirus reactivation by day 100 after transplantation did not differ (45% for HAPLO and 46% for URD recipients; P = .96). The HAPLO recipients experienced a lower incidence of Epstein-Barr virus reactivation by day 100 (6% versus 32%, P .001) but a higher incidence of Human Herpesvirus-6 reactivation (35% versus 10%, P = .001). Relapse risk, regimen-related mortality, progression-free survival, and overall survival probabilities did not differ between these 2 groups. These data support the use of HAPLO transplantation with post-transplantation Cy as an alternate transplantation technique for patients lacking HLA-matched sibling donors. Transplantation of peripheral blood stem cells does not appear to enhance the speed of neutrophil recovery. The different patterns of viral reactivation require additional studies to explain.

Background & Aim According to FACT standards, the cell processing facility should perform internal audits on a regular basis. In CTMF, HPC chart completeness is defined as one of the yearly key audit topics. This study is an example of the HPC chart completeness internal audit, in which selected parameters of the HPC chart were audited and analyzed, to indicate trend and help process improvement. Methods, Results & Conclusion Methods The HPC cryopreservation processes occurred in CTMF from 06/01/2018 to 07/15/2018. Total 5 autologous patients chart, 11 processes were audited. Goal: Compliance 95% at the time of audit, 100% after corrections made. Auditor is the laboratory supervisor, who has the knowledge of the processes, and did not participate in the processes being audited, and therefore independent. Results 1. 59 missing / incomplete entries identified at the time of audit, total 604 pages, 2543 entries audited, approximately 97.7% compliance (entries completed out of all audited entries). After correction, 100% compliance. 2. Incomplete Entry Analysis-per Incomplete Type: (1) Sampling Record and Coulter/Flow print-out contributed to a big portion (20%) of all incomplete entries. Major examples are Sampling and Testing Record cover sheet) missing review, or not initialed and dated. (2) Batch Record: label control took up 1/7 of all entries missed in the batch record. All 18 “Batch Record, Others” missing items were from the last day of patient “D”’s last day of the 4-day collection. (3) 45% (5 out of 11) CryoMed print-out did not have initial and / or date. (4) Chain of Custody, Storage Record, Release Criteria were other weak areas affecting the completion rate. See Figure 1. 3. Incomplete Entry Analysis-per timing Min number of collection/process was 1, max 4. 3 patients had 2 days collections. The 4-day collection had the highest incomplete entries per processing day (7.3). Out of the 59 incomplete entries, 43 (73%) were from Processing Days, 16 (27%) were from After Processing Days (post thaw, infusion). 4. Incomplete Entry Analysis-per staff, Incomplete Rate. Figure 2. 5. Incomplete Entry Analysis-as Performer/as Reviewer. Out of the 59 incomplete entries, 47 (80%) were from performers, 12 (20%) were from reviewers. 6. Incomplete Entry Analysis-per staff as Paperwork Manager. Figure 3. Conclusion Audit result is acceptable. Recommendation is to enhance good documentation practice, enhance Paperwork Magager and facility director review in a timely fashion, especially for multiple days collections.

