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Productivity of the food web supporting small pelagic fishes in the upper San Francisco Estuary is chronically low, and some of the native fish species are in a long-term decline. The low-salinity (oligohaline) zone (LSZ) is particularly depauperate in phytoplankton and zooplankton. Based on prior empirical studies, it is hypothesized that freshwater flow increases the subsidy of a key copepod prey species (Pseudodiaptomus forbesi) from its freshwater population center into the LSZ. We combined hydrodynamic and particle-tracking modeling with Bayesian analysis in a box-model approach to estimate the magnitude of this subsidy and its dependence on freshwater flow rates. Net gains of P. forbesi into the LSZ came mostly from freshwater, landward regions of higher copepod abundance. The subsidy increased with freshwater flow, a finding that supports previous empirical analyses. However, in the context of persistent drought and ongoing climate change, the levels required to achieve a detectable net gain may be difficult and costly to achieve.

Flip Chip Ball Grid Array (FCBGA) packages, together with many other heterogeneous integration packages, are widely used in high I/O (Input/Output) density and high-performance computing applications. The thermal dissipation efficiency of such packages is often improved through the use of an external heat sink. However, the heat sink increases the solder joint inelastic strain energy density, and thus reduces the board-level thermal cycling test reliability. The present study constructs a three-dimensional (3D) numerical model to investigate the solder joint reliability of a lidless on-board FCBGA package with heat sink effects under thermal cycling testing, in accordance with JEDEC standard test condition G (a thermal range of −40 to 125 °C and a dwell/ramp time of 15/15 min). The validity of the numerical model is confirmed by comparing the predicted warpage of the FCBGA package with the experimental measurements obtained using a shadow moiré system. The effects of the heat sink and loading distance on the solder joint reliability performance are then examined. It is shown that the addition of the heat sink and a longer loading distance increase the solder ball creep strain energy density (CSED) and degrade the package reliability performance accordingly.

To what extent plants thermoregulate their canopy temperature (Tc) in response to environmental variability is a fundamental question in ecology, and influences accurate projections of plants' metabolic response and resilience to climate change. However, debate remains, with opinions ranging from no to moderate plant thermoregulation capacities. Traditionally, it has been hypothesized that if plant thermoregulation occurs (i.e. ‘limited homeothermy’ hypothesis holds): 1) Tc will change more slowly than Ta over time, leading the Tcvs. Ta regression slope < 1; 2) Tc is cooler than Ta when Ta exceeds some threshold, typically during high net radiation conditions (e.g. at midday). Here, with global datasets of Tc, air temperature (Ta), and other environmental and biotic variables from FLUXNET and satellites, we tested the ‘limited homeothermy’ hypothesis across global extratropics, including temporal and spatial dimensions. Our results demonstrate that across daily to monthly timescales, over 80% of sites/ecosystems have Tcvs. Ta regression slopes≥1 or Tc>Ta around midday, which rejects the ‘limited homeothermy’ hypothesis. For those sites unsupporting the hypothesis, their Tc-Ta difference (ΔT) still exhibits considerable seasonality that is negatively, partially correlated with their canopy structure seasonality (as indicated by leaf area index), implying a certain degree of thermoregulation capability. Across global sites, both site-mean ΔT and slope indicator exhibit considerable spatial variability, with ΔT having greater variability than the slope indicator. Furthermore, this large spatial ΔT variation (0-6°C) can be mainly explained by environmental variables (38%) and, to a lesser extent, by biological factors (15%). Our results suggested that plant thermoregulation patterns are diverse across global extratropics, with most ecosystems rejecting the ‘limited homeothermy’ hypothesis, but their thermoregulation still occurs, implying that slope

In the phase 3 POLARIX study (NCT03274492), polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety in previously untreated diffuse large B-cell lymphoma. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intent-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cut-off (June 28, 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population and was superior with Pola-R-CHP versus R-CHOP (hazard ratio 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3-4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP versus R‑CHOP in the Asian and global populations in POLARIX.

IoT has continued to evolve over the years with a promise to provide the users with effective means to interact, communicate, transact and create strong relationship. The invention and the development of IoT have created benefits for many businesses and individuals. However, as the IoT continues to evolve and develop, it has been subjected to certain threats and vulnerabilities. The common vulnerabilities notable in IoT include the security, privacy and data protection concerns. These issues have not been addressed by many scholars thus necessitated the need for this research study. Therefor the research study was concerned with the developed of a new IoT model that can enhance the security and privacy of the users of the IoT. The results indicate that the new model can be effective in addressing the needs of the IoT users. However, it noted that future research studies are still needed to improve the performance of the IoT security models.

