Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Copper Efflux System Required in Murine Lung Infection by Haemophilus influenzae Composed of a Canonical ATPase Gene and Tandem Chaperone Gene Copies.

Copper is an essential micronutrient but is toxic at high concentrations. In Haemophilus influenzae mechanisms of copper resistance and its role in pathogenesis are unknown; however, our previous genetic screen by transposon insertion-site sequencing implicated a putative cation transporting ATPase (copA) in survival in a mouse lung infection model. Here, we demonstrate that H. influenzae copA (HI0290) is responsible for copper homeostasis involving the merR-type regulator, cueR, as well as six tandem copies of the metallochaperone gene, copZ. Deletion of the ATPase and metallochaperone genes resulted in increased sensitivity to copper but not to cobalt, zinc, or manganese. Nontypeable H. influenzae (NTHi) clinical isolate NT127 has the same locus organization but with three copies of copZ. We showed that expression of the NTHi copZA operon is activated by copper under the regulatory control of CueR. NTHi single copA and copZ mutants and, especially, the double deletion copZA mutant exhibited decreased copper tolerance, and the ΔcopZA mutant accumulated 97% more copper than the wild type when grown in the presence of 0.5 mM copper sulfate. Mutants of NT127 deleted of the ATPase (copA) alone and deleted of both the ATPase and chaperones (copZ1-3) were 4-fold and 20-fold underrepresented compared to the parent strain during mixed-infection lung challenge, respectively. Complementation of cop locus deletion mutations restored copper resistance and virulence properties. NTHi likely encounters copper as a host defense mechanism during lung infection, and our results indicate that the cop system encodes an important countermeasure to alleviate copper toxicity.

Cytomegalovirus seropositivity is associated with improved responses to CD38 monoclonal antibody therapies in multiple myeloma: A single-centre retrospective study.

The CD38-targeting monoclonal antibodies (CD38 mAbs) are well-established therapies in multiple myeloma (MM), but responses to treatment are not always deep or durable. Natural killer (NK) cells deficient in Fc epsilon receptor gamma subunits, known as g-NK cells, are found in higher numbers among individuals exposed to cytomegalovirus (CMV) and are able to potentiate the efficacy of daratumumab in vivo. Here, we present a single-centre, retrospective analysis of 136 patients with MM with known CMV serostatus who received a regimen containing a CD38 mAb (93.4% daratumumab and 6.6% isatuximab). CMV seropositivity was associated with an increased overall response rate to treatment regimens containing a CD38 mAb (odds ratio 2.65, 95% confidence interval [CI] 1.17-6.02). However, CMV serostatus was associated with shorter time to treatment failure in a multivariate Cox model (7.8 vs. 8.8 months in the CMV-seropositive vs. CMV-seronegative groups respectively, log-rank p = 0.18, hazard ratio 1.98, 95% CI 1.25-3.12). Our data suggest that CMV seropositivity may predict better response to CD38 mAbs, although this did not correspond to longer time to treatment failure. Larger studies directly quantitating g-NK cells are required to fully understand their effect on CD38 mAb efficacy in MM.

Structural Factors and Racial/Ethnic Inequities in Travel Times to Acute Care Hospitals in the Rural US South, 2007-2018.

