Search

Summary Background Indatuximab ravtansine (BT062) is an antibody-drug conjugate that binds to CD138 and synergistically enhances the antitumor activity of lenalidomide in preclinical models of multiple myeloma. This phase 1/2a study was done to determine the safety, activity, and pharmacokinetics of indatuximab ravtansine in combination with immunomodulatory drugs in patients with relapsed or refractory multiple myeloma. Methods This open-label, phase 1/2a study took place at nine hospital sites in the USA. Eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and ECOG performance status or Zubrod score of 2 or below. Patients who received indatuximab ravtansine with lenalidomide and dexamethasone (indatuximab ravtansine plus lenalidomide) had failure of at least one previous therapy. Patients treated with indatuximab ravtansine with pomalidomide and dexamethasone (indatuximab ravtansine plus pomalidomide) had failure of at least two previous therapies (including lenalidomide and bortezomib) and had progressive disease on or within 60 days of completion of their last treatment. In phase 1, patients received indatuximab ravtansine intravenously on days 1, 8, and 15 of each 28-day cycle in escalating dose levels of 80 mg/m2, 100 mg/m2, and 120 mg/m2, with lenalidomide (25 mg; days 1 to 21 every 28 days orally) and dexamethasone (20–40 mg; days 1, 8, 15, and 22 every 28 days). In phase 2, the recommended phase 2 dose of indatuximab ravtansine was given to an expanded cohort of patients in combination with lenalidomide and dexamethasone. The protocol was amended to allow additional patients to be treated with indatuximab ravtansine plus pomalidomide (4 mg; days 1 to 21 every 28 days orally) and dexamethasone, in a more heavily pretreated patient population than in the indatuximab ravtansine plus lenalidomide group. The phase 1 primary endpoint was to determine the dose-limiting toxicities and the maximum tolerated dose (recommended phase 2 dose) of indatuximab ravtansine, and the phase 2 primary endpoint was to describe the objective response rate (ORR; partial response or better) and clinical benefit response (ORR plus minor response). All patients were analysed for safety and all patients with post-treatment response assessments were analysed for activity. This study is registered with ClinicalTrials.gov , number NCT01638936 , and is complete. Findings 64 (86%) of 74 screened patients were enrolled between July 3, 2012, and June 30, 2015. 47 (73%) patients received indatuximab ravtansine plus lenalidomide (median follow-up 24·2 months [IQR 19·9–45·4]) and 17 (27%) received indatuximab ravtansine plus pomalidomide (24·1 months [17·7–36·7]). The maximum tolerated dose of indatuximab ravtansine plus lenalidomide was 100 mg/m2, and defined as the recommended phase 2 dose for indatuximab ravtansine plus pomalidomide. An objective response for indatuximab ravtansine plus lenalidomide was observed in 33 (71·7%) of 46 patients and in 12 (70·6%) of 17 patients in the indatuximab ravtansine plus pomalidomide group. The clinical benefit response for indatuximab ravtansine plus lenalidomide was 85% (39 of 46 patients) and for indatuximab ravtansine plus pomalidomide it was 88% (15 of 17 patients). The most common grade 3–4 adverse events in both groups were neutropenia (14 [22%] of 64 patients), anaemia (10 [16%]), and thrombocytopenia (seven [11%]). Treatment-emergent adverse events (TEAEs) that led to discontinuation occurred in 35 (55%) of the 64 patients. Five (8%) patients with a TEAE had a fatal outcome; none was reported as related to indatuximab ravtansine. Interpretation Indatuximab ravtansine in combination with immunomodulatory drugs shows preliminary antitumor activity, is tolerated, and could be further evaluated in patients with relapsed or refractory multiple myeloma. Funding Biotest AG.

Phytoplankton community composition impacts food webs, climate, and fisheries on regional and global scales, and can be assessed at coarse taxonomic resolution from biomarker pigments measured using high-performance liquid chromatography (HPLC). Presently, satellite ocean color provides unprecedented coverage of the global surface ocean and offers reliable estimates of bulk biological properties; however, existing multispectral sensors have limited ability to provide information about phytoplankton community composition. Satellite ocean color at hyperspectral resolution (e.g., NASA's upcoming Plankton, Aerosol, Cloud, and ocean Ecosystem sensor, PACE) is expected to improve estimates of phytoplankton community composition from space. Phytoplankton impact ocean color via contributions to absorption and fluorescence (through phytoplankton pigments) and scattering, especially on narrow spectral scales (5–100 nm). Here, a global open ocean dataset of concurrent HPLC pigments and hyperspectral remote sensing reflectance (Rrs(λ)) observations is used to model phytoplankton pigment composition from optical data. Phytoplankton pigments are reconstructed from Rrs(λ) using optimized principal components regression modeling. This work demonstrates that thirteen phytoplankton pigments, representing five phytoplankton pigment groups (e.g., diatoms, dinoflagellates, haptophytes, green algae, and cyanobacteria), can be modeled from hyperspectral Rrs(λ). Spectral information needed to model each phytoplankton pigment concentration is found throughout the entire visible spectrum and the model results are best at high spectral resolution (≤5 nm). The resulting model recreates observed relationships among pigment concentrations, providing support for the designation of five pigment-based phytoplankton groups for the global open ocean. This work represents a step toward developing robust, global spectral models for phytoplankton pigment composition. However, more high-quality data from a wide range of ecosystems and environments are still needed to achieve this goal.

Summary Background Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3–6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting. Findings Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46–0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]). Interpretation KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit–risk profile. Funding Amgen.

