Testing Continued Effectiveness Through Multiple Modifications of an Empirically Supported Treatment for Organization, Time Management, and Planning Deficits in ADHD and Related Disorders

Objectives: Organizational skills training (OST) for youth with ADHD is an efficacious treatment that addresses impairments at home and in school. Modifications of OST were conducted to treat children with or without ADHD, to reduce treatment barriers, and to respond to changes in school demands during the COVID-19 pandemic. Method(s): After an initial RCT documenting OST efficacy, 3 further studies involved: 1) an open replication of the original RCT confirming improvements in organization, time management, and planning (OTMP) in children diagnosed with ADHD (N = 15) using twice-weekly in-person visits;2) a subsequent open trial investigating children with deficient organizational skills with or without ADHD and altering delivery to involve a combination of in-person and virtual meetings (N = 29);and 3) a third study with subjects with low OTMP skills who do not necessarily have ADHD, receive treatment with combined in-person and virtual delivery or, in response to COVID-19 restrictions, fully virtual delivery (N = 27, thus far), and, in response to remote school delivery, have altered OST content to fit varied school instruction demands (eg, use of electronic documents instead of papers) while adhering to the principles of OST. Change was measured on the Children's Organizational Skills Scales (COSS). Result(s): 1) Improvements in OTMP skills (parent ratings d = 3.73;teacher ratings d = 1.12) in the first open study were comparable to the initial RCT findings. 2) In study 2, parents also reported substantial improvements (d = 3.04), and teachers reported large changes (d = 0.88) in pre-post comparisons. 3) In the ongoing RCT, subjects who received treatment immediately were reported to have large changes by parents (d = 2.17) and moderate changes by teachers (d = 0.47) when compared to waitlist controls. Conclusion(s): Initial analyses indicate that OST leads to OTMP improvements in children struggling with disorganization with and without ADHD diagnosis. Improvements are found when treatment is delivered fully in-person, delivered in hybrid in-person and virtual meetings, or delivered fully virtually. OST could help children with or without ADHD improve behavioral and emotional adjustment at home and in school, when treatment delivery is modified to increase treatment availability, and when school demands are varied. ADHD, CBT, EBP Copyright © 2022

Social Determinants Predict Poor Exercise Self-Efficacy Outcomes in Cardiac Rehabilitation

Background: Building confidence to exercise regularly (exercise self-efficacy) in the face of constraints is a key goal of cardiac rehabilitation (CR) because these beliefs are predictors of sustained exercise behaviours. This study identifies patient subgroups at risk of poor self-efficacy to enable targeting and tailoring of CR interventions. Methods: Patients with coronary heart disease at four CR sites in Australia completed the Exercise Self-Efficacy Scale at CR entry and completion (6-8 weeks). A General Linear Model was used to identify independent predictors of least change in exercise self-efficacy. Data collection included COVID-19 pandemic time, so delivery mode (in-person versus remote) was included in the analyses. Results: Patients (n=194) had a mean age of 65.9 (SD 10.5) years, 81% were males. The majority (80%) were married/partnered, 76% were White, and 24% were from an ethnic minority background. Patients received CR in-person (47%) or remote-delivered (54%). At CR entry, the mean exercise self-efficacy score was 24.9 (SD 6.0) of potential 30 points, which improved significantly by completion (p=0.027). Independent predictors of least improvements in exercise self-efficacy were being an ethnic minority (β= -2.96, 95%CI -4.90, -1.02), not having a spouse/partner (β=-2.42, 95% CI -4.49, -0.35), attending in-person CR (β= -1.75, 95%CI -3.39, -0.12), and having higher exercise self-efficacy at entry (β= -0.37, 95%CI -0.51, -0.23). Conclusions: Confidence to exercise improves in CR programs. Assessing exercise self-efficacy at CR entry is recommended to ensure interventions can be tailored for patients’ needs. The relative lesser increase in confidence in ethnic minorities and solo patients should be explored.

Delivery of antimicrobial stewardship competencies in UK pre-registration nurse education programmes: a national cross-sectional survey.