Policy Points Policymakers should invest in programs to support rural health systems, with a more targeted focus on spatial accessibility and racial and ethnic equity, not only total supply or nearest facility measures. Health plan network adequacy standards should address spatial access to nearest and second nearest hospital care and incorporate equity standards for Black and Latinx rural communities. Black and Latinx rural residents contend with inequities in spatial access to hospital care, which arise from fundamental structural inequities in spatial allocation of economic opportunity in rural communities of color. Long-term policy solutions including reparations are needed to address these underlying processes. CONTEXT: The growing rate of rural hospital closures elicits concerns about declining access to hospital-based care. Our research objectives were as follows: 1) characterize the change in rural hospital supply in the US South between 2007 and 2018, accounting for health system closures, mergers, and conversions; 2) quantify spatial accessibility (in 2018) for populations most at risk for adverse outcomes following hospital closure-Black and Latinx rural communities; and 3) use multilevel modeling to examine relationships between structural factors and disparities in spatial access to care. METHODS: To calculate spatial access, we estimated the network travel distance and time between the census tract-level population-weighted centroids to the nearest and second nearest operating hospital in the years 2007 and 2018. Thereafter, to describe the demographic and health system characteristics of places in relation to spatial accessibility to hospital-based care in 2018, we estimated three-level (tract, county, state-level) generalized linear models. FINDINGS: We found that 72 (10%) rural counties in the South had ≥1 hospital closure between 2007 and 2018, and nearly half of closure counties (33) lost their last remaining hospital to closure. Net of closures, mergers, and conversions meant hospital supply declined from 783 to 653. Overall, 49.1% of rural tracts experienced worsened spatial access to their nearest hospital, whereas smaller proportions experienced improved (32.4%) or unchanged (18.5%) access between 2007 and 2018. Tracts located within closure counties had longer travel times to the nearest acute care hospital compared with tracts in nonclosure counties. Moreover, rural tracts within Southern states with more concentrated commercial health insurance markets had shorter travel times to access the second nearest hospital. CONCLUSIONS: Rural places affected by rural hospital closures have greater travel burdens for acute care. Across the rural South, racial/ethnic inequities in spatial access to acute care are most pronounced when travel times to the second nearest open acute care hospital are accounted for.

Polymer Grafting to Polydopamine Free Radicals for Universal Surface Functionalization.

Modifying surfaces using free radical polymerization (FRP) offers a means to incorporate the diverse physicochemical properties of vinyl polymers onto new materials. Here, we harness the universal surface attachment of polydopamine (PDA) to "prime" a range of different surfaces for free radical polymer attachment, including glass, cotton, paper, sponge, and stainless steel. We show that the intrinsic free radical species present in PDA can serve as an anchor point for subsequent attachment of propagating vinyl polymer macroradicals through radical-radical coupling. Leveraging a straightforward, twofold soak-wash protocol, FRP over the PDA-functionalized surfaces results in covalent polymer attachment on both porous and nonporous substrates, imparting new properties to the functionalized materials, including enhanced hydrophobicity, fluorescence, or temperature responsiveness. Our strategy is then extended to covalently incorporate PDA nanoparticles into organo-/hydrogels via radical cross-linking, yielding tunable PDA-polymer composite networks. The propensity of PDA free radicals to quench FRP is studied using in situ 1H nuclear magnetic resonance and electron paramagnetic resonance spectroscopy, revealing a surface area-dependent macroradical scavenging mechanism that underpins PDA-polymer conjugation. By combining the arbitrary surface attachment of PDA with the broad physicochemical properties of vinyl polymers, our strategy provides a straightforward route for imparting unlimited new functionality to practically any surface.

Antibody and T-cell responses by ultra-deep T-cell receptor immunosequencing after COVID-19 vaccination in patients with plasma cell dyscrasias.

We investigated antibody and coronavirus disease 2019 (COVID-19)-specific T-cell mediated responses via ultra-deep immunosequencing of the T-cell receptor (TCR) repertoire in patients with plasma cell dyscrasias (PCD). We identified 364 patients with PCD who underwent spike antibody testing using commercially available spike-receptor binding domain immunoglobulin G antibodies ≥2 weeks after completion of the initial two doses of mRNA vaccines or one dose of JNJ-78436735. A total of 56 patients underwent TCR immunosequencing after vaccination. Overall, 86% tested within 6 months of vaccination had detectable spike antibodies. Increasing age, use of anti-CD38 or anti-B-cell maturation antigen therapy, and receipt of BNT162b2 (vs. mRNA-1273) were associated with lower antibody titres. We observed an increased proportion of TCRs associated with surface glycoprotein regions of the COVID-19 genome after vaccination, consistent with spike-specific T-cell responses. The median spike-specific T-cell breadth was 3.11 × 10-5 , comparable to those in healthy populations after vaccination. Although spike-specific T-cell breadth correlated with antibody titres, patients without antibody responses also demonstrated spike-specific T-cell responses. Patients receiving mRNA-1273 had higher median spike-specific T-cell breadth than those receiving BNT162b2 (p = 0.01). Although patients with PCD are often immunocompromised due to underlying disease and treatments, COVID-19 vaccination can still elicit humoral and T-cell responses and remain an important intervention in this patient population.

Health-related quality of life in patients with light chain amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone ± daratumumab: Results from the ANDROMEDA study.