Background Patients (pts) with RRMM who were exposed to immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) have poor outcomes with subsequent treatments. Ide-cel, a BCMA-directed CAR T-cell therapy, has shown frequent, deep, and durable responses in triple-class exposed pts with RRMM in the pivotal KarMMa study (NCT03361748; Munshi NC et al. N Engl J Med 2021). Here, we report updated results from this trial. Methods Eligible pts had received ≥3 prior regimens (including an immunomodulatory agent, a PI, and an anti-CD38 mAb) and had disease refractory to their last regimen per IMWG criteria. After 3 days of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2), pts received 150–450×106 CAR+ T cells (target dose levels). Primary endpoint was overall response rate (ORR); key secondary endpoint was complete response (CR) rate (CR + stringent CR). Other secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results In total, 128/140 enrolled pts received ide-cel. Data are presented for the treated pts. Median age was 61 y. Pts had received a median of 6 (range, 3–16) prior regimens, with 84% being triple-class refractory and 26% penta-refractory (lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab). Most pts (88%) had received bridging therapy. At data cutoff (Dec 21, 2020), the median follow-up among surviving pts was 24.8 mo. In total, 94/128 pts (73%) achieved an overall response, with a CR rate of 33%; median DOR and PFS were 10.9 mo and 8.6 mo, respectively. In pts who achieved ≥CR, median DOR was 21.5 mo and median PFS was 22.4 mo. Outcomes improved at higher doses, with ORR of 81%, CR rate of 39%, median DOR of 11.3 mo, and median PFS of 12.2 mo at 450×106 CAR+ T cells; in pts who achieved ≥CR at this dose, median DOR was not reached. Responses were observed in all subgroups, including difficult-to-treat subsets (eg, high tumor burden [ORR, 71%], extramedullary disease [70%], and R-ISS stage III disease [48%]). Median OS was 24.8 mo; the estimated 24-mo OS rate was 51%. The most common any-grade toxicities were neutropenia (91%) and cytokine release syndrome (CRS; 84%). CRS was mostly grade 1/2; 5 pts (4%) had grade 3, 1 pt each had grade 4 and 5 events (both at 300×106). Investigator-identified neurotoxicity was reported in 23 pts (18%); 5 (4%) had grade 3 and 0 had grade ≥4 events. Tocilizumab was used in 67 and 3 pts, and steroids were used in 19 and 10 pts with CRS and neurotoxicity, respectively. Conclusion Updated results from the KarMMa trial continue to demonstrate durable and deep responses with ide-cel in heavily pretreated, triple-class–exposed pts with RRMM. Efficacy and safety data are consistent with prior reports and support a favorable clinical benefit–risk profile for ide-cel across the target dose levels.

BACKGROUND: Longer intervals between prostate-specific antigen (PSA) tests for routine prostate cancer screening can reduce the harms while maintaining the benefits of screening. Limited information has been published on PSA screening frequency. The purpose of this report is to describe the number of PSA tests in the last 5 years reported by men in the United States. METHODS: Using data from National Health Interview Survey Cancer Control Supplements in 2010, 2015, and 2018, the number of PSA tests in the last 5 years reported by men ≥40 years was categorized as 4 to 5 PSA tests, 1 to 3 PSA tests, and no PSA tests. Logistic regression was used to calculate model-adjusted prevalence risk ratios (aPRs) for the number of PSA tests in the last 5 years, adjusting for age, racial-ethnic group, education, marital status, and health insurance. RESULTS: The proportion of men aged ≥70 years who reported 4 to 5 PSA tests in the last 5 years decreased from 37.2% in 2010 to 31.1% in 2018, while the proportion reporting 1 to 3 PSA tests increased from 25.5% to 31.9%. In 2018, aPRs for 4 to 5 PSA tests vs. 1 to 3 PSA tests in the last 5 years were significantly higher among men aged 70 to 79 years than among men aged 55 to 69 years. CONCLUSIONS: Men aged ≥70 years reported a small shift to less intense PSA testing between 2010 and 2018, but PSA testing intensity remained higher in men aged ≥70 years than in men aged 55 to 69 years. Published by Elsevier Inc.

Natural killer (NK) cells are part of the innate arm of the immune system; as such NK cells can be activated rapidly to target virus-infected cells and tumor cells without prior sensitization. The human NK-92MI cell line is among the most widely used NK cell in preclinical research studies and has also been approved for clinical applications. Previous studies have shown that osteoblasts (OSB) confer drug resistance in multiple myeloma (MM) and other cancers that metastasize to the bone marrow.We evaluated here how OSB, which are bone forming cells and a key cellular component of the bone marrow microenvironment, modulate the cytotoxic activity of NK-92MI cells against the MM.1S multiple myeloma cell line.The osteoblastic niche was recapitulated with either the osteoblastic cell line hFOB 1.19 (hFOB) or primary osteoblasts (P-OSB) derived from surgical resections. Time-lapse imaging was utilized to quantify changes in MM.1S cell viability under different conditions, including: (1) Co-culture of MM.1S with NK92MI cells, (2) triple-culture of hFOB or P-OSB with MM.1S and NK-92MI, and (3) MM.1S or NK-92MI cells primed with OSB-derived supernatant. Cytokine analysis was conducted to quantify potential secreted factors associated with the protective effects of OSB.The physical presence of OSB hindered the activity of NK-92MI cells, resulting in the increased viability of MM.1S compared to co-cultures which lacked OSB. This observation was accompanied by reduced perforin and granzyme A secretion from NK-92MI cells. Contact of OSB and NK-92MI cells also induced interleukin 6 (IL-6) and interleukin 10 (IL-10) production; two cytokines which are known to impair the NK cell immunity against MM and other cancers. OSB supernatant also conferred cytoprotection to MM.1S, suggesting a dual mechanism by which OSB may modulate both NK and MM cells.We demonstrated here that OSB can negatively impact the activity of NK cells against MM. As NK cells and their chimeric antigen receptor-modified versions become more widely used in the clinic, our results suggest that understanding the role of OSB as potential immunoregulators of the NK cell-mediated cytotoxic response in the bone marrow tumor microenvironment may provide new opportunities for enhancing the effectiveness of this potent immunotherapeutic approach.