BACKGROUND: Registered nurses perform numerous functions critical to the success of antimicrobial stewardship, but only 63% of pre-registration nursing programmes include any teaching about stewardship. Updated nursing standards indicate that nurses require antimicrobial stewardship knowledge and skills. AIM: To explore the delivery of key antimicrobial stewardship competencies within updated pre-registration nursing programmes. METHODS: This study had a cross-sectional survey design. Data were collected between March and June 2021. FINDINGS: Lecturers from 35 UK universities responsible for teaching antimicrobial stewardship participated in this study. The provision of antimicrobial stewardship teaching and learning was inconsistent across programmes, with competencies in infection prevention and control, patient-centred care and interprofessional collaborative practice taking precedent over competencies pertaining to the use, management and monitoring of antimicrobials. Online learning and teaching surrounding hand hygiene, personal protective equipment and immunization theory was reported to have increased during the pandemic. Only a small number of respondents reported that students shared taught learning with other healthcare professional groups. CONCLUSION: There is a need to ensure consistency in antimicrobial stewardship across programmes, and greater knowledge pertaining to the use, management and monitoring of antimicrobials should be included. Programmes need to adopt teaching strategies and methods that allow nurses to develop interprofessional skills in order to practice collaboratively.

Influences on nurses' engagement in antimicrobial stewardship behaviours: a multi-country survey using the Theoretical Domains Framework.

BACKGROUND: Antimicrobial resistance (AMR) is affected significantly by inappropriate antibiotic use, and is one of the greatest threats to human health. Antimicrobial stewardship (AMS) is a programme of actions promoting responsible use of antimicrobials, and is essential for limiting AMR. Nurses have an important role to play in this context. AIM: To investigate the determinants of nurse AMS behaviours and the impact of past training. METHODS: A cross-sectional multi-country survey design with mixed methods was employed. Participants were 262 nurses {223 female; mean age 44.45 [standard deviation (SD) 10.77] years} of 10 nationalities, with individual survey links sent via professional networks in five countries, alongside Twitter. Nine AMS behaviours and 14 behavioural determinants were assessed quantitatively using the Theoretical Domains Framework (TDF), and mapped to the Capability, Opportunity, Motivation - Behaviour (COM-B) model. Analysis identified differences between nurses with and without AMS training. The influence of coronavirus disease 2019 (COVID-19) on AMS behaviour was investigated qualitatively using free-text data. FINDINGS: Nurses performed all nine AMS behaviours, which were significantly higher [t (238) -4.14, P<0.001] among those who had received AMS training [mean 53.15 (SD 7.40)] compared with those who had not received AMS training [mean 48.30 (SD 10.75)]. Nurses who had received AMS training scored significantly higher in all of the TDF domains. The TDF was able to explain 27% of the variance in behaviour, with 'Skills' and 'Behavioural regulation' (e.g. ability to self-monitor and plan) shown to be the most predictive of AMS actions. Both of these domains are situated in the 'Capability' construct of the COM-B model, which can be enhanced with the intervention strategies of education and training. An increase in AMS behaviours was reported since the COVID-19 pandemic, regardless of previous training. Six core themes were linked to AMS: (1) infection prevention and control; (2) antimicrobials and antimicrobial resistance; (3) diagnosis of infection and use of antibiotics; (4) antimicrobial prescribing practice; (5) person-centred care; and (6) interprofessional collaborative practice. CONCLUSION: Nurse training has a significant beneficial effect on AMS behaviour and its determinants. Nurses who had received AMS training scored higher in all TDF determinants of behaviour compared with those who had not received AMS training, resulting in higher capability, opportunity and motivation to perform AMS behaviour. AMS education and training should be offered to nurses to enhance these factors. Future research should consider the optimal level of training to optimize AMS behaviour, with a focus on developing skills and behavioural regulation.

Cingulate transcranial direct current stimulation in adults with HIV.