In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires. Treatment effect through cycle 6 was measured by a repeated-measures, mixed-effects model. The magnitude of changes in PROs versus baseline was generally low, but between-group differences favored the D-VCd group. Results were generally consistent irrespective of hematologic, cardiac, or renal responses. More patients in the D-VCd group experienced meaningful improvements in PROs; median time to improvement was more rapid in the D-VCd group versus the VCd group. After cycle 6, patients in the D-VCd group received daratumumab monotherapy and their PRO assessments continued, with improvements in health-related quality of life (HRQoL) reported through cycle 19. PROs of subgroups with renal and cardiac involvement were consistent with those of the intent-to-treat population. These results demonstrate that the previously reported clinical benefits of D-VCd were achieved without decrement to patients' HRQoL and provide support of D-VCd in patients with AL amyloidosis.

Outcomes of kidney transplant recipients with ESKD due to plasma cell dyscrasia: A case series.

Transplant centers have historically been reluctant to proceed with kidney transplantation in individuals with plasma cell dyscrasias (PCDs) due to concern for high rates of PCD recurrence and PCD-related mortality. As novel therapies for PCDs have improved hematologic outcomes, strategies to optimize kidney transplantation in individuals with PCD-mediated kidney disease are needed. In this single-center case series we discuss our protocol for the transplantation of individuals with ESKD attributed to PCD as well as the hematologic and allograft outcomes of 12 kidney transplant recipients with ESKD attributed to PCD. Median follow-up time after kidney transplantation was 44 months (IQR 36, 84). All patients had a functioning allograft 1 year after kidney transplantation. 9/12 patients were alive and had a functioning allograft 5 years after kidney transplantation. Five patients experienced relapse of PCD (of whom three responded well to subsequent therapies) and four patients developed secondary malignancies, including three patients with urologic malignancies. This case series demonstrates that patients with kidney disease attributed to PCD have favorable outcomes with kidney transplantation. Transplant evaluation in patients with PCDs should involve a multidisciplinary team of transplant nephrologists and oncologists to select appropriate candidates. Providers should consider screening for urologic malignancies pre- and post-transplantation.

Evaluation of subcutaneous daratumumab injections in the ambulatory care setting.

INTRODUCTION: Subcutaneous daratumumab is non-inferior to intravenous daratumumab for the treatment of multiple myeloma and significantly reduced incidence of systemic reactions. However, manufacturer for subcutaneous daratumumab has not provided guidance regarding optimal methods for monitoring for hypersensitivity reactions following subcutaneous daratumumab administration. METHODS: A retrospective analysis was performed in two cohorts of patients who received at least two doses of subcutaneous daratumumab for the treatment of plasma cell disorders: patients with previous exposure to intravenous daratumumab (dara-exposed) and patients without history of intravenous daratumumab (dara-naïve). The primary outcome was incidence of systemic and injection-site reactions following first dose of subcutaneous daratumumab. Secondary analysis included time to systemic and injection-site reactions, grading of adverse reaction, and incidence of second systemic reaction. RESULTS: Thirty-one patients were dara-naïve and 49 patients were dara-exposed. Differences in incidence of systemic (dara-naïve: 9.7% vs dara-exposed: 6.1%, p = 0.67) and injection-site reactions (dara-naïve: 12.9% vs dara-exposed: 14.3%, p = 0.99) did not reach statistical significance. Difference in median time to systemic reaction (dara-naïve: 3 h vs dara-exposed: 12 h, p = 0.18) was clinically important but did not reach statistical significance. Median time to injection-site reactions (dara-naïve: 6 h vs dara-exposed: 24 h, p = 0.03) was shorter in the dara-naïve cohort. No clinically meaningful difference was observed for incidence of second systemic reaction. CONCLUSION: Most reactions were mild and did not require medical intervention. Following first subcutaneous daratumumab dose, monitoring for 3 h for dara-naïve patients and no monitoring time for dara-exposed patients for hypersensitivity reactions may be a safe and reasonable practice.

A scoping review of the playground experiences of children with AAC needs.