Summary Background Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been proposed to mitigate the cytokine storm syndrome associated with severe COVID-19. We aimed to investigate the association between tocilizumab exposure and hospital-related mortality among patients requiring intensive care unit (ICU) support for COVID-19. Methods We did a retrospective observational cohort study at 13 hospitals within the Hackensack Meridian Health network (NJ, USA). We included patients (aged ≥18 years) with laboratory-confirmed COVID-19 who needed support in the ICU. We obtained data from a prospective observational database and compared outcomes in patients who received tocilizumab with those who did not. We applied a multivariable Cox model with propensity score matching to reduce confounding effects. The primary endpoint was hospital-related mortality. The prospective observational database is registered on ClinicalTrials.gov , NCT04347993 . Findings Between March 1 and April 22, 2020, 764 patients with COVID-19 required support in the ICU, of whom 210 (27%) received tocilizumab. Factors associated with receiving tocilizumab were patients' age, gender, renal function, and treatment location. 630 patients were included in the propensity score-matched population, of whom 210 received tocilizumab and 420 did not receive tocilizumab. 358 (57%) of 630 patients died, 102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. Overall median survival from time of admission was not reached (95% CI 23 days–not reached) among patients receiving tocilizumab and was 19 days (16–26) for those who did not receive tocilizumab (hazard ratio [HR] 0·71, 95% CI 0·56–0·89; p=0·0027). In the primary multivariable Cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (HR 0·64, 95% CI 0·47–0·87; p=0·0040). Similar associations with tocilizumab were noted among subgroups requiring mechanical ventilatory support and with baseline C-reactive protein of 15 mg/dL or higher. Interpretation In this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited. Funding None.

Background Lenalidomide (LEN) with or without a proteasome inhibitor (PI) administered until disease progression is a standard treatment (Tx) approach for patients (pts) with newly diagnosed multiple myeloma (MM). Clinical trials investigating triplet therapies included few pts whose disease was relapsed/refractory to LEN after early-line Tx. The phase 2 MM-014 trial (NCT01946477) was designed to investigate outcomes with pomalidomide (POM)-based therapy immediately after first- or second-line LEN-based Tx failure in pts with relapsed/refractory MM (RRMM). In cohort B (n=112) of this trial, POM + dexamethasone (DEX) + daratumumab (DARA) demonstrated promising efficacy and safety with an overall response rate (ORR) of 78% and median progression-free survival (PFS) of 30.8 mo. Efficacy and safety in a subgroup of pts in cohort B previously exposed to LEN+PI are reported. Methods Pts with RRMM (1–2 prior Tx lines), LEN-based Tx for ≥2 consecutive cycles as most recent regimen, and disease progression during/after last line of Tx received POM+DEX+DARA (28-d cycles) until disease progression. POM 4 mg/d was given orally (PO) on d1–21; DEX 40 mg/d (20 mg/d in pts aged >75 y) PO on d1, 8, 15, and 22; and DARA 16 mg/kg IV on d1, 8, 15, and 22 of cycles 1–2, d1 and 15 for cycles 3–6, and d1 for cycles 7+. The primary endpoint was ORR; secondary endpoints included PFS and safety. Results In cohort B, 89/112 pts (79%; median age, 65 y) received prior LEN+PI. In this subgroup, 67 pts (75%) had LEN-refractory MM and 22 (25%) had LEN-relapsed MM; most pts (52 [58%]) received 1 vs 2 (37 [42%]) prior Tx lines. Median duration of Tx with POM, DEX, and DARA was 15.9, 14.0, and 16.1 mo, respectively. At a median follow-up of 28.4 mo (data cutoff Mar 2020), the ORR was 79% (≥very good partial response [VGPR], 55%). The ORR was 81% (≥VGPR, 63%) and 76% (≥VGPR, 43%) in pts with 1 vs 2 prior lines of Tx, respectively. Median duration of response and median PFS were not yet reached (1-y PFS rate, 74%). Infusion-related reactions occurred in 28% of pts and were primarily low grade (Gr). Overall, 98% of pts had ≥1 Gr 3/4 Tx-emergent adverse event. The most common Gr 3/4 hematologic events were neutropenia (64%; febrile, 12%), anemia (19%), and thrombocytopenia (13%). Gr 3/4 infections occurred in 40% of pts, including 16% with pneumonia. Conclusion POM+DEX+DARA administered immediately after LEN failure in a subgroup of pts previously treated with LEN+PI demonstrated a high response rate and a safety profile consistent with that in the overall cohort B population. Results support the use of POM-based therapy, integrating the monoclonal antibody DARA, as early as second line in pts with RRMM, potentially immediately after LEN Tx failure. Furthermore, the data support subsequent Tx with the same immunomodulatory agent class in a pt population with LEN-relapsed or -refractory MM. Previous presentation Bahlis NJ, et al. HemaSphere 2021;5:e482–483. EP1019.