Background & Aim To study the Environment Monitoring (EM) activities in a hospital-based Cell Therapy Manufacturing Facility (mainly processes islet cells and HPC(s), to ensure compliance with FACT (03/2018), ISO14644 (12/2015), validation standards and facility EM SOP. Methods, Results & Conclusion Methods Available EM data from 08/2014 to 12/2017 analyzed, including initial validation EM by vendor. EM are normally performed on a monthly basis, while some months had partial or no EM done due to facility construction, schedule conflicts, or machine error. EM includes particle count (PC), air sampling (AS), contact plate bacterial & fungal (CP). See Image 1 for routine EM locations. CR: Cleanroom; GR: Gown Room; DR: Degown Room; BSC: Biosafety Cabinet. Results In the 41 months, 37 months of particle counts, 40 months of Air Sampling, 38 months of contact plate data were analyzed. Among them, (1) One was In-Process EM, all the others were At Rest EM. The In-Process particle counts were significantly higher than those At-Rest. (2) All critical ISO 5 areas were all within expected ranges for all three EM parameters. (3) Two deviations filed due to high air sampling counts, and both passed after improving operator technique and after facility cleaning. (4) In this 3 year data, particle counts and contact plates results are trending low or stable, within expected range, while Air Sampling results had some fluctuations, see Image 2 and 3. (5) Besides the regular/routine sampling locations, several non-routine sampling locations were also sampled, which detected “mold” in Incubator, “>100 CFU” in freezer, and both repeated “0 CFU” count after equipment decontamination. See Image 3. Conclusion (1) The facility's EM program monitors particulates, microbial contamination, with proper sampling sites, frequency, investigative and corrective actions when specified limits exceeded. (2) All BSC data were satisfactory and safe for cell therapy manufacturing processes. (3) Gown Room and Degown Room were built per ISO 8, and met ISO 7 requirements. (4) More In-Process EM shall be performed to provide baseline data during manufacturing. (5) Non-routine sampling in ISO unclassified areas helps detect suspected/ at risk areas, and help improve the cleanliness of the facility.

Introduction Allogeneic stem cell transplant (alloSCT) provides pts with FLT3-ITD+ AML the highest likelihood of sustained remission, but relapse rates remain high. Post-SCT maintenance therapy may improve this outcome. Objective RADIUS, a randomized, open-label, phase 2 exploratory trial (NCT01883362) investigated whether SOC ± mido after alloSCT reduced relapse rates in pts with FLT3-ITD+ AML. Methods Eligible adults (aged 18-70 y) who had undergone myeloablative alloSCT in first complete remission (hematologic recovery and transfusion independence) were enrolled after engraftment and randomized 28 to 60 days after alloSCT to receive SOC ± mido 50 mg twice daily for up to 12 (4-week) cycles. The primary endpoint was relapse-free survival (RFS) at 18 mo after alloSCT; safety, pharmacokinetics (PK), in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay, overall survival (OS), and RFS at 24 mo after alloSCT were also assessed. The study was not adequately powered to detect a statistical difference between arms; a sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power if the incidence of relapse in the SOC + mido arm was 15%. Results 60 pts were randomized (30 per arm); 30 completed 12 cycles of therapy (14 with SOC; 16 with SOC + mido). The median dose intensity was 93 mg/day (range, 15-100 mg/day). Early discontinuations were similar between arms (15 with SOC; 13 with SOC + mido), often due to adverse events (AEs; 3% vs 27%) and consent withdrawal (20% vs 7%). 19 pts (63%) had mido dose modifications (84% due to AEs; concomitant CYP3A4 inhibitor, n = 1). With SOC alone, the estimated RFS (95% CI) at 18 mo was 76% (54%-88%) vs 89% (69%-96%) with SOC + mido (HR, 0.46 [95% CI, 0.12-1.86]; P = .27); the predicted relative reduction in the risk of relapse with the addition of mido was 54%. At 24 mo, OS (95% CI) was 85% with addition of mido (65%-94%) vs 76% with SOC alone (54%-89%) (P = .3418). PIA was evaluable in 28 pts in each arm; PK was evaluated in the SOC + mido arm. There was wide interpatient variability in trough levels of mido and its active metabolites ([CGP62221] + [CGP52421/5.4]) and in the degree of FLT3 inhibition. With mido, phosphorylated FLT3 (pFLT3) levels were With SOC and SOC + mido, AEs occurred in 87% and 100% of pts; serious AEs occurred in 57% and 30% of pts, respectively. 12 pts died on study (during follow-up phase; 8 with SOC and 4 with SOC + mido [n = 4 vs n = 2 due to AML disease progression]). Conclusion Mido as maintenance therapy was safely added for ≤ 1 y after alloSCT and, when added to SOC, reduced the predicted risk of relapse at 18 mo after alloSCT by 54% (vs SOC). Correlative analysis suggests that high levels of pFLT3 inhibition may positively influence outcomes.