Unstructured play on playgrounds is beneficial to children's development, but children with disabilities are often unable to use playgrounds in the same ways as their peers without disabilities. No research to date has focused exclusively on the playground experiences of children who use augmentative and alternative communication (AAC). Therefore, in this scoping review, information from 10 studies published between 1990 and 2020 that investigated the playground experiences of children with disabilities, including those with limited speech, is synthesized. Included studies used experimental or non-experimental designs and involved the collection of either quantitative or qualitative data. The findings indicate that children with limited speech have diverse playground experiences and can benefit in some of the same ways as children with typical development from playground play but that they encounter barriers to participation that go beyond a lack of physical access. Additional research focusing specifically on understanding the communication experiences of children who use AAC on playgrounds is essential to address the complex issues associated with playground participation, including access to aided AAC systems on the playground. To foster more inclusive playgrounds, accessibility standards must address the unique needs of children with limited speech to support participation and access to communication on the playground.

Sialic Acid Protects Nontypeable Haemophilus influenzae from Natural IgM and Promotes Survival in Murine Respiratory Tract.

Nontypeable Haemophilus influenzae (NTHi), a common inhabitant of the human nasopharynx and upper airways, causes opportunistic respiratory tract infections that are frequently recurring and chronic. NTHi utilizes sialic acid from the host to evade antibacterial defenses and persist in mucosal tissues; however, the role of sialic acid scavenged by NTHi during infection is not fully understood. We previously showed that sialylation protects specific epitopes on NTHi lipooligosaccharide (LOS) targeted by bactericidal IgM in normal human serum. Here, we evaluated the importance of immune evasion mediated by LOS sialylation in the mouse respiratory tract using wild-type H. influenzae and an isogenic siaB mutant incapable of sialylating the LOS. Sialylation protected common NTHi glycan structures recognized by human and murine IgM and protected NTHi from complement-mediated killing directed by IgM against these structures. Protection from IgM binding by sialylated LOS correlated with decreased survival of the siaB mutant versus the wild type in the murine lung. Complement depletion with cobra venom factor increased survival of the siaB mutant in the nasopharynx but not in the lungs, suggesting differing roles of sialylation at these sites. Prior infection increased IgM against H. influenzae but not against sialic acid-protected epitopes, consistent with sialic acid-mediated immune evasion during infection. These results provide mechanistic insight into an NTHi evasive strategy against an immune defense conserved across host species, highlighting the potential of the mouse model for development of anti-infective strategies targeting LOS antigens of NTHi.

Prophylactic Inhibition of Colonization by Streptococcus pneumoniae with the Secondary Bile Acid Metabolite Deoxycholic Acid.

Streptococcus pneumoniae colonizes the nasopharynx of children and the elderly but also kills millions worldwide yearly. The secondary bile acid metabolite deoxycholic acid (DoC) affects the viability of human pathogens but also plays multiple roles in host physiology. We assessed in vitro the antimicrobial activity of DoC and investigated its potential to eradicate S. pneumoniae colonization using a model of human nasopharyngeal colonization and an in vivo mouse model of colonization. At a physiological concentration, DoC (0.5 mg/ml; 1.27 mM) killed all tested S. pneumoniae strains (n = 48) 2 h postinoculation. The model of nasopharyngeal colonization showed that DoC eradicated colonization by S. pneumoniae strains as soon as 10 min postexposure. The mechanism of action did not involve activation of autolysis, since the autolysis-defective double mutants ΔlytAΔlytC and ΔspxBΔlctO were as susceptible to DoC as was the wild type (WT). Oral streptococcal species (n = 20), however, were not susceptible to DoC (0.5 mg/ml). Unlike trimethoprim, whose spontaneous resistance frequency (srF) for TIGR4 or EF3030 was ≥1 × 10-9, no spontaneous resistance was observed with DoC (srF, ≥1 × 10-12). Finally, the efficacy of DoC to eradicate S. pneumoniae colonization was assessed in vivo using a topical route via intranasal (i.n.) administration and as a prophylactic treatment. Mice challenged with S. pneumoniae EF3030 carried a median of 4.05 × 105 CFU/ml 4 days postinoculation compared to 6.67 × 104 CFU/ml for mice treated with DoC. Mice in the prophylactic group had an ∼99% reduction of the pneumococcal density (median, 2.61 × 103 CFU/ml). Thus, DoC, an endogenous human bile salt, has therapeutic potential against S. pneumoniae.