Background CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and preliminary efficacy of IBER, an oral, novel cereblon E3 ligase modulator (CELMoD®) compound, with different treatment combinations in independent cohorts, in pts with MM. Here we report results from the IBER+DARA+DEX (IberDd), IBER+BORT+DEX (IberVd), and IBER+CFZ+DEX (IberKd) cohorts in RRMM. Methods Eligible pts received ≥2 (IberDd and IberKd cohorts) or ≥1 prior regimens (IberVd cohort), containing lenalidomide or pomalidomide, and a proteasome inhibitor. All pts had progressed ≤60 days from last therapy. Escalating oral doses of IBER were given on day (D)1–21 of each 28-D cycle in the IberDd cohort and in the IberKd cohort with weekly CFZ, and on D1–14 of each 21-D cycle in the IberVd cohort. DEX was given weekly in all 3 cohorts. Results As of April 8, 2021, 43 pts had received IberDd, 25 IberVd, and 9 IberKd. Median age was 67, 64, and 61 years, and median time since diagnosis was 7.35, 7.1, and 6.7 years in the IberDd, IberVd, and IberKd cohorts, respectively. Extramedullary plasmacytomas were present in 7 (16%), 4 (16%), and 2 (22%) pts in the IberDd, IberVd, and IberKd cohorts, respectively. Exposure to prior regimens was heterogeneous; all pts were refractory to their last prior regimen and ≥33% pts in the 3 cohorts were triple-class refractory. IBER doses ranged from 1.0 to 1.6 mg. Median follow-up was 4.17, 4.86, and 5.03 months, 22 (51%), 6 (24%), and 5 (56%) pts continue on treatment, and median cycles received were 4, 6, and 5 with IberDd, IberVd, and IberKd, respectively. Hematologic grade (G) 3–4 treatment-emergent adverse events (TEAEs) of interest included neutropenia (67%), leukopenia (23%), anemia (21%), and febrile neutropenia (5%) with IberDd; neutropenia (28%) and thrombocytopenia (24%) with IberVd; and lymphopenia (44%) and neutropenia (33%) with IberKd. Neutropenia was manageable with G-CSF. Occurrence of non-hematologic TEAEs was low, with very few G3–4 fatigue, rash, and gastrointestinal disorders. The overall response rate was 46% with IberDd, 56% with IberVd, and 50% with IberKd, including a VGPR or better of 24%, 28%, and 38%, respectively. Median time to response was 4.1 (4.0–12.0), 3.6 (3.0–13.1), and 4.1 (4.1–8.1) weeks, in the IberDd, IberVd, and IberKd cohorts, respectively. Median duration of response is 35.7 weeks in the IberVd cohort (not reached in the other cohorts). RP2D was determined at 1.6 mg in the IberDd cohort; dose evaluation continues in the other cohorts. Conclusions In pts with heavily pretreated RRMM, IberDd, IberVd, and IberKd showed a tolerable safety profile and promising efficacy. These results support further development of IBER-based regimens in MM, including the initiation of phase 3 combination studies. Previously published in Lonial S, et al. HemaSphere 2021;5(S2):49.

Objective To determine the impact of skin-to-tumor (STT) distance on the risk for treatment failure following percutaneous cryoablation (PCA). Methods We retrospectively reviewed patients who underwent PCA with documented T1a recurrent renal cell carcinoma (RCC) at 2 academic centers between 2005 and 2015. Patient demographics, tumor characteristics, and perioperative and postoperative course variables were collected. Additionally, we measured the STT distance by averaging the distance from the skin to the center of the tumor at 0°, 45°, and 90° on preoperative computed tomography imaging. Results We identified 86 patients with documented T1a RCC. The mean age at the time of surgery was 69 years (range: 37-91 years), and the mean tumor size was 2.7 cm (range: 1.0-4.0 cm). With a mean follow-up of 24 months (range: 3-63 months), 11 (12.8%) treatment failures occurred. Patients with treatment failure had significantly higher mean STT distance than those without: 11.0 cm (range: 6.3-20.1 cm) compared to 8.4 cm (range: 4.4-15.2 cm), respectively (P = .002). STT distance was an independent predictor of treatment failure (odds ratio: 1.32, 95% confidence interval: 1.04-1.69, P = .029). STT distance greater than 10 cm had a fourfold increased risk of tumor treatment failure (odds ratio: 4.43, 95% confidence interval: 1.19-16.39, P = .018). Tumor size, R.E.N.A.L. Nephrometry score, and number of cryoprobes placed were not associated with treatment failure. Conclusion STT, an easily measured preoperative variable, may inform the risk of RCC treatment failure following PCA.

The compassionate use of available medications with unproven efficacy is often in conflict with their clinical evaluation in placebo-controlled clinical trials. For ultra-rare diseases where no approved treatments exist, such as fibrodysplasia ossificans progressiva (FOP), routine clinical trial enrollment for available medications may be difficult to achieve. Therefore adaptive methods of evaluation are often desirable. Off-on-off-on (O4) approaches offer an opportunity to rapidly assess the potential symptomatic efficacy and tolerability of a medication with a limited number of patients and may aid in the design of more focused clinical trials that are amenable to enrollment. Here we report three children with classic FOP who had recalcitrant flare-ups of the back and who had been treated with an O4 regimen of imatinib. In all three children, fewer flare-ups, decreased swelling and improved function with activities of daily living were reported by the parents and treating physician when the children were “on” imatinib than when they were “off” imatinib. The median time to improvement on imatinib was 2–3 weeks. The anecdotal O4 experience with imatinib reported here in three children with FOP who had recalcitrant flare-ups of the back supports the design of a brief placebo controlled trial to assess the potential efficacy of imatinib in reducing the symptoms in children with refractory flare-ups of FOP. A tool to prospectively measure and quantitate flare-up symptoms is presently being developed and validated and will be used for such a study.

The Santa Barbara Channel, CA (SBC) is a biodiverse marine ecosystem fueled largely by phytoplankton productivity, and the composition of the phytoplankton community influences the magnitude and fates of this productivity. Here, we create a 22-year monthly time series of phytoplankton biomarker pigment concentrations in the SBC by combining 12 years of high performance liquid chromatography phytoplankton pigment concentrations with bio-optical models and 10 additional years of bio-optical observations. The bio-optical models skillfully predict biomarker pigment concentrations representative of five distinct phytoplankton groups (PGs; diatoms, dinoflagellates, chlorophytes, prymnesiophytes, and picophytoplankton) and resolve seasonal responses to the annual upwelling-relaxation cycle for all PGs except the dinoflagellates. Our observations indicate that nanophytoplankton groups respond most rapidly to seasonal upwelling, followed by diatoms, and then by picophytoplankton as the water column stratifies in the summer. A Regional Ocean Modeling System (ROMS) solution is used to relate advection of different source waters to the observed PG dynamics. The ROMS simulation results suggest that, on seasonal time scales, pronounced cross-SBC differences in PG seasonality are related to cross-SBC differences in source waters. El Nino Southern Oscillation events drive interannual variability in the upwelling response of most PGs. On decadal time scales, dinoflagellate blooms are associated with the warm phase of the North Pacific Gyre Oscillation and anomalous advection of Southern California Bight source waters into the SBC. Taken together, our results provide a novel view of phytoplankton community succession in response to seasonal upwelling by considering the dynamics of pico- and nano-phytoplankton and suggest that regional surface ocean advection plays a substantial role in driving phytoplankton composition in the SBC.

