Aesthetics in nursing practice as experienced by nurses in Indonesia: A phenomenological study

Background: While aesthetics in nursing practice brings out the beauty in nursing, studies regarding how aesthetics are implemented in practice are lacking. Objective: To describe the meanings of aesthetics in nursing practice experienced by nurses in Indonesia. Methods: This qualitative study employed a hermeneutic phenomenological approach based on Gadamerian philosophy. Thirteen nurses were asked to reflect on their experiences of providing aesthetics in their practice through drawing, followed by individual face-to-face interviews. Data were collected in a public hospital in West Sumatra, Indonesia. The interview transcripts and the pictures were analysed following van Manen’s approach. Results: Five thematic categories were revealed: 1) Engaging in caring for persons; 2) Full of compassion; 3) Sympathetic place of care; 4) A joyful time of care; and 5) Distracting the inconvenience in care. Conclusion: Aesthetics in nursing practice is understood and experienced by Indonesian nurses in various ways, not only limited to the visual beauty, cleanness or tidiness of nursing intervention, but are expressed in other ways within caring, including providing care with compassion, applying the art of communication, relieving the pain, and applying innovation in care. These findings can be used to inform nurses in practising aesthetic nursing for enhancing the quality of care. Funding: Faculty of Nursing Research Grant, Prince of Songkla University, Thailand.

Poland as a periphery in Immanuel Wallerstein’s theory

The article presents the issue of peripheries and its reference to Poland’s position in the world-system concept of Immanuel Wallerstein. The article discusses problems related to international security of Poland. It also presents the perception of Poland as a peripheral country and, on the basis of theoretical considerations, argues for the possibility of viewing Poland as a semi-peripheral country. Publication financed under the project implemented in the Research Grant Program of the Ministry of National Defence of the Republic of Poland.

Effect of Gender, Age and Vaccine on Reactogenicity and Incapacity to Work after COVID-19 Vaccination: A Survey among Health Care Workers

Background The aim of our study was to assess the influence of gender and age on reactogenicity by the different vaccines and their combinations. Further parameters were the reduction in working capacity after vaccination and the influence of the time of day when vaccines were administered. Methods We conducted a survey on COVID-19 vaccinations and eventual reactions among employees of 89 hospitals of the Helios Group. On May 19th, 2021 employees received an invitation by e-mail from the chief medical officer with a link to the survey tool. Participation was voluntary and non-traceable. The survey was closed on June 21st, 2021. Results 8,375 participants reported on 16,727 vaccinations. Reactogenicity was reported in 75% of COVID-19 vaccinations. In 23% the capacity to work was affected. Major risk factors were female gender, younger age and vaccine other than BNT162b2. ChAdOx induced impairing reactogenicity mainly after the prime vaccination (70.5%), while mRNA-1273 led to more pronounced reactions after the second dose (71.7%). Heterologous prime-booster vaccinations with ChAdOx followed by either mRNA-1273 or BNT162b2 were associated with the highest risk for impairment (81.4%). The time of day of the vaccinations showed no influence. Conclusions Young women had the highest chance to experience reactogenicity and to be unable to work after COVID-19 vaccination. When vaccinating a large part of a workforce, especially in professions with a higher proportion of women like health care, employers as well as employees must be prepared for a noticeable amount of absenteeism. Trial registration The study was approved by the Ethic Committee of the Aerztekammer Berlin on May 27th, 2021 (Eth-37/21) and registered in the German Clinical Trials Register (DRKS 00025745). The study was supported by the Helios research grant HCRI-ID 2021-0272.