Phase 1b trial of isatuximab, an anti-CD38 monoclonal antibody, in combination with carfilzomib as treatment of relapsed/refractory multiple myeloma.

BACKGROUND: Isatuximab (Isa), an anti-CD38 monoclonal antibody, and carfilzomib (K), a next-generation proteasome inhibitor (PI), both have potent single-agent activity in relapsed and refractory multiple myeloma (RRMM). METHODS: This phase 1b study evaluated the combination of Isa and K in 33 patients with RRMM. Isa was administered by intravenous infusion in 3 dosing cohorts: dose level 1 (Isa at 10 mg/kg biweekly), dose level 2 (DL2; Isa at 10 mg/kg weekly for 4 doses and then biweekly), and dose level 3 (Isa at 20 mg/kg weekly for 4 doses and then biweekly) and all patients received K (20 mg/m2 intravenously for cycle 1, days 1 and 2, and then 27 mg/m2 for all subsequent doses). A standard 3+3 dose-escalation design was used, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. An expansion cohort of 18 patients was enrolled at DL2 to further evaluate safety and efficacy. Responses were assessed with the International Myeloma Working Group response criteria, and patients continued treatment until disease progression or unacceptable toxicity. RESULTS: With a median follow-up of 26.7 months, in this heavily pretreated population with a median of 3 prior lines (refractory to PIs and immunomodulatory drugs, 76%; refractory to K, 27%), the overall response rate was 70% (stringent complete response/complete response, 4; very good partial response, 8; partial response, 11). The median progression-free survival was 10.1 months, and the 2-year survival probability was 76%. The most common treatment-related adverse events (grade 2 or higher) were anemia, leukopenia, neutropenia, thrombocytopenia, hypertension, and infection. Infusion reactions were common (55%) but did not limit dosing. CONCLUSIONS: Treatment with Isa plus K was well tolerated with no unexpected toxicity. The combination was effective despite the enrollment of heavily pretreated patients with RRMM. LAY SUMMARY: This phase 1b study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of isatuximab and carfilzomib in patients with relapsed and refractory multiple myeloma. Thirty-three patients were treated: 15 in dose escalation and 18 in dose expansion. Patients received an average of 10 cycles. The treatment was safe and effective. No unexpected toxicity or drug-drug interactions were noted. Seventy percent of the subjects responded to therapy, and the progression-free survival was 10.1 months.

The proportion of North American cancer trials that evaluate novel targets.

Major advances in cancer care often emerge from the development of novel targets. We randomly sampled 10% of cancer trials on clinicaltrials.gov with start dates 2013-2016 to determine the proportion of trials and research subjects directed at evaluating novel targets. We found that 87 of 378 trials (23.0%) enrolling 9225 of 44,525 patients (20.7%) tested interventions that are directed towards novel targets. 146 of 378 trials (38.6%) enrolling 19,132 of 44,525 patients (43.0%) investigated treatments that were not FDA approved but utilized a previously studied target for treating cancer. Combined, 233 of 378 trials (61.6%) enrolling 28,357 of 44,525 patients (63.9%) investigated treatments that were not FDA approved. Furthermore, 36 of 378 trials (9.5%) enrolling 6592 of 44,525 patients (14.8%) investigated FDA approved anticancer drugs in their approved indication and combination while 109 of 378 trials (28.8%) enrolling 9576 of 44,525 patients (21.5%) investigated FDA approved anticancer drugs outside of their approved indication or combination. Logistic regression found that phase 1 trials were significantly more likely to test novel target interventions than phase 2 and 3 trials (p value = 0.00197 and 0.00130 respectively). Industry sponsored trials were also significantly more likely to involve novel target interventions than non-industry trials (p value <0.001). In conclusion, most cancer trials involve unapproved treatments, but a majority of these treatments are well-characterized or involve a previously studied target to treat cancer.

Recognition of conserved antigens by Th17 cells provides broad protection against pulmonary Haemophilus influenzae infection.