Multi-decadal, monthly observations of optical and biogeochemical properties, made as part of the Bermuda Bio-Optics Project (BBOP) at the Bermuda Atlantic Time-series Study (BATS) site in the Sargasso Sea, allow for the examination of temporal trends in vertical light attenuation and their potential controls. Trends in the magnitude of the diffuse attenuation coefficient, Kd(λ), and a proxy for its spectral shape reflect changes in phytoplankton and chromophoric dissolved organic matter (CDOM) characteristics. The length and methodological consistency of this time series provide an excellent opportunity to extend analyses of seasonal cycles of apparent optical properties to interannual and decadal time scales. Here, we characterize changes in the magnitude and spectral shape proxy of diffuse attenuation coefficient spectra and compare them to available biological and optical data from the BATS time series program. The time series analyses reveal a 1.01%±0.18% annual increase of the magnitude of the diffuse attenuation coefficient at 443 nm over the upper 75 m of the water column while showing no significant change in selected spectral characteristics over the study period. These and other observations indicate that changes in phytoplankton rather than changes in CDOM abundance are the primary driver for the diffuse attenuation trends on multi-year timescales for this region. Our findings are inconsistent with previous decadal-scale global ocean water clarity and global satellite ocean color analyses yet are consistent with recent analyses of the BATS time series and highlight the value of long-term consistent observation at ocean time series sites.

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.

The Defective Self Model of nonsuicidal self-injury (NSSI) proposes that some people engage in NSSI to punish themselves and/or to respond to self-critical cognitions. Although there is a growing body of research to support this theory, there has been a lack of ecologically valid approaches employed to critically examine its tenets. The current study aimed to fill this gap in the literature. A sample of 64 undergraduates with a history of repetitive NSSI were recruited and completed an ecological momentary assessment (EMA) protocol. At baseline, participants completed trait measures of self-criticism and self-punishment cognitions. Over the EMA period, participants reported their experience of self-critical and self-punitive cognitions, and NSSI urge intensity three times daily. Our between-persons level findings suggest that trait and aggregated state self-punishment, but not self-critical cognitions, predict NSSI urges experienced over the EMA period. Our findings additionally provide evidence that both momentary self-critical and self-punishment cognitions are concomitantly and prospectively associated with NSSI urge intensity as measured in real-time and modeled at a within-persons level. However, after adjusting for concurrent NSSI urge intensity in prospective models, these within-persons level findings do not hold. Nevertheless, our findings provide greater support for the Defective Self Model of NSSI.

Background Carfilzomib is approved by the US Food and Drug Administration for the treatment of patients with relapsed and refractory multiple myeloma (MM) who have received at least 2 previous treatments. The approval was based on phase II trials that used a starting dose of 20 mg/m 2 escalated to a target dose of 27 mg/m 2 in cycle 2. We examined dose-outcome relationships in MM patients who received these 2 carfilzomib doses. Materials and Methods Patient data from 4 cohorts of MM patients treated with single-agent carfilzomib in phase II trials were examined post hoc. The relationship between administered doses and overall response rate (ORR) was assessed using logistic regression models. Secondary analyses were performed using Cox regression models to assess the association between administered doses and time to event outcomes and using generalized estimating equations for cycle-specific response status (CSRS). Results A total of 476 intention to treat patients were enrolled, 461 of whom were evaluable for efficacy. In the primary analysis, adjustment for cohort and baseline covariates yielded an odds ratio for ORR of 1.28 (95% confidence interval, 1.16-1.41; P 2 increase in the average administered dose of carfilzomib per patient (up to 27 mg/m 2 ). Qualitatively similar and statistically significant results were seen for the association between administered dose and CSRS, duration of response, time to progression, progression-free survival, and overall survival when adjusted for cohort and baseline covariates. Conclusion This post hoc analysis provides evidence for a dose-response relationship between the administered dose of carfilzomib and efficacy.

Background: Regimens containing IMiDs (immunomodulatory imide drugs) are standard of care for patients with newly diagnosed multiple myeloma. The IMiD-free regimen of carfilzomib, dexamethasone, and daratumumab (KdD) is recommended by NCCN guidelines and has recently been evaluated in two studies: 1) In the randomized phase 3 CANDOR study, KdD with carfilzomib at the twice-weekly dose of 56 mg/m2 (KdD56) resulted in a 37% risk reduction of disease progression or death (vs Kd); 2) In the phase 1b EQUULEUS study, KdD with a weekly carfilzomib dose of 70 mg/m2 (KdD70) was promising. Objective: Twice-weekly KdD56 and weekly KdD70 have not been directly compared in the same trial, therefore a cross-study comparison of efficacy and safety was performed with data from the two studies just described. Methods: In order to evaluate efficacy in comparable populations, as all the patients from the KdD arm of the EQUULEUS study were required to have prior therapy with bortezomib and an IMiD, similar patients (i.e., prior treatment with bortezomib and an IMiD) were selected from the KdD arm of the CANDOR study. To adjust for selection bias, we used propensity scoring for efficacy based on prespecified prognostic baseline covariates to estimate the inverse probability of treatment weights (IPTW). Results: Before and after IPTW adjustment, overall response rate (ORR) and progression-free survival (PFS) were similar for the twice-weekly KdD56 and weekly KdD70 groups. Safety data were consistent with the known safety profiles of individual study treatments. The safety data were not adjusted as the IPTW were constructed for efficacy endpoint prognostic factors. Conclusions: We previously established in CANDOR that twice-weekly KdD56 has a favorable benefit-risk profile. This robust cross-study analysis showed evidence that KdD70 was similar to KdD56 with respect to efficacy and safety. The weekly KdD70 dosing option represents a more convenient regimen that might encourage the longer adherence important for treating patients until disease progression and thus may ultimately lead to better clinical outcomes for these patients. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved.