Advanced imaging is commonly used for staging of early-stage breast cancer, despite recommendations against this practice. The objective of this study was to evaluate and compare use of imaging for staging of breast cancer in two integrated health care systems, Kaiser Permanente (KP) and Intermountain Healthcare (IH). We also sought to distinguish whether imaging was routine or used for diagnostic purposes.We identified patients with stages 0 to IIB breast cancer diagnosed between 2010 and 2012. Using KP and IH electronic health records, we identified use of computed tomography, positron emission tomography, or bone scintigraphy 30 days before diagnosis to 30 days postsurgery. We performed chart abstraction on a random sample of patients who received a presurgical imaging test to identify indication.For the sample of 10,010 patients, mean age at diagnosis was 60 years (range, 22 to 99 years); with 21% stage 0, 47% stage I, and 32% stage II. Overall, 15% of patients (n = 1,480) received at least one imaging test during the staging window, 15% at KP and 14% at IH (P = .5). Eight percent of patients received imaging before surgery, and 7% postsurgery. We found significant intraregional variation in imaging use. Chart abstraction (n = 129, 16% of patients who received presurgical imaging) revealed that 48% of presurgical imaging was diagnostic.Use of imaging for staging of low-risk breast cancer was similar in both systems, and slightly lower than has been reported in the literature. Approximately half of imaging tests were ordered in response to a sign or symptom.

Syphilis recognition in HIV-positive patients has important implications. Initial data from this study, established in June 2012 to better understand the natural history of syphilis and treatment response, examine the characteristics of patients including sexual behaviour, rates of concurrent sexually transmitted infections (STI) and type of treatment given.Patients were recruited from Ireland, Poland and Germany. Data gathered included demographics, method of syphilis acquisition, stage of syphilis infection, HIV status, nadir and current CD4 counts and HIV viral suppression rates. Data were then subanalysed into HIV-positive and HIV-negative groups.Of 175 patients recruited, 68% were HIV-positive and 86.3% were men who have sex with men. Most HIV-positive patients presented with secondary syphilis (55.7% vs 13.2%) (p=0.0001) while the majority of HIV-negative patients had primary syphilis noted at the time of recruitment (47.2% vs18.9%, p=0.0002). Approximately half of all patients had a HIV RNA viral load40 copies/mL (55%). Previous syphilis infection occurred more frequently in HIV-positive than HIV-negative patients (p=0.0001). Concurrent STIs at the time of syphilis diagnosis were found in 26.8%, of whom 31 (25.4%) were HIV-positive (p=0.64). HIV-positive patients received doxycycline more frequently than their HIV-negative counterparts (33.6% vs 1.9%, p=0.0001) while HIV-negative patients were treated with long-acting penicillin in 88.7% of cases vs 58% of HIV-positive patients (p=0.0002).A 40% rate of unsuppressed viraemia, high levels of STIs and varying treatment regimens represent a public health risk for Europe, suggesting the model of sexual healthcare delivery in HIV-positive patients requires further evaluation.

The newly recognized Markagunt gravity slide (MGS) represents gravitationally induced, catastrophic collapse, ca. 21–22 Ma, of the southwest sector of the Oligocene to Miocene Marysvale volcanic field in southwest Utah (USA). The ∼90-km-long slide mass consists of ∼1700–2000 km 3 of andesitic volcanic mudflow breccias and subordinate lava flows, sandstones, and intertongued regional ash-flow tuffs. The MGS extends over an area of >3400 km 2 and advanced >30 km to the south over the Miocene land surface. The low-angle basal slip surface is in Eocene–Oligocene Brian Head Formation, a weak, clay-rich, tuffaceous sedimentary unit at the base of the volcanic section. The presence of a basal zone of cataclastic and sheared breccia with associated clastic dikes, and pseudotachylyte along secondary shear planes, provides strong evidence of catastrophic emplacement. The uniformity of directional indicators, stratigraphy, and overall geometry of the MGS suggests that it represents a single-emplacement event coeval with late-stage magmatic doming of the volcanic field. The MGS thus represents one of the largest subaerial volcanic landslides on Earth, and along with the comparable Heart Mountain gravity slide in northwest Wyoming, constitutes a class of catastrophic collapse hazard not widely recognized within modern volcanic fields.

Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning is an appealing option for patients with high-risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft-versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1 to 21 of 28 days cycles, with intrapatient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age, 54 years) with high-risk MM were enrolled at 8 centers between 2009 and 2012. The median time from alloHCT to LEN initiation was 96 days (range, 66 to 171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%). Most common reasons for discontinuation were acute graft-versus-host disease (GVHD) (37%) and disease progression (37%). Cumulative incidence of grades III to IV acute GVHD from time of initiation of LEN was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplantation-related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN after alloHCT is feasible at lower doses, although it is associated with a 38% incidence of acute GVHD. Survival outcomes observed in this high-risk MM population warrant further study of this approach.

We conducted a study of patients with multiple myeloma (MM) undergoing allogeneic transplantation to evaluate outcome parameters. Fifty-seven consecutive patients with MM received an allogeneic transplantation between 2004 and 2011 at our institution. Patients who had received at least 1 prior autologous transplantation were included. Twenty-six patients underwent allogeneic transplantation for consolidation after a response to their first autograft, and 30 patients received an allogeneic transplantation as salvage therapy. Donor source was evenly distributed between related and unrelated. The median follow-up was 52 months. Thirty-two (57.1%) patients achieved a complete response (CR). At 5 years, 49.2% of all patients were in CR. Sixteen patients received either donor lymphocyte infusions or immune suppression withdrawal for disease progression, with a 62.5% response rate. The 5-year overall survival (OS) for all patients was 59%. The 5-year OS for the 30 patients in the consolidation group was 82% compared with 38% for those in the salvage group. In multivariate analysis, 3 factors remained significantly associated with OS. These include being in the salvage group (hazard ratio [HR], 4.05; P = .0196), acute graft-versus-host disease (aGVHD) (HR, 2.99; P = .034), and chronic graft-versus-host disease (cGVHD), which was highly protective, with a 5-year OS of 78.8% for patients with cGVHD versus 42.6% for patients without cGVHD (HR .17, P = .008). Our data show that allogeneic transplantation for MM can lead to sustained remissions. aGVHD is significantly deleterious to OS and progression-free survival, whereas cGVHD is strongly favorable, supporting an important role for the graft-versus-myeloma effect.

According to Roderick Chisholm, there are three ways of responding to the Problem of the Criterion and they all leave something to be desired. Michael DePaul, Paul Moser, and Earl Conee have each proposed variations of a fourth way of responding to this problem that rely on reflective equilibrium. We argue that these four options for responding to the Problem of the Criterion leave one with a tough choice: accept one of the three that Chisholm describes or DePaul’s reflective equilibrium approach and beg the question or accept a reflective equilibrium response of the sort Conee and Moser propose and embrace epistemic circularity.

Objective Although hematopoietic stem cell transplant (HSCT) patients may experience neurocognitive impairment, experiences of neurobehavioral problems (including apathy and disinhibition) are understudied. These experiences reflect behavioral signs and symptoms of neurological dysfunction that can potentially reduce health-related quality of life (HRQOL). Understanding them is important because they may be confused with other diagnoses, including depression, potentially leading to inappropriate treatments. The objectives of this preliminary cross-sectional study were to describe HSCT patients' neurobehavioral functioning pre-HSCT and post-HSCT and to examine relations with HRQOL. Methods Patients (n = 42) 9 months to 3 years post-HSCT completed measures of neurobehavioral functioning to report apathy and disinhibition pre-HSCT (retrospectively) and post-HSCT (currently). Paired t-tests and McNemar tests were used to explore differences in the incidence of patient-reported neurobehavioral problems within and across time points. Regression analyses were conducted to examine relations between neurobehavioral functioning and physical and mental HRQOL. Results Elevated levels of apathy were reported by many patients post-HSCT (36%) and increased significantly from pre-HSCT to post-HSCT (p = 0.001). Hierarchical regression analysis indicated that higher levels of apathy were associated with reduced mental HRQOL (p