BACKGROUND: Neuronal dysfunction plays an important role in the high prevalence of HIV-associated neurocognitive disorders (HAND) in people with HIV (PWH). Transcranial direct current stimulation (tDCS)-with its capability to improve neuronal function-may have the potential to serve as an alternative therapeutic approach for HAND. Brain imaging and neurobehavioral studies provide converging evidence that injury to the anterior cingulate cortex (ACC) is highly prevalent and contributes to HAND in PWH, suggesting that ACC may serve as a potential neuromodulation target for HAND. Here we conducted a randomized, double-blind, placebo-controlled, partial crossover pilot study to test the safety, tolerability, and potential efficacy of anodal tDCS over cingulate cortex in adults with HIV, with a focus on the dorsal ACC (dACC). METHODS: Eleven PWH (47-69 years old, 2 females, 100% African Americans, disease duration 16-36 years) participated in the study, which had two phases, Phase 1 and Phase 2. During Phase 1, participants were randomized to receive ten sessions of sham (n = 4) or cingulate tDCS (n = 7) over the course of 2-3 weeks. Treatment assignments were unknown to the participants and the technicians. Neuropsychology and MRI data were collected from four additional study visits to assess treatment effects, including one baseline visit (BL, prior to treatment) and three follow-up visits (FU1, FU2, and FU3, approximately 1 week, 3 weeks, and 3 months after treatment, respectively). Treatment assignment was unblinded after FU3. Participants in the sham group repeated the study with open-label cingulate tDCS during Phase 2. Statistical analysis was limited to data from Phase 1. RESULTS: Compared to sham tDCS, cingulate tDCS led to a decrease in Perseverative Errors in Wisconsin Card Sorting Test (WCST), but not Non-Perseverative Errors, as well as a decrease in the ratio score of Trail Making Test-Part B (TMT-B) to TMT-Part A (TMT-A). Seed-to-voxel analysis with resting state functional MRI data revealed an increase in functional connectivity between the bilateral dACC and a cluster in the right dorsal striatum after cingulate tDCS. There were no differences in self-reported discomfort ratings between sham and cingulate tDCS. CONCLUSIONS: Cingulate tDCS is safe and well-tolerated in PWH, and may have the potential to improve cognitive performance and brain function. A future study with a larger sample is warranted.

Predictors of poor exercise self-efficacy improvements after cardiac rehabilitation

Background/Introduction: Building confidence to exercise regularly (exercise self-efficacy (ESE)) in the face of constraints and barriers, is a key goal of cardiac rehabilitation (CR) because such self-efficacy beliefs are predictors of sustained exercise behaviours. Therefore, identifying patient subgroups at risk of poor ESE enables tailoring of CR and appropriate targeting of support interventions. Purpose: To identify independent predictors of poor ESE and poor improvements in ESE in CR participants. Methods: The study used a prospective observational cohort design and recruited patients with coronary heart disease at CR entry across four sites in Metropolitan Sydney, Australia (2019-2020). Data were also compared for traditional in-person and remote-delivered CR during COVID-19 pandemic restrictions. The Exercise Self Efficacy Scale was used to measure ESE at CR entry and completion, and General Linear Models were used for analyses. Results: Participants (n=194) had a mean age of 65.94 (SD 10.46) years, with 80.9% males;and 80.0% were married or partnered, with 23.6% from an ethnic minority background. Referral diagnosis included elective percutaneous coronary intervention (PCI) (40.2%), coronary artery bypass surgery (26.3%), and myocardial infarction with or without PCI (33.5%). At CR entry, the mean ESE score was 24.93 (SD 5.99) points, which improved significantly by completion (p=.027). The GLM of ESE change (Adjusted R2=.247) identified that predictors of less change in ESE scores by CR completion included ethnic minorities (β=2.96, p=.003), not having a spouse or an intimate partner (β=-2.42, p=.023), and attending in-person CR (β=1.75, p=.036). Having higher ESE scores at entry was also associated with less ESE change on completion, such that for every point increase in ESE at entry, there was a reduction of .37 points in change (p<.001). These variables were also the same predictors of poor ESE at CR completion. Conclusions: Confidence to exercise improves in CR, and screening for ESE at CR entry enables identification of patients at-risk of poor improvements. Tailoring of interventions to provide appropriate support such as extending CR should be considered for patients from ethnic minorities and those who are single/widowed. Exploring the reasons for differences in outcomes from in-person and remote-delivered CR using appropriate methods should be the focus of future research.