Background and Aims: Expert endoscopists previously reported ERCP outcomes for the first commercialized single-use duodenoscope. We aimed to document usability of this device by endoscopists with different levels of ERCP experience. Methods: Fourteen “expert” (>2000 lifetime ERCPs) and 5 “less-expert” endoscopists performed consecutive ERCPs in patients without altered pancreaticobiliary anatomy. Outcomes included ERCP completion for the intended indication, rate of crossover to another endoscope, device performance ratings, and serious adverse events. Results: Two hundred ERCPs including 81 (40.5%) with high complexity (American Society for Gastrointestinal Endoscopy grades 3-4) were performed. Crossover rate (11.3% vs 2.5%, P =.131), ERCP completion rate (regardless of crossovers) (96.3% vs 97.5%, P =.999), median ERCP completion time (25.0 vs 28.5 minutes, P =.130), mean cannulation attempts (2.8 vs 2.8, P =.954), and median overall satisfaction with the single-use duodenoscope (8.0 vs 8.0 [range, 1.0-10.0], P =.840) were similar for expert versus less-expert endoscopists, respectively. The same metrics were similar by procedural complexity except for shorter median completion time for grades 1 to 2 versus grades 3 to 4 (P Conclusions: In consecutive ERCPs including high complexity procedures, endoscopists with varying ERCP experience had good procedural success and reported high device performance ratings. (Clinical trial registration number: NCT04223830.)

Purpose: The purpose of this study was to understand the perceived benefits and clinical utility of cardiopulmonary exercise testing (CPET) from the perspectives of physiotherapists and patients and to explore the factors that influence adopting CPET in a stroke rehabilitation setting. Method: A qualitative descriptive study was conducted. Physiotherapists ( n = 6) participated in a focus group to discuss the use of CPET in practice. Patients ( n = 8) who had completed CPET during stroke rehabilitation participated in a semi-structured interview to explore their experiences. Thematic analysis was performed. Results: CPET increased the physiotherapists’ confidence in prescribing exercise, especially for medically complex patients. Ongoing medical management early post-stroke was a barrier to referral. Physiotherapists expressed decreased confidence in interpreting test results. Consultation with local experts facilitated the use of CPET. Patients described how CPET increased their confidence to participate in exercise. They desired more information before and after CPET to better understand the purpose and results and their relation to their rehabilitation goals. Conclusions: Both physiotherapists and patients described the benefit of having CPET available to support them as they participated in exercise in a stroke rehabilitation setting. Physiotherapists would benefit from having educational tools to support their interpretation and application of test results, and patients would benefit from improved communication and education to support their understanding of the relevance of CPET to their rehabilitation goals. Future research should explore these findings in other stroke rehabilitation settings.

In 2016, a massive bloom of the chain-forming diatom Aulacoseira granulata occurred in the upper San Francisco Estuary, California, with chlorophyll concentrations up to 75 μg Chl L−1. In this study, quantitative PCR was used to investigate consumption of the bloom organism by the numerically dominant zooplankter Pseudodiaptomus forbesi (Copepoda: Calanoida) and to estimate the contribution of the bloom to egg production. Copepods were collected on four transects during May and June 2016; egg production rates were somewhat elevated above previous rates measured in the estuary. Ingestion of A. granulata was highest on the first sampling day, just after the peak of the bloom, ranging from 175 to 945 cells copepod−1 day−1. One month later ingestion rates dropped to 0–130 cells copepod−1 day−1, despite continued dominance of A. granulata in the plankton. Ingestion of A. granulata provided from 0 to 21% (median 1%) of the estimated daily carbon required for growth and reproduction of P. forbesi. Although the copepods probably obtained nutrition from a microbial food web stimulated by the bloom, monitoring data showed little demographic response to this bloom. Thus, a massive diatom bloom in an unproductive estuary provided only a minor stimulus through an abundant consumer to the pelagic food web.

Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N=123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N=130,684). Because these GWAS implicated the geneCADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants inCADM2in a multi-ancestral 23andMe cohort (N=3,229,317, European; N=579,623, Latin American; N=199,663, African American). Finally, we producedCadm2mutant mice and used them to perform a Mouse-PheWAS (“MouseWAS”) by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (∼6-11%), and moderate genetic correlations (rg=.20-.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such asTCF4andPTPRF, and also identified nominal associations proximal toDRD2andCRHR1. PheWAS forCADM2variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role ofCADM2in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.