Background: Panobinostat (pano) is a pan histone deacetylase inhibitor (HDAC-i) FDA-approved for use with bortezomib (btz) and dexamethasone (dex) for patients with multiple myeloma (MM) who have had ≥2 prior lines of therapy, including both btz and an immunomodulatory agent (IMiD). This retrospective study evaluates efficacy and safety of pano combined with other FDA-approved agents used in relapsed/refractory (RR) MM. Methods: From February 2015-July 2017, 47 consecutive patients with RRMM treated with commercial pano identified in the EMR were reviewed. Results: Median age was 58.7 (27-78) years with 55% men. 41 (87%) were Durie-Salmon Stage 3. 12 (26%) had high-risk FISH: t(14;16), t(4;14), del 17p, and gain 1q21. Median number of prior lines was 6 (2-14). 38 (81%) were RR to the last line of therapy. 29 (62%) were btz-refractory, 36 (77%) lenalidomide-refractory, 36 (77%) pomalidomide-refractory, and 36 (77%) carfilzomib-refractory. 33 (70%) were refractory to carfilzomib with an IMiD. 15 (32%) had prior daratumumab and 7 (15%) had prior HDAC-i therapy. Median pano cycles was 3 (0.25-18). ORR (≥PR) was 25.0% and clinical benefit rate (≥MR) was 38.6%. Median duration of response (≥SD) was 4.3 months. Median PFS was 2.4 months (95% CI: [1.61,4.01]). Median OS from initiation of pano through 1/16/19 was 6.25 months (95% CI: [5.10,12.95]). Three patients discontinued pano due to toxicity. Grade 3-4 non-hematologic toxicities were diarrhea (N=1), and respiratory failure (N=2). Grade 3-4 hematologic adverse events (AEs) occurred in 19 (40%) patients, 12 (26%) with anemia,15 (32%) with neutropenia, and 13 (28%) with thrombocytopenia. Serious AEs included acute kidney injury, GI bleed, febrile neutropenia, heart failure exacerbation, and dyspnea in 4 patients, respectively. PFS is negatively associated with a greater number of lines of treatment prior to initiating pano (HR 1.21: 95% CI 1.02-1.4). High-risk FISH (HR 0.71: 95% CI 0.31-1.60) and being refractory to the last prior line of therapy (HR 0.51: 95% CI 0.17-1.60) show no significant association with PFS. Conclusion: Use of pano outside of the FDA indication, in combination with PI and IMiD-based regimens, has activity and is well tolerated in heavily pretreated RRMM patients.

Global, repeat satellite imagery serves as an essential tool to understand ecological patterns and processes over diverse temporal and spatial scales. Recently, the use of spaceborne imagery has become indispensable for monitoring giant kelp, a globally distributed foundation species that displays variable seasonal and interannual dynamics. In order to develop and maintain a continuous and spatially expansive time series, we describe a fully automated protocol to classify giant kelp canopy biomass across three Landsat sensors. This required correcting kelp canopy estimates to account for changes in the spectral response functions between the three sensors by simulating data using hyperspectral imagery. Combining multiple sensors also necessitated the use of an extended (15 year) time series of diver estimated kelp biomass to validate each sensor. We also describe a novel gap filling technique using known spatial scales of kelp biomass synchrony to correct for missing data due to the Enhanced Thematic Mapper Plus scan line corrector failure. These developments have led to a publicly available 34-year, seasonal time series of kelp canopy biomass across ~1500 km of California coastline. We then use this time series to examine the role of temporal and spatial scale on the detection of long-term biomass trends. We found that kelp canopy biomass trends are associated with trends in low frequency marine climate oscillations, like the North Pacific Gyre Oscillation. Long-term (~20 year) increases in the state of the North Pacific Gyre Oscillation have led to a cooler, nutrient-rich environment that benefits the growth of giant kelp across a large portion of the kelp biomass time series, however recent warming events have led to weak, or nonexistent trends over the length of the time series. The cyclical nature of these low frequency marine climate oscillations complicates the detection of trends that may be associated with anthropogenic climate change. A longer and continuous time series is needed to analyze long-term canopy biomass trends outside of natural low frequency climate variability for giant kelp ecosystems along the coast of California, if we are to make accurate assessments of the impacts of climate change.

Fundamental to the field of ionic liquids is the understanding that structure begets function. In this work, we reported the development of thioether-based ionic liquids, with enhanced hydrophobicity and low melting point (Tm), via the thiol‒yne reaction. Cationic lipids can simply be converted to macroscopically hydrophobic ionic liquids by replacing their native chloride counteranion with Tf2N. Features that specifically increase or decrease fluidity are identified by juxtaposing the wide-ranging Tm values of these highly lipophilic salts with elements of their cation structures. Most importantly, when these Tm-increasing and -decreasing features are incorporated into the same cation, an “averaged” Tm value is observed. These findings may prove to be elements of the “know-how” needed to design functional ionic liquids that liquefy within relatively predictable temperature ranges.