Objectives The incidence of human papillomavirus (HPV)-associated anal cancer is increasing. Men who have sex with men (MSM), particularly those coinfected with HIV, are disproportionately affected. Documenting the molecular epidemiology of HPV infection is important in guiding policy makers in formulating universal and/or targeted vaccine guidelines. Methods A prospective cohort study was conducted. HIV-positive and HIV-negative MSM > 18 years old were invited to participate. Provider-performed anal swabs were collected and anal HPV infection was detected using consensus primer solution phase polymerase chain reaction (PCR) followed by type-specific PCR for high-risk (HR)-HPV types 16, 18 and 31. Between-group differences were analysed using χ2 tests and Wilcoxon rank tests. Results One hundred and ninety-four MSM [mean (standard deviation (SD)) age 36 (10) years; 51% HIV-positive) were recruited. The median number of sexual contacts in the preceding 12 months was 4 (interquartile range 2-10). HIV-positive subjects had a mean (SD) CD4 count of 557 (217) cells/μL, and 84% were on highly active antiretroviral therapy (HAART). Thirty-one samples were B-globin negative and thus excluded from further analysis. A total of 113 subjects (69%) had detectable HPV DNA. Sixty-eight subjects (42%) had an HR-HPV type detected. HR HPV type 16 was detected in 44 samples (27%), HR-HPV type 18 in 26 samples (16%) and HR-HPV type 31 in 14 samples (23%). Twenty-eight subjects (17%) had more than one type of HR-HPV type detected. When HPV and HR-HPV were stratified by age, those > 35 years had a higher prevalence (P = 0.001 and P = 0.028, respectively). HIV-positive subjects were more likely than HIV-negative subjects to have any detectable HPV (77% vs. 61%, respectively; P = 0.04), to have HR-HPV type 18 or 31 (P = 0.05 and P = 0.006, respectively) and to be infected with more than one HR-HPV type (31% vs. 3%, respectively; P

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The ten-eleven translocation 1 ( TET1 ) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia ( MLL ) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL -rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL -rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 ( Hoxa9 )/myeloid ecotropic viral integration 1 ( Meis1 )/pre-B-cell leukemia homeobox 3 ( Pbx3 ) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/Pbx3 signaling axis in MLL -rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.

We report on design of a multi-color laser set up that allows for high spectral, time and spatial resolution imaging based on second- and third-order optical nonlinearities in soft condensed matter. Two femtosecond optical parametric oscillators (OPOs) are pumped simultaneously to provide intrinsically synchronized pulses at more than a dozen tunable colors across visible and infrared wavelengths. We demonstrate the use of independently tunable OPOs in a variety of imaging modalities. In one useful application, we explore brain tissue in a two-photon absorption fluorescence imaging experiment with near infrared optical pulses (λ ~ 1,070 nm). We also demonstrate second and sum-frequency generation microscopies in different tissues. Results from application of time-resolved, three-color coherent anti-stokes Raman scattering in tissue are presented to demonstrate feasibility of quantitative spectroscopic imaging.

BACKGROUND: The purpose of this retrospective medical record review was to report on recidivism to the ICU among adult postoperative cardiac and thoracic patients managed with a respiratory therapy assess-and-treat (RTAT) protocol. Our primary null hypothesis was that there would be no difference in all-cause unexpected readmissions and escalations between the RTAT group and the physician-ordered respiratory care group. Our secondary null hypothesis was that there would be no difference in primary respiratory-related readmissions, ICU length of stay, or hospital length of stay. METHODS: We reviewed 1,400 medical records of cardiac and thoracic postoperative subjects between January 2015 and October 2016. The RTAT is driven by a standardized patient assessment tool, which is completed by a registered respiratory therapist. The tool develops a respiratory severity score for each patient and directs interventions for bronchial hygiene, aerosol therapy, and lung inflation therapy based on an algorithm. The protocol period commenced on December 1, 2015, and continued through October 2016. Data relative to unplanned admissions to the ICU for all causes as well as respiratory-related causes were evaluated. RESULTS: There was a statistically significant difference in the all-cause unplanned ICU admission rate between the RTAT (5.8% [95% CI 4.3–7.9]) and the physician-ordered respiratory care (8.8% [95% CI 6.9–11.1]) groups (P = .034). There was no statistically significant difference in respiratory-related unplanned ICU admissions with RTAT (36% [95% CI 22.7–51.6]) compared with the physician-ordered respiratory care (53% [95% CI 41.1–64.8]) group (P = .09). The RTAT protocol group spent 1 d less in the ICU (P CONCLUSIONS: RTAT protocol implementation demonstrated a statistically significant reduction in all-cause ICU readmissions. The reduction in respiratory-related ICU readmissions did not reach statistical significance.