Final Results of a Phase 1/2 Study of SYK Inhibitor Entospletinib in Combination with Obinutuzumab in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Therapeutic resistance and intolerance of Bruton tyrosine kinase (BTK) inhibitors is an emerging need in CLL. SYK is integral to the activation of BTK and the B-cell receptor (BCR) signaling cascade and is overexpressed in CLL. We have shown that BAFF-mediated SYK activation triggered BCR signaling and rendered protection of CLL cells from spontaneous apoptosis in vitro. Single agent small molecule SYK inhibitor entospletinib was efficacious in treatment of patients with R/R CLL. Here we report final results of a single arm, open label, investigator-initiated phase 1/2 clinical trial which evaluated safety and efficacy of entospletinib in combination with obinutuzumab, a glycoengineered monoclonal anti-CD20 antibody, in patients with R/R CLL (NCT03010358). Patients enrolled in the Phase 1 dose-escalation portion of the trial included adults with CLL or non-Hodgkin lymphoma (Phase 1 part only) after ≥1 prior therapy. Patients were enrolled at 2 dose levels to receive entospletinib 200 or 400 mg twice-daily orally according to 3+3 design. The primary endpoint for the phase 1 portion of the study was to determine the RP2D of the combination. All patients received single agent entospletinib as part of a 7-day run-in. Thereafter, patients received entospletinib on days 1-28 of each 28-day cycle continuously, and obinutuzumab intravenously in standard doses for 6 cycles. Once the RP2D was determined, a phase 2 study enrolled patients with R/R CLL only, where complete response (CR) was the primary endpoint. A total of 24 patients (22 CLL, 2 follicular lymphoma) were enrolled. Twelve patients were enrolled in the phase 1 part of the study. The phase 2 part of the study included 17 patients with CLL. Of 6 patients who received entospletinib 200 mg on the Phase 1 part of the study, one patient experienced a DLT (grade 3 asymptomatic AST/ALT abnormalities) attributed to entospletinib. No DLTs were observed among the six patients who received entospletinib 400 mg. Thus, entospletinib 400 mg twice-daily was determined to be the RP2D in combination with obinutuzumab. Efficacy of entospletinib+obinutuzumab was analyzed in the 21 patients with CLL, of which 17 received entospletinib at RP2D (400 mg twice daily). Patients with CLL had a median age of 66 years. Thirteen patients (62%) had TP53 aberration (n=9), complex karyotype (n=6), or NOTCH1 or SF3B1 mutation. The median number of prior therapies was two (range, 1-6). Seven patients had received prior ibrutinib (4 patients discontinued due to intolerance and 2 due to progression). Median follow-up was 31 months. Among the 21 efficacy-evaluable participants with CLL, the ORR was 67% (95%CI, 43-85%). Three patients (14%, 95%CI 3-36%) achieved a CR, and 11 patients (53%) had a partial response (PR). patients with confirmed CR had undetectable MRD in the bone marrow. Median event-free survival was 27.5 months (95%CI: 16 months-NR), treatment duration - 31 months (95%CI: 27-40; Figure). Thirteen patients with high-risk CLL had an ORR of 54% (5 PRs and 2 CRs). Among the eight patients who had previously received kinase inhibitors, ORR was 62.5% (all PRs). Treatment-related adverse events were reported in 96% of patients (Table). Grade 3 or higher AEs occurred in 65%. Neutropenia (43.5%; including 4 patients [17%] who had transient grade 4 neutropenia attributed to obinutuzumab) was the most common grade ≥3 hematologic toxicity. The median onset of neutropenia was 7 days after the first obinutuzumab infusion, median duration was 28 days. Growth factor support was not required and grade ≥3 infection occurred in only 1 patient. Only one patient on study discontinued therapy due to adverse events (recurrent AST/ALT abnormalities which resolved upon cessation of entospletinib). Pharmacodynamic analysis demonstrated that treatment with entospletinib led to rapid downmodulation of pSTAT3 and the anti-apoptotic protein MCL1 in CLL cells. Furthermore, six months of combination therapy was accompanied by a reduction in IFNγ secretion in CD4 + T-cells and a reversal of exhausted phenotype, as evidenced by downregulation of PD-1. Thus, the combination of entospletinib and obinutuzumab shows an acceptable safety profile. Efficacy of this combination (EFS 27.5 months in predominantly high-risk population ) compares favorably with chlorambucil/obinutuzumab in R/R CLL (13 months), thus warranting continued exploration of the regimen. Figure 1 Figure 1. Disclosures Danilov: Genentech: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead Sciences: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding. Spurgeon: Bristol Myers Squibb: Other: Institution: Research Grant/Funding; BeiGene: Other: Institution: Research Grant/Funding; AstraZeneca: Other: Institution: Research Grant/Funding; Acerta Pharma: Other: Institution: Research Grant/Funding; Pharmacyclics: Consultancy; Janssen: Consultancy, Other: Institution: Research Grant/Funding; Genentech: Consultancy, Other: Institution: Research Grant/Funding; Karyopharm: Consultancy; Velos Bio: Consultancy, Other: Institution: Research Grant/Funding; Gilead Sciences: Other: Institution: Research Grant/Funding; Ionis: Other: Institution: Research Grant/Funding; Merck & Co., Inc.: Other: Institution: Research Grant/Funding; Fred Hutchinson Cancer Research Center: Other: Data Safety Monitoring Board. Kittai: Abbvie: Consultancy; Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy.