This study examines the potential of the Hyperspectral Infrared Imager (HyspIRI) mission for monitoring the biomass and physiological condition of giant kelp forests on local to global scales. Giant kelp is a highly dynamic foundation species that supports an ecologically and economically important ecosystem found throughout the globe. Satellite, airborne, and field data are used to evaluate the suitability of HyspIRI's spatial, temporal, and spectral coverage for capturing variability in giant kelp biomass and physiological state. We analyze a 28-year time series of giant kelp biomass derived from Landsat satellite imagery in order to identify the dominant temporal modes of variability in giant kelp biomass using the California coast as a model region likely to be relevant to other regions of the globe. Temporal variability in California kelp canopy biomass is compared to the expected availability of cloud-free HyspIRI Visible Shortwave Infrared (VSWIR) views for regions of the world that contain giant kelp populations. Spectral variability is explored by assessing how changes in the physiological condition of giant kelp canopy are exhibited in the reflectance and transmittance of kelp fronds. We compare chlorophyll a to carbon ratios (Chl:C) of kelp fronds collected off the coast of California to laboratory and airborne measurements of hyperspectral reflectance in order to develop metrics of kelp physiological condition. The seasonal cycle dominates giant kelp canopy biomass temporal variability. However, the strength and timing of this cycle varies in both space and time. Our projections of cloud-free HyspIRI coverage indicate that the sensor will be able to capture at least 1 cloud free view each season for nearly all of the global giant kelp habitats, thereby illustrating that HyspIRI will resolve the dominant seasonal cycles in giant kelp biomass. A novel spectral index developed here from field observations explained 76% of the variance in Chl:C and was applied to hyperspectral aircraft observations. These results demonstrate that the spatial, temporal, and spectral coverage provided by HyspIRI has the potential to provide new insights into the ecology and biophysiology of giant kelp.

Purpose Approximately 1 of 6 children in the United States is obese. This has important implications for drug dosing and safety because pharmacokinetic (PK) changes are known to occur in obesity due to altered body composition and physiologic mechanisms. Inappropriate drug dosing in an emergency setting can limit therapeutic efficacy and increase drug-related toxic effects for obese children. Few systematic reviews examining PK properties and drug dosing in obese children have been performed. Methods We identified 25 emergency care drugs from the Strategic National Stockpile and Acute Care Supportive Drugs List and performed a systematic review for each drug in 3 study populations: obese children (2–18 years of age), normal weight children, and obese adults (aged >18 years). For each study population, we first reviewed a drug’s Food and Drug Administration label and then performed a systematic literature review. From the literature, we extracted drug PK data, biochemical properties, and dosing information. We then reviewed data in 3 age subpopulations (2–7 years, 8–12 years, and 13–18 years) for obese and normal weight children and by route of drug administration (intramuscular, intravenous, oral, and inhaled). If sufficient PK data were not available by age and route of administration, a data gap was identified. Findings Only 2 of 25 emergency care drugs (8%) contained dosing information on the Food and Drug Administration label for obese children and adults compared with 22 of 25 (88%) for normal weight children. We found no sufficient PK data in the literature for any of the emergency care drugs in obese children. Sufficient PK data were found for 7 of 25 emergency care drugs (28%) in normal weight children and 3 of 25 (12%) in obese adults. Implications Insufficient information exists to guide dosing in obese children for any of the emergency care drugs reviewed. This knowledge gap is alarming, given the known PK changes that occur in the setting of obesity. Future clinical trials examining the PK properties of emergency care medications in obese children should be prioritized.

The Santa Barbara Channel (SBC) eddy is a cyclonic mesoscale eddy and a dominant oceanographic feature of the SBC. In June 1998 and 1999, the SBC eddy was surveyed for fishes. In 1998, very high numbers of small pelagic fishes were observed within the eddy, but not in 1999 when the eddy was far less stable. The ocean conditions that contributed to the interannual differences of fish abundances inside the eddy are investigated with three-dimensional numerical modeling. The life history and kinematic characteristics of the SBC eddy, which includes its life span, size, trajectory, three-dimensional rotational structure, and isopycnal displacement, are evaluated using a three-dimensional ocean circulation model. The retention ability of the eddy is quantified using a three-dimensional particle tracking model, which is driven by the flow fields from the circulation model. The kinematic characteristics and particle retention of the SBC eddy differ significantly in 1998 and 1999. In 1998, when the SBC eddy is rotating at a steady rate in space and time with vertically coherent flow, the particle retention is high and the isopycnal uplift sustained. However, in 1999, when the SBC eddy is rotating unsteadily without vertically coherent flow, the particle retention is low and the isopycnal uplift fluctuates. We theorize that the steady vertically coherent rotation of the eddy in 1998 has two important impacts on the fish abundances. First, it provides a prolonged period of cold nutrient rich water uplifting into the euphotic zone, which stimulates primary productivity attracting zooplankton prey. Second, it allows the zooplankton prey to be retained inside the eddy, which attracts small pelagic fish. We conclude that biological productivity inside mesoscale eddies may be linked to the stability of their three-dimensional rotational structure and their consequent ability to retain particles.

Children are the members of our population who are most vulnerable to the effects of a chemical, biological, radiological, nuclear, and explosive (CBRNE) attack. It has been more than 12 years since 9/11 and most clinicians who would be providing care to children in the event of another attack still lack the requisite disaster preparedness training. Much of the needed pediatric education and training content for the diagnosis and treatment of the injurious effects of CBRNE agents has recently been both developed and well vetted. Bringing together these efforts in an educational program will result in a workforce that is better trained and prepared to address the needs of children impacted by these types of disasters. In 2011, the National Center for Disaster Medicine and Public Health convened a Pediatric Disaster Preparedness Conference. Much of the initial groundwork for development of a pediatric disaster preparedness curriculum, including the identification of target audiences and requisite role-specific CBRNE curriculum content, was the product of this conference. The purpose of this report is to provide an overview of the recent developments that will enable the affordable creation of key chemical, biological, radiologic, nuclear, and explosive educational and just-in-time material.

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.