Remdesivir is an antiviral used for the treatment of COVID-19 requiring hospitalisation. Information on its cardiovascular safety profile is scarce. We report the case of a 37-year-old man with COVID-19 who developed bradycardia after receiving remdesivir. We recommend a baseline ECG for all patients prior to receiving remdesivir and continuous cardiac monitoring during treatment, especially among those with underlying cardiovascular disease, elderly and using β-blockers.

Gene editing following designer nuclease cleavage in the presence of a DNA donor template can revert mutations in disease-causing genes. For optimal benefit, reversion of the point mutation in HBB leading to sickle cell disease (SCD) would permit precise homology-directed repair (HDR) while concurrently limiting on-target non-homologous end joining (NHEJ)-based HBB disruption. In this study, we directly compared the relative efficiency of co-delivery of a novel CRISPR/Cas9 ribonucleoprotein targeting HBB in association with recombinant adeno-associated virus 6 (rAAV6) versus single-stranded oligodeoxynucleotides (ssODNs) to introduce the sickle mutation (GTC or GTG; encoding E6V) or a silent change (GAA; encoding E6optE) in human CD34+ mobilized peripheral blood stem cells (mPBSCs) derived from healthy donors. In vitro, rAAV6 outperformed ssODN donor template delivery and mediated greater HDR correction, leading to both higher HDR rates and a higher HDR:NHEJ ratio. In contrast, at 12–14 weeks post-transplant into recipient, immunodeficient, NOD, B6, SCID Il2rγ−/− Kit(W41/W41) (NBSGW) mice, a ∼6-fold higher proportion of ssODN-modified cells persisted in vivo compared to recipients of rAAV6-modified mPBSCs. Together, our findings highlight that methodology for donor template delivery markedly impacts long-term persistence of HBB gene-modified mPBSCs, and they suggest that the ssODN platform is likely to be most amenable to direct clinical translation. Keywords: sickle cell disease, gene editing, rAAV6, ssODN, homology-directed repair, Crispr/Cas9, hemoglobin disorders, NHEJ versus HDR, in vivo engraftment, NBSGW41 mice, CD34, hematopoietic stem cells, stem cell cures

Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34+ cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia., Graphical Abstract

7517 Background: Overexpression of BCL2 and MYC, and translocation of MYC, BCL2, and BCL6, are associated with poorer outcomes in patients (pts) with DLBCL (Horn et al. Blood 2013). We previously reported progression-free survival (PFS) from POLARIX in subgroups of pts with DLBCL receiving Pola-R-CHP or R-CHOP, including pts with double expressor lymphoma (DEL; favoring Pola-R-CHP: hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.42–0.97), and double- or triple-hit lymphoma (DHL/THL; favoring R-CHOP: HR 3.81, 95% CI 0.82–17.64) (Tilly et al. NEJM 2022). In this prespecified exploratory analysis, we further analyzed immunohistochemistry (IHC) expression status of BCL2, MYC, and rearrangements (R) of BCL2, BCL6 and MYC as independent prognostic markers. We also explored the prognostic impact of DEL within treatment arms. Methods: BCL2 and MYC protein expression were assessed by IHC and identified as IHC+ (≥50% [BCL2]/≥40% [MYC]) or IHC−; MYC-R, BCL2-R, and BCL6-R were detected by fluorescence in situ hybridization (Tilly et al. NEJM, 2022). Exploratory multivariate Cox regression models were adjusted for treatment, stratification factors (IPI, bulky disease, geographic region), age >60 years, cell of origin, and biomarker evaluated, as appropriate. Results: The prevalence, univariate HR, and 2-year (yr) PFS estimates of BCL2+/MYC+ and BCL2-R/ MYC-R/ BCL6-R subgroups are presented (Table) except for BCL6-R, because all 4 PFS events in this subgroup were with Pola-R-CHP. Multivariate analyses results for Pola-R-CHP vs R-CHOP in pts with BCL2+ (HR 0.60, 95% CI 0.43–0.86) and in pts with MYC+ (HR 0.63, 95% CI 0.45–0.89) were similar to results of univariate analyses. Multivariate analyses of other subgroups were not performed due to the low pt number with BCL2-R/ MYC-R/ BCL6-R. While pts with DEL treated with Pola-R-CHP had improved PFS vs pts treated with R-CHOP (HR 0.64, 0.42–0.97), the prognostic impact of DEL vs non-DEL was more pronounced with R-CHOP (univariate HR 1.53, 95% CI 1.06–2.21; multivariate HR 1.29, 95% CI 0.88–1.91) vs Pola-R-CHP (univariate HR 1.10, 95% CI 0.72–1.69; multivariate HR 1.42, 95% CI 0.89–2.28). Conclusions: Multivariate analyses support the benefit of Pola-R-CHP in pts with BCL2+ and MYC+ DLBCL. The poor prognostic impact associated with DEL appears reduced in Pola-R-CHP- vs R-CHOP-treated pts. Clinical trial information: NCT03274492. [Table: see text]