Purpose To identify a robust prognostic gene expression signature as an independent predictor of survival of patients with acute myeloid leukemia (AML) and use it to improve established risk classification. Patients and Methods Four independent sets totaling 499 patients with AML carrying various cytogenetic and molecular abnormalities were used as training sets. Two independent patient sets composed of 825 patients were used as validation sets. Notably, patients from different sets were treated with different protocols, and their gene expression profiles were derived using different microarray platforms. Cox regression and Kaplan-Meier methods were used for survival analyses. Results A prognostic signature composed of 24 genes was derived from a meta-analysis of Cox regression values of each gene across the four training sets. In multivariable models, a higher sum value of the 24-gene signature was an independent predictor of shorter overall (OS) and event-free survival (EFS) in both training and validation sets (P < .01). Moreover, this signature could substantially improve the European LeukemiaNet (ELN) risk classification of AML, and patients in three new risk groups classified by the integrated risk classification showed significantly (P < .001) distinct OS and EFS. Conclusion Despite different treatment protocols applied to patients and use of different microarray platforms for expression profiling, a common prognostic gene signature was identified as an independent predictor of survival of patients with AML. The integrated risk classification incorporating this gene signature provides a better framework for risk stratification and outcome prediction than the ELN classification.

An objection to reductionism in the epistemology of testimony that is often repeated but rarely defended in detail is that there is not enough positive evidence to provide the non-testimonial, positive reasons reductionism requires. Thus, on pain of testimonial skepticism, reductionism must be rejected. Call this argument the ‘Not Enough Evidence Objection’ (or ‘NEEO’). I will defend reductionism about testimonial evidence against the NEEO by arguing that we typically have non-testimonial positive reasons in the form of evidence about our testifier's evidence. With a higher-level evidence principle borrowed from recent work on the epistemology of disagreement, I argue that, granting some plausible assumptions about conversational norms, the NEEO is unsound.

Hypothyroidism is a clinical disorder commonly encountered by the primary care physician. Untreated hypothyroidism can contribute to hypertension, dyslipidemia, infertility, cognitive impairment, and neuromuscular dysfunction. Data derived from the National Health and Nutrition Examination Survey suggest that about one in 300 persons in the United States has hypothyroidism. The prevalence increases with age, and is higher in females than in males. Hypothyroidism may occur as a result of primary gland failure or insufficient thyroid gland stimulation by the hypothalamus or pituitary gland. Autoimmune thyroid disease is the most common etiology of hypothyroidism in the United States. Clinical symptoms of hypothyroidism are nonspecific and may be subtle, especially in older persons. The best laboratory assessment of thyroid function is a serum thyroid-stimulating hormone test. There is no evidence that screening asymptomatic adults improves outcomes. In the majority of patients, alleviation of symptoms can be accomplished through oral administration of synthetic levothyroxine, and most patients will require lifelong therapy. Combination triiodothyronine/thyroxine therapy has no advantages over thyroxine monotherapy and is not recommended. Among patients with subclinical hypothyroidism, those at greater risk of progressing to clinical disease, and who may be considered for therapy, include patients with thyroid-stimulating hormone levels greater than 10 mIU per L and those who have elevated thyroid peroxidase antibody titers.