AUR = acute urinary retention, BOO = bladder outlet obstruction, BPH = benign prostatic hyperplasia, FDA = U.S. Food and Drug Administration, IDE = investigational device exemption, IPSS = International Prostate Symptom Score, LUTS = lower urinary tract symptoms, PAE = prostatic artery embolization, PV = prostate volume, QOL = quality of life, TUMT = transurethral microwave thermotherapy, TURP = transurethral resection of the prostate, RCP = research consensus panel, UTI = urinary tract infection

Summary Background We aimed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma. Methods In our randomised, double-blind, placebo-controlled, phase 3 trial, we enrolled adults (≥18 years) at 174 university hospitals in 31 countries worldwide. Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment (one to three regimens) but were currently progressing, ECOG performance statuses of 2 or less, and no continuing toxic effects from previous treatment. We excluded patients with known resistance to bortezomib. We randomly allocated patients (1:1) using an interactive voice response system to receive 21 day cycles of bortezomib (1·3 mg/m 2 intravenously on days 1, 4, 8, and 11) in combination with oral vorinostat (400 mg) or matching placebo once-daily on days 1–14. We stratified patients by baseline tumour stage (International Staging System stage 1 or stage ≥2), previous bone-marrow transplantation (yes or no), and number of previous regimens (1 or ≥2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed adverse events in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number 00773747. Findings Between Dec 24, 2008, and Sept 8, 2011, we randomly allocated 317 eligible patients to the vorinostat group (315 of whom received at least one dose) and 320 to the placebo group (all of whom received at least one dose). Median PFS was 7·63 months (95% CI 6·87–8·40) in the vorinostat group and 6·83 months (5·67–7·73) in the placebo group (hazard ratio [HR] 0·77, 95% CI 0·64–0·94; p=0·0100). 312 (99%) of 315 patients in the vorinostat group and 315 (98%) of 320 patients in the placebo group had adverse events (300 [95%] adverse events in the vorinostat group and 282 [88%] in the control group were regarded as related to treatment). The most common grade 3–4 adverse events were thrombocytopenia (143 [45%] patients in the vorinostat group vs 77 [24%] patients in the placebo group), neutropenia (89 [28%] vs 80 [25%]), and anaemia (53 [17%] vs 40 [13%]). Interpretation Although the combination of vorinostat and bortezomib prolonged PFS relative to bortezomib and placebo, the clinical relevance of the difference in PFS between the two groups is not clear. Different treatment schedules of bortezomib and vorinostat might improve tolerability and enhance activity. Funding Merck.

Absorption of ultraviolet radiation (UV, 280–400 nm) by chromophoric dissolved organic matter (CDOM) precedes a host of light-sensitized surface ocean processes relevant to global climate. These include photo- and biogeochemical cycling of organic material, release of sulfur and carbon-containing gases to the atmosphere, and the photoprotection of marine microorganisms. Synoptic CDOM absorption data in the UV is highly desired yet difficult to estimate by satellite methods as the atmosphere interferes with direct detection of water-leaving UV radiance. The absorption spectrum of CDOM is typically modeled as an exponential function in which a spectral slope parameter, S, describes the rate of decrease in absorption with increase in wavelength. Significant functional relationships are observed in aquatic environments between S and the CDOM absorption coefficient at 443 nm, aCDOM(443). In this paper, we use a large, systematic dataset of spectroscopic CDOM measurements from the U.S. CO2/CLIVAR Repeat Hydrography Survey to examine the relationship between S and aCDOM(443) as a means to model aCDOM(λ) in the UV from ocean color. Our resultant model predicts aCDOM(λ) at wavelengths from 325 to 412 nm from the absorption coefficient of colored dissolved and detrital materials (CDM) at 443 nm, aCDM(443), retrieved by an existing semi-analytical ocean color algorithm. Expected agreement (near 1:1) with the training dataset was achieved (r2 = 0.71–0.85, p = 0, n = 127). Considering inherent satellite data uncertainties as well as the model's limitations in regions with potential terrestrial influence, good correspondence between modeled and in situ values was observed during independent validation with open ocean CDOM data, such as from BIOSOPE (r2 = 0.77–0.85, p 7500 samples) from diverse Case I waters.

Many marine organisms spend their early lives as planktonic larvae dispersed by ocean currents. Predictions of larval transport are important for a wide range of applications including the interpretation of population genetics, fisheries management, and the planning of no-take marine protected areas. A popular method for predicting larval transport is through the use of coupled ocean circulation and particle tracking models, termed “biophysical” models. Although much research has been done on the sensitivity and uncertainty of ocean circulation models, the sensitivity of particle tracking models for the assessment of larval transport has been largely overlooked. This study investigates the sensitivity of larval transport predictions to three input parameters universally required for particle tracking in biophysical models; namely the number of particles released, the particle release depth, and the particle tracking time. Using a three-dimensional biophysical model of the Southern California Bight, estimates of larval transport are quantified using a two-dimensional vertically-integrated particle density distribution (PDD) and the difference between PDDs is assessed using the fraction of unexplained variance (FUV). Overall, our study shows that larval transport predictions are sensitive to changes in all three input parameters and that the sensitivity is affected by the strength of mixing in the system. For the number of particles released, the FUV falls off rapidly as the number of particles increases. A minimum number of particles is identified that guarantees robustness of model predictions; this number increases as the complexity of the circulation patterns increases. For the particle release depth, the FUV between PDDs grew linearly as particles are released farther apart. The FUV is also inversely proportional to the strength of vertical mixing as the FUV is smaller in the winter when a deep mixed layer and weak stratification are present and larger in the summer when the system is strongly stratified. For the particle tracking time, the FUV between daily PDDs is much larger for short tracking times of 15 days or less than for longer tracking times of 20 days or more, showing a dependence on the length of time the particles take to be evenly mixed throughout the system. Our study quantifies the parameter sensitivity of larval transport predictions and presents a straightforward methodology to achieve robust predictions of larval transport from biophysical models.