7558 Background: In the pivotal Phase III POLARIX trial, Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP, with a similar safety profile in patients with previously untreated DLBCL (Tilly et al. 2022). An Asia subpopulation analysis was included as part of the trial design; patients enrolled in Asia were analyzed for the purpose of registration in China of POLARIX (NCT03274492). Methods: Patients from mainland China, Hong Kong, Japan, South Korea, and Taiwan (enrolled during the global phase), and from the China extension cohort were included in the Asia subpopulation. POLARIX methods were previously described (Tilly et al. 2022). Briefly, patients with untreated DLBCL were randomized 1:1 using the same stratification factors to receive six cycles of Pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The purpose of this analysis was to evaluate consistency of PFS (defined as ≥50% risk reduction in PFS) in the Asia subpopulation with the global population. Results: Overall, 281 patients (intent-to-treat population; 150, 85, 31 and 15 patients in mainland China, Japan, South Korea and Taiwan, respectively) were analyzed (141 received Pola-R-CHP and 140 received R-CHOP); 160 patients from the global population and 121 from the China extension cohort. Median age was 63 (range 19–79) years, and most patients had an International Prognostic Index of 3–5 (61.9%). At the data cut-off of June 28, 2021, (median follow-up of 24.2 months) PFS was superior with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.40–1.03) and met the consistency definition with the global population. The 2-year PFS rate was 74.2% (95% CI: 65.7–82.7) with Pola-R-CHP vs 66.5% (95% CI: 57.3–75.6) with R-CHOP. Other key efficacy results were similar to the global study results (Table). The safety profile was generally comparable for Pola-R-CHP vs R-CHOP, including rates of grade 3–4 adverse events (AEs; 72.9% vs 66.2%), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to discontinuation of any study treatment (5.0% vs 7.2%), and incidence of peripheral neuropathy (all grades, 44.3% vs 50.4%), respectively. Key efficacy results. CR, complete response. Conclusions: The results from the Asia subpopulation of POLARIX were consistent with the global study, with a clinically meaningful improvement in PFS (risk of disease progression, relapse or death reduced by 36%) following treatment with Pola-R-CHP vs R-CHOP, and a comparable safety profile in Asian patients with previously untreated DLBCL. Clinical trial information: NCT03274492. [Table: see text]

Background and aims Gastrointestinal (GI) bleeding has been observed amongst patients hospitalized with COVID-19. Recently, anticoagulation has shown to decrease mortality, but it is unclear whether this contributes to increased GI bleeding. The aims of this study are: (i) to examine whether there are risk factors for GI bleeding in COVID-19 patients and (ii) to study whether there is a mortality difference between hospitalized patients with COVID-19 with and without GI bleeding. Methods This is a propensity score matched case-control study from a large health system in the New York metropolitan area between March 1st and April 27th. COVID-19 patients with GI bleeding were matched 1:1 to COVID-19 patients without bleeding using a propensity score that took into account comorbidities, demographics, GI bleeding risk factors and length of stay. Results Of 11, 158 hospitalized with COVID-19, 314 patients were identified with GI bleeding. The point prevalence of GI bleeding was 3%. There were no identifiable risk factors for GI bleeding. Use of anticoagulation medication or antiplatelet agents was not associated with increased risk of GI bleeding in COVID-19 patients. For patients who developed a GI bleed during the hospitalization, there was an increased mortality risk in the GI bleeding group (OR 1.58, P = 0.02). Conclusion Use of anticoagulation or antiplatelet agents was not risk factors for GI bleeding in a large cohort of hospitalized COVID-19 patients. Those with GI bleeding during the hospitalization had increased mortality.