Nontypeable Haemophilus influenzae (NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. A current effort in NTHi vaccine development has focused on generating humoral responses and has been greatly impeded by antigenic variation among the numerous circulating NTHi strains. In this study, we showed that pulmonary immunization of mice with killed NTHi generated broad protection against lung infection by different strains. While passive transfer of immune antibodies protected only against the homologous strain, transfer of immune T cells conferred protection against both homologous and heterologous strains. Further characterization revealed a strong Th17 response that was cross-reactive with different NTHi strains. Responding Th17 cells recognized both cytosolic and membrane-associated antigens, while immune antibodies preferentially responded to surface antigens and were highly strain specific. We further identified several conserved proteins recognized by lung Th17 cells during NTHi infection. Two proteins yielding the strongest responses were tested as vaccine candidates by immunization of mice with purified proteins plus an adjuvant. Immunization induced antigen-specific Th17 cells that recognized different strains and, upon adoptive transfer, conferred protection. Furthermore, immunized mice were protected against challenge with not only NTHi strains but also a fully virulent, encapsulated strain. Together, these results show that the immune mechanism of cross-protection against pneumonia involves Th17 cells, which respond to a broad spectrum of antigens, including those that are highly conserved among NTHi strains. These mechanistic insights suggest that inclusion of Th17 antigens in subunit vaccines offers the advantage of inducing broad protection and complements the current antibody-based approaches.

Shifting eye balance using monocularly directed attention in normal vision.

In binocular vision, even without conscious awareness of eye of origin, attention can be selectively biased toward one eye by presenting a visual stimulus uniquely to that eye. Monocularly directed visual cues can bias perceptual dominance, as shown by studies using discrete measures of percept changes in continuous-flash suppression. Here, we use binocular rivalry to determine whether eye-based visual cues can modulate eye balance using continuous percept reporting. Using a dual-task versus single-task paradigm, we investigated whether the attentional load of these cues differentially modulates eye balance. Furthermore, both color-based and motion-based cue stimuli, non-overlaid and peripheral to the rivalry grating stimuli, were used to determine whether shifts in eye balance were stimulus specific. Aligned to cue stimulus onset, time series of percept reports were constructed and averaged across trials and participants. Specifically, for the monocular attention conditions, we found a significant shift in eye balance toward the cued eye and a significant difference in the time taken to switch from the dominating percept, regardless of whether the attention stimuli is color based or motion based. Although we did not find a significant main effect of attentional load, we found a significant interaction effect between the attentionally cued eye and attentional load on the shift in eye balance, indicating an influence of monocular attention on the shift in eye balance.

The Protein Corona Leads to Deformation of Spherical Micelles.

The formation of a non-specific protein corona around nanoparticles (NPs) has been identified as one of the culprits for failed nanomedicine. The amount and type of adsorbed protein from the blood plasma are known to determine the fate of NPs and the accessibility of targeting ligands. Herein, we show that the adsorbed protein may not only enlarge the NPs and change their surface properties but also, in the case of soft NPs such as polymer micelles, lead to deformation. Poly(1-O-methacryloyl -ß-D-fructopyranose)-b-poly(methylmethacrylate) (P(1-O-MAFru)-b-PMMA) block co-polymers were self-assembled into NPs with a spherical core-shell morphology as determined by small angle neutron scattering (SANS). Upon incubation with albumin, TEM, SANS, and small angle X-ray scattering (SAXS) revealed the adsorption of albumin and deformation of the NPs with a spheroid geometry. Removal of the protein led to the reversal of the morphology back to the spherical core-shell structure. Structural studies and cell studies of uptake of the NPs imply that the observed deformation may influence blood circulation time and cell uptake.

Impact of Plerixafor Use at Different Peripheral Blood CD34+ Thresholds on Autologous Stem Cell Collection in Patients with Multiple Myeloma.