MYD88 L265P Augments Proximal B-Cell Receptor Signaling in Large B-Cell Lymphomas Via an Interaction with DOCK8

Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease comprised of five subtypes including a subset of poor-prognosis activated B cell (ABC)-enriched tumors with frequent MYD88L265P mutations, often in association with CD79B alterations (Cluster 5 DLBCLs) (Nat. Med. 2018; 24:679-690). Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) have similar genetic signatures including recurrent MYD88L265P mutations and concurrent CD79B alterations (Blood 2016; 127: 869-81). These findings prompted us to evaluate a potential role for MYD88L265P in proximal B-cell receptor (BCR) signaling, in addition to its defined function as an intermediary in the Toll-Like Receptor (TLR) pathway and downstream NF-kB activation. In previous studies by Jabara et al., wild-type (WT) MYD88 was found to be constitutively associated with the DOCK8 adapter and the PYK2 tyrosine kinase in normal B-cells (Nat. Immunol. 2012; 13:612-20). In this setting, physiologic ligation of TLR9 with CpG oligodeoxynucleotides (CpG) induced PYK2-mediated phosphorylation of DOCK8, recruitment of Src kinases, including LYN, and downstream activation of the proximal BCR pathway member, spleen tyrosine kinase (SYK) (Nat. Immunol. 2012; 13:612-20). We postulated that mutated MYD88L265P might similarly augment proximal BCR signaling in DLBCLs in the absence of physiologic (CpG-induced) TLR9 signaling. Using three DLBCL cell lines (OCI-Ly1, SU-DHL4 and OCI-Ly7) with intact BCR signaling and WT endogenous MYD88 and CD79B, we first established that physiologic CpG activation of TLR signaling induced the phosphorylation of PYK2 and the proximal BCR signaling components, SYK and Bruton's tyrosine kinase (BTK). Thereafter, we genetically engineered these three DLBCL cell lines to express MYD88 L265P or MYD88 WT, alone or in association with CD79B Y196F. In all three cell lines, the co-expression of MYD88 L265P and CD79B Y196F significantly increased magnitude and duration of SYK and BTK phosphorylation following BCR crosslinking. These findings highlight the likely role of MYD88L265P in CD79BY196F-associated proximal BCR signaling in DLBCL. To elucidate the potential role of the DOCK8 adapter in MYD88 L265P-augmented BCR signaling, we first assessed the colocalization of MYD88 WT or MYD88 L265P with DOCK8 in the same three genetically engineered DLBCL cell lines using proximity ligation assays (PLA), which detect protein-protein interactions at less than 40 nm in situ. In each of these cell lines, we detected significantly increased co-localized MYD88 L265P/DOCK8 signals in comparison to MYD88 WT/DOCK8 signals (p<.0001, all). Additionally, there were significantly increased co-localized DOCK8/LYN signals in DLBCL cell lines that expressed MYD88 L265P rather than MYD88 WT (p<.0001, all). These data provide the first direct evidence of an enhanced association between MYD88 L265P, DOCK8 and LYN in BCR-dependent DLBCLs and a basis for enhanced BCR signaling in primary tumors with concurrent MYD88L265P and CD79B genetic alterations. We next analyzed the consequences of MYD88 L265P-associated, DOCK8-dependent increased proximal BCR signaling by depleting DOCK8 in BCR-dependent DLBCL cells with endogenous MYD88L265P/CD79BY196F alterations (HBL1 and TMD8) or endogenous unmutated MYD88 WT/CD79B WT (OCI-Ly1 and SU-DHL4). ShRNA-mediated DOCK8 knockdown (KD) significantly decreased BCR-mediated phosphorylation of SYK and BTK in MYD88L265P/CD79BY196F DLBCL cell lines but not in lines with MYD88 WT/CD79B WT, highlighting the specific role of DOCK8 in MYD88 L265P-associated proximal BCR signaling. Of great interest, DOCK8 KD selectively decreased the proliferation of MYD88L265P/CD79BY196F, but not MYD88WT/CD79BWT, DLBCLs (p<.004, HBL1 and p<.009, TMD8; p = non sig., OCI-Ly1 and SU-DHL4). Additionally, DOCK8 KD significantly increased the efficacy of chemical PI3Kα/δ (copanlisib) and BTK (ibrutinib) inhibition in MYD88L265P/CD79BY196F DLBCLs (HBL1 and TMD8). Taken together, these data identify DOCK8 as an intermediary in MYD88L265P-driven proximal BCR signaling and a possible treatment target in LBCLs with co-occurring MYD88L265P/CD79BY196F mutations. Disclosures Shipp: AstraZeneca: Consultancy, Research Funding; Immunitas Therapeutics: Consultancy; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Bayer: Other: Institution: Research Grant/Funding; Abbvie: Other: Institution: Research Grant/Funding.