COVID-19 vaccine responsiveness in patients with multiple myeloma and waldenström macroglobulinemia

BACKGROUND: Multiple myeloma (MM) and Waldenström macroglobulinemia (WM) are associated with significant immunoparesis. Based on the ongoing COVID-19 pandemic, there is an urgent need to understand whether patients are able to mount a sufficient response to COVID-19 vaccines. METHODS: MM and WM patients are vaccinated with mRNA-1273 (Moderna), BNT162b2 mRNA (Pfizer/BioNTech), or JNJ-78436735 (Johnson & Johnson) in a prospective clinical trial. Primary endpoint is SARS-CoV-2 spike protein (S) antibody (Ab) detection 28 days after final vaccination. Secondary endpoints include functional serologic assessments and T-cell responses at 28 days, 6 months, 9 months, and 12 months following vaccination. S Abs were detected by Elecsys assay (Roche Diagnostics), with 3 0.80 U/mL defined as positive and titers > 250 U/mL considered stronger correlates of neutralization. SARS-CoV-2 wildtype and variant S-specific Ab isotypes and FcγR binding profiles were quantified by custom Luminex assay. Antibody-dependent neutrophil and cellular phagocytosis (ADNP and ADCP) were assessed using flow cytometry. RESULTS: To date 141 patients have been enrolled, 137 (91 MM and 46 WM) of whom had an S Ab assessment. Median Ab titer was 178.0 (IQR, 16.10-1166.0) for MM and 3.92 (IQR, 0-278.9) for WM. S Ab response rate was 91% (83/91) in MM and 56% (27/46) in WM. However, responses achieving S Ab >250 U/mL were 47.3% (43/91) in MM and 26.1% (12/46) in WM. In patients 375 years, responses >250 u/mL were 13.3% (2/15;p<0.05). Vaccine-specific S Ab responses >250 u/mL following mRNA-1273, BNT162b2, and JNJ-78436735 were 67.6% (23/34;p<0.05), 38.3% (18/47;p=NS), and 20% (2/10;p=NS) in MM and 50.0% (8/16;p<0.05), 14.8% (4/27;p<0.05), and 0% (0/3;p=NS) in WM. Among MM patients with progressive disease, S Ab response >250 u/mL occurred in 30% (6/20) as opposed to 55.6% (30/54) for VGPR+ (p<0.05). MM patients having autologous stem cell transplant within 12 months demonstrated 100% (5/5;p<0.05) S Ab responses. For MM patients actively receiving an anti-CD38 monoclonal Ab or an immunomodulatory drug, S Ab response occurred in 38.9% (14/36;p=NS) and 50.9% (28/55;p<0.05). Among WM patients, S Ab responses >250 U/mL occurred in 63.6% (7/11;p<0.05) previously untreated;0% (0/9;p<0.05) who received rituximab within 12 months;10% (2/20);p<0.05) on an active Bruton Tyrosine Kinase (BTK) inhibitor;and 20% (3/15;p=NS) who received other therapies. Functional Ab studies were performed on 14 MM patients, 14 WM, patients, and 14 healthy donors (HD) (Figure 1). All patients were assessed 28 days following their final vaccination and myeloma patients had an additional assessment 28 days following initial vaccination. MM and WM patients demonstrated less IGG1 and IGG3 S Ab production than HD. MM patients showed increased IgA and IgM S Ab production as well as increased FcgR2A binding following a second vaccine in contrast to HD. Both ADNP and ADCP were reduced in MM and WM patients. MM patients demonstrated improved ADCP in SARS-CoV-2 variants B.1.351, B.1.117, and P.1 versus wildtype (p<0.05). CONCLUSIONS: We report the first known evidence of impaired functional humoral responses following COVID-19 vaccines in patients with MM and WM. Overall, WM patients showed more severe impairment of COVID-19 S Ab responses. Most previously untreated WM patients achieved S Ab responses, however the most significant reduction in S Ab responses were seen in WM patients who received rituximab within 12 months or active BTK inhibitors. For MM patients, being in disease remission associated with improved S Ab response. Among MM and WM patients, age 375 years associated with significantly lower rates and vaccination with MRNA-1273 (Moderna) elicited significantly higher S Ab response rates than other vaccines. A defect in ADNP and more profound defect in ADCP suggests overall compromised opsinophagocytic activity among MM and WM patients. Data comparing first and second vaccine responses in MM patients, suggest less efficient class switching to IGG as well as incomple e maturation of their FcgR2A binding profiles but normal maturation of FcgR3A. Interestingly, ADCP was improved in several emerging SARS-CoV-2 variants. T-cell studies are pending and will be updated. Further understanding of the immunological response to COVID19 vaccination is needed to clarify patients risks, and necessity for booster or alternative protective measures against COVID-19. (Figure Presented).