Patients with multiple myeloma (MM) scheduled for autologous stem cell transplantation must undergo autologous stem cell mobilization; unfortunately, however, many do not obtain an adequate collection yield. Despite the availability of plerixafor, its widespread and uniform use is limited by its cost, and consequently, many institutions have adopted various risk-adapted algorithms. We report our mobilization experience as we have modified our plerixafor algorithm to a more liberal one, with the expectation of greater collection efficiency and mobilization success with higher plerixafor use. A total of 344 mobilization attempts were analyzed over 3 time periods and using 3 different peripheral blood CD34+ cell counts to guide plerixafor use: <15/µL (n = 66), <20/µL (n = 130), and <40/µL (n = 148). The primary endpoints were evaluation of changes in mean plerixafor utilization and apheresis days and assessment of the impact on overall mobilization costs. Secondary endpoints were a description of the impact of lenalidomide use on mobilization and evaluation of the rate of mobilization failure. We found that mean plerixafor use increased from 1.32 to 1.65 to 1.74 doses per mobilization (P = .026) and the mean days of apheresis decreased from 2.15 to 2.17 to 1.89 days per mobilization for the <15/µL, <20/µL, and <40/µL cohorts, respectively (P = .011). The combined cost of plerixafor and apheresis procedures at a threshold of 40/µL is close to that at a threshold of 15/µL, while saving 26 apheresis days per 100 patients. In general, there were low rates of mobilization failure across all thresholds. Patients who received more than 6 cycles of lenalidomide demonstrated impaired mobilization and required more apheresis sessions (P < .013) and greater plerixafor use (P < .001) to achieve target stem cell yields. Overall, using plerixafor in patients with MM, with a day 4 pCD34 count of <40/µL is a reasonable and cost-effective strategy to optimize apheresis utilization.

A Cost-Effectiveness Analysis of Corticosteroid Injections and Open Surgical Release for Trigger Finger.

PURPOSE: To evaluate the cost-effectiveness of corticosteroid injection(s) versus open surgical release for the treatment of trigger finger. METHODS: Using a US health care payer perspective, we created a decision tree model to estimate the costs and outcomes associated with 4 treatment strategies for trigger finger: offering up to 3 steroid injections before to surgery or immediate open surgical release. Costs were obtained from a large administrative claims database. We calculated expected quality-adjusted life-years for each treatment strategy, which were compared using incremental cost-effectiveness ratios. Separate analyses were performed for commercially insured and Medicare Advantage patients. We performed a probabilistic sensitivity analysis using 10,000 second-order Monte Carlo simulations that simultaneously sampled from the uncertainty distributions of all model inputs. RESULTS: Offering 3 steroid injections before surgery was the optimal strategy for both commercially insured and Medicare Advantage patients. The probabilistic sensitivity analysis showed that this strategy was cost-effective 67% and 59% of the time for commercially insured and Medicare Advantage patients, respectively. Our results were sensitive to the probability of injection site fat necrosis, success rate of steroid injections, time to symptom relief after a steroid injection, and cost of treatment. Immediate surgical release became cost-effective when the cost of surgery was below $902 or $853 for commercially insured and Medicare Advantage patients, respectively. CONCLUSIONS: Multiple treatment strategies exist for treating trigger finger, and our cost-effectiveness analysis helps define the relative value of different approaches. From a health care payer perspective, offering 3 steroid injections before surgery is a cost-effective strategy. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and Decision Analyses II.

Disability, wages, and commuting in New York.

In the U.S., substantial employment and wage gaps persist between workers with and without disabilities. A lack of accessible transportation is often cited as a barrier to employment in higher wage jobs for people with disabilities, but little is known about the intraurban commuting patterns of employed people with disabilities in relation to their wage earnings. Our study compares wages and commute times between workers with and without disabilities in the New York metropolitan region and identifies the intraurban zones where residents experience higher inequities in wage earnings and commute times. We obtained our data from the Public Use Microdata Sample (PUMS) of the American Community Survey (ACS) for the 2008-2012 time period. We used linear mixed-effects models and generated separate models with log hourly wage or one-way commute time as the dependent variable. We find significant differences in wages and commute times between workers with and without disabilities at the scale of the metropolitan region as well as by intraurban zone. At the metropolitan scale, disabled workers earn 16.6% less and commute one minute longer on average than non-disabled workers. High commute and wage inequalities converge in the center, where workers with disabilities are more likely to use public transit, earn 17.1% less, and travel nearly four minutes longer on average than workers without disabilities. These results suggest that transport options are less accessible and slower for disabled workers than they are for non-disabled workers. Our findings indicate a need for more accessible and quicker forms of transportation in the center along with an increased availability of centrally located and affordable housing to reduce the disability gap in wages and commute times. We also find that workers with disabilities generally seek higher wages in exchange for longer commute times, but the results differ by race/ethnicity and gender. Compared to white men, minority workers earn much less, and white and Hispanic women have significantly shorter commute times. Our findings offer new geographic insights on how having a disability can influence wage earnings and commute times for workers in different intraurban zones in the New York metropolitan region.