Results from two randomized trials have shown that oral beclomethasone dipropionate (BDP) is effective for treatment of acute gastrointestinal graft-versus-host disease. Here, we report results of a double-blind, randomized placebo-controlled phase II study designed to test the hypothesis that acute graft-versus-host disease could be prevented by administration of oral BDP, beginning before hematopoietic cell transplantation and continuing until day 75 after hematopoietic cell transplantation after myeloablative conditioning. Study drug (BDP or placebo) was administered as 1-mg immediate-release formulation plus 1-mg delayed-release formulation orally four times daily. According to the primary endpoint, systemic glucocorticoid treatment for graft-versus-host disease was given to 60 of the 92 participants (65%) in the BDP arm, versus 31 of 46 participants (67%) in the placebo arm. The secondary efficacy endpoints showed no statistically significant differences between the two arms. The proportion of participants who took at least 90% of the prescribed study drug during the first 4 weeks after hematopoietic cell transplantation was 54% overall. Lower severity of mucositis strongly correlated with higher adherence to the schedule of study drug administration. Inconsistent adherence related to mucositis during recovery after myeloablative conditioning may have obscured a beneficial therapeutic effect in the current study.

Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially.

Versión final embargada hasta 24-08-2081 por política editorial The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and new antivenoms for meeting urgent regional needs. We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary, multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency. UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)

This report summarizes highlights of the ‘Philadelphia Chromosome Symposium: Past, Present and Future’, held September 28, 2010, to commemorate the 50th anniversary of the discovery of the Philadelphia chromosome. The symposium sessions included presentations by investigators who made seminal contributions concerning the discovery and molecular characterization of the Ph chromosome and others who developed a highly successful therapy based on the specific molecular alteration observed in chronic myelogenous leukemia. Additional presentations highlighted future opportunities for the design of molecularly targeted therapies for various types of cancer. Also included here are reminiscences connected with the discovery of the Ph chromosome by David Hungerford and Peter Nowell, the discovery that the abnormality arises from a chromosomal translocation, by Janet Rowley, and the cloning of the 9;22 translocation breakpoints by Nora Heisterkamp, John Groffen and colleagues.

Objective: Hematopoietic stem cell transplant (HSCT) survivors who are 1 to 3 years posttransplant are challenged by the need to resume valued social roles and activities—a task that may be complicated by enduring transplant-related psychological distress common in this patient population. The present study investigated whether transplant survivors who receive adequate social support from their spouse or intimate partner experience lower distress. Method: Effects of receiving a greater quantity of partner support (a common approach to studying enacted support) were compared with effects of receiving more effective partner support (i.e., support that more closely matches their needs in terms of its quantity and quality). Men and women (N 230) who were 1 to 3 years posttransplant completed measures of partner support quantity (Manne & Schnoll, 2001), partner social support effectiveness (Rini & Dunkel Schetter, 2010), and psychological distress (Brief Symptom Inventory; Derogatis & Spencer, 1982). Potential medical and sociodemographic confounds were controlled in analyses. Results: As hypothesized, survivors reported less distress when they received more effective partner support (p .001). Quantity of partner support was not associated with distress (p .23). An interaction revealed that when partner support was effective, the quantity of support survivors received was not associated with their distress (p .90); however, when partner support was ineffective, receiving a greater quantity of partner support was associated with substantially elevated distress (p .002). Conclusions: Findings suggest that clinical approaches to addressing or preventing enduring distress after HSCT should target features of partner support related to its appraised effectiveness.

We make a number of contributions to the study of the Quantified Constraint Satisfaction Problem (QCSP). The QCSP is an extension of the constraint satisfaction problem that can be used to model combinatorial problems containing contingency or uncertainty. It allows for universally quantified variables that can model uncertain actions and events, such as the unknown weather for a future party, or an opponent's next move in a game. In this paper we report significant contributions to two very different methods for solving QCSPs. The first approach is to implement special purpose algorithms for QCSPs; and the second is to encode QCSPs as Quantified Boolean Formulas and then use specialized QBF solvers. The discovery of particularly effective encodings influenced the design of more effective algorithms: by analyzing the properties of these encodings, we identify the features in QBF solvers responsible for their efficiency. This enables us to devise analogues of these features in QCSPs, and implement them in special purpose algorithms, yielding an effective special purpose solver, QCSP-Solve. Experiments show that this solver and a highly optimized QBF encoding are several orders of magnitude more efficient than the initially developed algorithms. A final, but significant, contribution is the identification of flaws in simple methods of generating random QCSP instances, and a means of generating instances which are not known to be flawed.