Proteomic Profiling Based Classification of CLL Provides Prognostication for Modern Therapy and Identifies Novel Therapeutic Targets

The availability of targeted therapy and improved molecular characterization of Chronic Lymphocytic Leukemia (CLL) require a re-evaluation of treatment paradigms. As CLL heterogeneity is dependent on molecular and environmental factors, there is a need to create a new classification based on the integration of several factors. Here, we accomplish this goal by identifying CLL signatures using Reverse Phase Protein Array. Protein expression for 384 total and post translationally modified proteins was assessed in 871 CLL and Mature Small B Cell Leukemia (MSBL: HCL, HCLV, LGL-T, MCL, MZL, PLL, Richter's, T-Cell PLL) patients and was integrated with clinical data to identify strategies for improving diagnostics and therapy, making this the largest CLL proteomics study to date. Proteins were categorized into 40 protein functional groups (PFGs) based on literature and intra-dataset protein correlations and patients clustered based on PFG expression patterns into 6 recurrent protein expression signatures (PES) (Figure 1A). Individual protein expression (58/384 proteins), PFG expression (32/40) and overall PES were all highly prognostic of survival (OS) and time to first or second treatment (TTFT, TTST) (Figures 1B-C). The adhesion, apoptosis-occurring, apoptosis-regulating, heat shock, histone1 (marks), histone 2 (modifiers) and the STP-regulation PFGs were prognostic for all 3 outcome measures. Notably SG-A contained most of the MSBL and 15/16 cases of hairy cell leukemia, but the CLL cases within this SG fared very poorly. For OS, groups A and C had markedly inferior survival (P<0.0001) (10.3 and 20.3 median years) relative to the other 4 groups, which were statistically similar to each other. First treatment occurred sooner for Groups A and C (5.8 and 5.23 median years). Additionally, the TTST was also inferior for Group A (median 3.5 years). There were significant differences in age, hemoglobin, platelets, % BM and PB lymphocytes and β2M between the SG, but not for race (p = 0.84) or gender (p = 0.72). , Historically adverse cytogenetic aberrations del 11q and del17p events (23% overall) were less common in SG A, B, D and E (15, 14, 16, 17%) and overrepresented in SG C (32%), while historically favorable 13q changes were seen across all groups as was Trisomy 12 (14% overall), although SGs A and E were enriched (25%, 22%) while SG-F was low (5%) for Trisomy 12. SG membership superseded other traditional prognostic factors (Rai Staging, IGHV Status) and were prognostic for modern (BTK inhibition) and older CLL therapies. SGs A and C responded poorly to chemotherapy regimens compared to the other groups, whereas all groups responded well to BTK inhibitors except for SG-A. SGs and PFGs membership provided novel drug targets (see our other abstracts on TP53BP1 and ASNS) and defined optimal candidates for Watch and Wait (WaW) vs. early intervention. A model based on the accumulation of irregularities in ANXA1, TFRC, and SMAD2.p245 expression, optimally predicted TTFT overall and in early stage CLL patients. Patients with < 1 negative level of either of the 3 proteins, have a median TTFT of 14.59 years, whereas patients having 2-3 have a median of 5-6.27 years (P<0.0001). CHEK1.pS345, GAB2, IGFBP2, S100A4, WEE1.pS642, and ZAP70 were universally overexpressed by all SGs, suggesting them as ideal targets for inhibition. Collectively proteomics demonstrates promise for improving classification, therapy strategy determination, and identifying novel therapeutic targets. Figure 1 Figure 1. Disclosures Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Thompson: Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Burger: Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Wierda: Xencor: Research Funding; Karyopharm: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; Juno Therapeutics: Research Funding; KITE Pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Janssen: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding.