eP280: Continued improvement in adults with acid sphingomyelinase deficiency after 2 years of olipudase alfa in the ASCEND placebo-controlled trial

Introduction: Acid sphingomyelinase deficiency (ASMD), also historically known as Niemann-Pick disease A (OMIM #257200) and B (OMIM#607616), is a rare and debilitating lysosomal storage disease caused by pathogenic variants in SMPD1 gene. Deficient activity of the lysosomal enzyme acid sphingomyelinase (ASM) leads to sphingomyelin accumulation in various organs. Visceral manifestations of ASMD include interstitial lung disease and pulmonary dysfunction, splenomegaly, hepatomegaly, dyslipidemia, thrombocytopenia, and anemia and are present across ASMD phenotypes (ASMD type A, B and A/B). In more severe cases of ASMD (ASMD type A), there are also central nervous system manifestations. No disease-specific treatment is currently approved for patients with ASMD. Olipudase alfa, an intravenous-recombinant-human ASM, is in late-stage development (Sanofi Genzyme) for the non-central-nervous-system manifestations of ASMD in children and adults. Two open-label trials, a phase 1b trial in 5 adults (NCT01722526) and a phase 1/2 trial in 20 children with chronic ASMD (ASCEND-Peds, NCT02292654) demonstrated improvement of pulmonary function, reduction of liver and spleen volume, reversal of dyslipidemia, decreased disease biomarkers, and in children, improved growth. A phase 2/3 placebo-controlled trial, the ASCEND study (NCT02004691) in 36 adults with ASMD who had splenomegaly and pulmonary dysfunction, has completed its primary analysis. Olipudase-alfa-treated patients compared to placebo-treated patients (1:1 randomization) had statistically significant increases in percent-predicted diffusing capacity of carbon monoxide (DLCO) and statistically significant decreases in spleen and liver volume after 1 year of placebo or olipudase alfa. Thirty-five of 36 patients continued in an open-label trial extension including 17 of the 18 patients who initially received placebo in the first year and all 18 patients who received olipudase alfa. Here we report Year 2 results of the ASCEND trial for the former placebo group after 1 year of olipudase alfa treatment and for the initial olipudase alfa group after 2 years of olipudase alfa treatment. Methods: All patients underwent gradual dose-escalation to 3.0 mg/kg every 2 weeks for approximately 14 weeks when starting olipudase alfa. Efficacy outcomes include percent-predicted DLCO, spleen volume, liver volume, lung high-resolution computerized tomography (HRCT) scores for ground glass appearance, histopathologic clearance of sphingomyelin in the liver, platelet count, plasma lyso-sphingomyelin, liver function, and lipid profile. Change from baseline results are presented as least-square mean (analysis of covariance [ANCOVA]) percent change ± standard error of the mean (SEM), except for ground glass appearance, which is the least-square mean ANCOVA absolute change from baseline, and percent liver tissue area occupied by sphingomyelin and plasma lyso-sphingomyelin, which are presented as mean changes ± standard deviation (SD). Absolute values at Baseline, Year 1, and Year 2 are presented as mean ± SD (Table). Results: Overall, 33 of 35 patients completed Year 2 of ASCEND;one former placebo patient withdrew due to COVID-19 travel restrictions, and one continuing olipudase alfa patient withdrew consent. COVID-19 travel restrictions also resulted in at least one