580. Hesitancy in Uptake and Recommendation of COVID-19 Vaccines by US Healthcare Workers

Background The COVID-19 pandemic has brought vaccination to the forefront of discourse on public health. The rapid speed of COVID-19 vaccine development, utilization of novel technology, and an atmosphere of politicized misinformation have created a perfect storm for vaccine hesitancy. As early adopters of vaccination, HCWs set an example for the general population; as trusted sources of medical information, they educate and inform. However, comparatively little work has investigated HCWs' attitudes toward vaccination and how those attitudes drive their recommendation behavior. Methods We surveyed hospital employees about their personal reasons for hesitancy and beliefs about patient hesitancies and randomly assigned them to see one of three messages aimed at increasing vaccine confidence. Message themes included an appeal to return to normal life (Normalcy), a risk comparison between vaccinating or not (SDT), and an explanation of the speed of safe and effective vaccine development (Process). Results Of the 674 NC hospital employees who completed our survey in February 2021, 98% had been offered the COVID-19 vaccine, and 80% had already accepted. For the 20% who had not received the vaccine, the top reasons for hesitancy involved the speed of development and testing, and concerns of vaccine safety and effectiveness. We also found differences in susceptibility to misinformation and vaccine hesitancy across political affiliation, which was higher in Republicans compared to Democrats. HCWs were generally very comfortable recommending the COVID-19 vaccine to patients and supported the idea of sharing the message they read. Although the risk comparison message was most trusted personally, the process message was rated as both the most helpful to patients and the most likely to be shared with them (see Figure 1). This suggests that what is most appealing on a personal level is not necessarily what a HCW would recommend to their patients. Rating of personal opinions of the passages. On a scale from 1 to 7 with 1 = Strongly Disagree and 7 = Strongly Agree. This chart shows the average message ratings across the board when answering whether they thought the passages were understandable, helpful, correct, believable, and trustworthy. (Error bars are 95% CI) There was no significant difference across the messages. The Process message is seen as most helpful and is most likely to be shared with patient than the other messages On left, the average answer on a scale from 1 to 5 for “Do you think the passage you just read would help your patients feel more comfortable about getting the vaccine?” and on right, the average answer for “Would you share this passage with your patients?” Conclusion HCWs' high uptake and minimal hesitancy in recommending the COVID-19 vaccine is encouraging and merits further exploration for how to increase confidence in HCW who are hesitant to discuss and recommend vaccines to patients, as several highlighted the importance of respecting patient autonomy. Disclosures Rebecca Rayburn-Reeves, PhD, Centene Corporation (Grant/Research Support, Research Grant or Support) Jenna Clark, PhD, Centene Corporation (Grant/Research Support, Research Grant or Support) Jan Lindemans, PhD, Centene Corportation (Grant/Research Support, Scientific Research Study Investigator)