missed assessment in six patients. In Year 2, improvements for patients in the former placebo group paralleled the olipudase alfa group in the primary analysis while clinical improvement continued for patients who received 2 years of olipudase alfa (Table). For patients in the former placebo group, percent-predicted DLCO increased by 28.0 ±6.2% (n=10);spleen volume decreased by 36.0 ±3.0% (n=11);liver volume decreased by 30.7 ±2.5% (n=11), and platelet count increased by 21.7 ±6.4% (n=15). In patients with 2 years of olipudase alfa treatment, percent-predicted DLCO increased by 22.2 ±3.4% (n=17) at Year 1 and 28.5±6.2% at Year 2 (n=10);spleen volume decreased by 39.5 ±2.4% (n=17) at Year 1 and 47.0 ±2.7% (n=14) at Year 2 liver volume decreased by 27.8 ±2.5% (n=17) at Year 1 and 33.4 ±2.2% (n=14) at Year 2, and platelet count increased by 16.6 ±4.0% at Year 1 (n=18) and 24.9 ±6.9% (n=13) at Year 2. HRCT ground glass appearance score decreased 0.30 ±0.5 (n=14) at Year 2 for patients in the former placebo group and decreased by 0.45 ±0.13 (n=18) at Year 1 and 0.48 ±0.07 (n=16) at Year 2 for patients continuing to receive olipudase alfa. Liver sphingomyelin clearance at Year 2 was 93.3 ±5.0% (n=10) for patients in the former placebo group and 92.7 ±5.8% at Year 1 (n=13) and 98.4 ±2.0% at Year 2 (n=10) for patients continuing to receive olipudase alfa. Plasma lyso-sphingomyelin decreased by 79.4 ±11.3% (n=14) for patients in the former placebo group and by 78.0 ±11.1% (n=18) at Year 1 and 64.4 ±28.5% (n=15) at Year 2 for patients continuing to receive olipudase alfa;several patients had transient increases due to missed infusions. Alanine aminotransferase decreased by 45.2 ±34.4% (n=15) for patients in the former placebo group, and by 36.5 ±8.4% (n=18) in Year 1 and 32.0 ±10.2% (n=12) in Year 2 for patients continuing to receive olipudase alfa. For patients in the former placebo group, high-density lipoprotein cholesterol (HDL-C) increased by 59.7 ±9.7% (n=14) and low-density lipoprotein cholesterol (LDL-C) decreased by 27.5 ±6.8% (n=13) in Year 2. For patients continuing to receive olipudase alfa, HDL-C increased by 40.0 ±6.8% (n=18) in Year 1 and 64.4 ±10.5% (n=12) in Year 2 and LDL-C decreased by 25.8 ±4.8% (n=18) in Year 1 and 23.0 ±7.1% (n=12) in Year 2. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles in patient with previously documented cardiomyopathy). No patient discontinued due to an adverse event. Conclusion: During Year 2 of ASCEND, patients crossing over from placebo to olipudase alfa had the same magnitude and time course of clinical improvement seen in patients receiving olipudase alfa for 1 year, while continuing olipudase-alfa patients had sustained or further improvements. Olipudase alfa reduced sphingomyelin storage in the liver and lyso-sphingomyelin in plasma. Clinically, olipudase alfa improved pulmonary function, reduced splenomegaly and hepatomegaly, and improved liver function and dyslipidemia for up to 2 years. These results are consistent with the published 30- and 42-month data for adults reported in the long-term extension of the open-label Phase 1b study. Treatment with olipudase alfa reduces manifestations of chronic ASMD in adults and has sustained efficacy. [Formula presented]

Two-year results of the ASCEND trial of olipudase alfa adults with chronic acid sphingomyelinase deficiency show parallel improvements in former placebo patients and further improvement in continuing olipudase alfa patients

Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal disease characterized by pulmonary dysfunction, hepatosplenomegaly, and dyslipidemia. Olipudase alfa, intravenous-recombinant-human ASM, is in late-stage development (Sanofi Genzyme) for non-central-nervous-system manifestations of ASMD. We report 2-year outcomes for 33/36 ASMD adults with splenomegaly (mean baseline spleen volume: 11.3 multiples of normal [MN]) and respiratory impairment (mean baseline percent-predicted-diffusing capacity for carbon monoxide [DLCO]: 49.3%) who participated in the 1-year double-blind placebo-controlled primary-analysis period [PAP] of the ASCEND trial of olipudase alfa (NCT02004691) and completed a second year in the open-label extension. Patients underwent gradual dose-escalation to 3.0 mg/kg/2-weeks. During the PAP, olipudase-alfa-treated compared to placebo-treated patients (1:1 randomization) had statistically significant increases in DLCO and decreases in spleen and liver volume. One placebo patient withdrew during year-1. In year-2, improvements in former placebo patients paralleled the olipudase-alfa group in the PAP (all values: ANCOVA LS-mean percent change from trial baseline ± SEM): DLCO increased 28.0 ± 6.2% (n = 10);spleen volume decreased 36.0 ± 3.0% (n = 11);liver volume decreased 30.7 ± 2.5% (n = 11). Olipudase-alfa patients who received 2 years of treatment continued improving: DLCO increased 28.5 ± 6.2%, n = 10 (year-1 increase: 22.2 ± 3.4%, n = 17);spleen volume decreased 47.0 ± 2.7%, n = 14 (year-1 decrease: 39.5 ± 2.4%, n = 17), liver volume decreased 33.4 ± 2.2%, n = 14 (year-1 decrease: 27.8 ± 2.5, n = 17). Improvements in dyslipidemia, liver function, liver sphingomyelin clearance, and plasma lyso-sphingomyelin in former placebo patients paralleled those seen in olipudase-alfa patients in the PAP;continuing olipudase-alfa patients maintained these benefits in year-2. Overall, 99% of treatment-emergent adverse events were mild/moderate, with one treatment-related serious adverse event. During year-2, six patients missed ≥1 assessments and one patient discontinued due to COVID-19 travel restrictions;one additional patient discontinued (withdrawal of consent). In summary, during year-2 of ASCEND, crossover-placebo patients improved to a similar extent as olipudase-alfa patients in year-1 and patients continuing on olipudase alfa showed sustained or further improvements.

United States Civil Reserve Air Fleet (CRAF): A Brief History-Formation, Functionality, and Future

Air mobility has been a military strategic advantage used by the United States (U.S.) from the onset of aircraft carriers, to supporting air bases worldwide. The U.S. government and defense components rely heavily on a civilian fleet of aircraft to supplement air transportation requirements in both peace times and during national emergencies. This paper reviews the historical and legal development of the Civil Reserve Air Fleet (CRAF) and discusses previous struggles and successes of the program by looking at the functionality of the program, before addressing how current events bring about the realization that the program must change. Current changes in the way U.S. airlines operate, the way warfare has been changed, and the financial hardships associated with the COVID-19 pandemic are all used to envision a future of the CRAF program to provide future air transportation capabilities to allow the U.S. government to maintain the necessary strategic advantage of responsive airlift capabilities.

Sustained Online Amplification of COVID-19 Elites in the United States

In the absence of clear, consistent guidelines about the COVID-19 pandemic in the United States, many people use social media to learn about the virus, public health directives, vaccine distribution, and other health information. As people individually sift through a flood of information online, they collectively curate a small set of accounts, known as crowdsourced elites, that receive disproportionate attention for their COVID-19 content. However, these elites are not all created equal: not all accounts have received the same attention during the pandemic, and various demographic and ideological groups have crowdsourced their own elites. Using a mixed-methods approach with a panel of Twitter users in the United States over the first year of the COVID-19 pandemic, we identify COVID-19 crowdsourced elites. We distinguish sustained amplification from episodic amplification and demonstrate that crowdsourced elites vary across demographics with respect to race, geography, and political alignment. Specifically, we show that different subpopulations preferentially amplify elites that are demographically similar to them, and that they crowdsource different types of elite accounts, such as journalists, elected officials, and medical professionals, in different proportions. In light of this variation, we discuss the potential for using the disproportionate online voice of crowdsourced COVID-19 elites to equitably promote public health information and mitigate misinformation across networked publics.