Preventive Regimens Research Articles

Strategies commercially-insured families use to manage the cost of asthma care: a qualitative interview study

Objective Families affected by asthma report difficulty adhering to care regimens because of high medication costs, coupled with increased cost sharing required by some insurance plans. To inform efforts to support adherence, we conducted a qualitative study to explore how families manage asthma care costs. Methods We conducted phone interviews with commercially-insured, US adults (n = 59) who had asthma and/or a child with asthma. Our purposive sample included participants with high- and low/no-deductible health plans. We analyzed data using thematic content analysis to identify strategies for managing asthma care costs and to assess strategies’ implications for adherence. Results Our analysis identified four overarching strategies for managing asthma care costs. First, participants used prevention strategies to avoid costly acute care by minimizing exposure to asthma triggers and adhering strictly to preventive medication regimens. Second, participants used shopping strategies to reduce costs, including by comparing medication prices across pharmacies, using medication coupons or free samples, and switching to lower-cost medications. Third, budgeting strategies involved putting aside funds, including in tax-exempt health savings accounts, or taking on debt to pay for care. Finally, some participants sought to reduce costs by forgoing recommended care, including by skipping medication doses or replacing prescribed medications with alternative therapies. Conclusion Commercially-insured families use a wide range of strategies to manage asthma care costs, with both positive and negative implications for adherence. Our typology of asthma cost management strategies can inform insurance redesign and other interventions to help families safely reduce costs and maximize adherence to recommended care.

Point-of-care semi-quantitative test for adherence to tenofovir alafenamide or tenofovir disoproxil fumarate.

Objective measurement of antiretrovirals may aid clinical interventions for improving adherence to HIV prevention or treatment regimens. A point-of-care urine test could provide real-time information about recent adherence to regimens containing tenofovir disoproxil fumarate or tenofovir alafenamide. We developed a lateral flow immunoassay (LFA) and ELISA for urinary tenofovir. The intensity of the LFA test line was quantified using an optical reader and visually scored 0-5 by two independent people, using a reference card. The sensitivity and specificity of both the ELISA and LFA were determined for two different tenofovir concentration cut-offs for tenofovir disoproxil fumarate and tenofovir alafenamide adherence-1500 and 150 ng/mL, respectively. To validate the assays, we measured 586 urine samples from 28 individuals collected as part of a study of tenofovir pharmacokinetics in adults, which were also measured by MS for reference. Both the LFA signal and ELISA signal were each strongly correlated with drug concentrations (0.91 and 0.92, respectively). The LFA signal and ELISA were highly sensitive and specific at both thresholds (LFA sensitivity/specificity: tenofovir disoproxil fumarate, 89%/96%; and tenofovir alafenamide, 90%/96%) (ELISA sensitivity/specificity: tenofovir disoproxil fumarate, 94%/94%; and tenofovir alafenamide, 92%/84%). Visual scoring of the LFA was also highly sensitive and specific at both the tenofovir disoproxil fumarate threshold and the tenofovir alafenamide threshold (sensitivity/specificity: tenofovir disoproxil fumarate, 91%/94%; and tenofovir alafenamide, 87%/90%). Our rapid semi-quantitative test can measure tenofovir concentrations relevant to both tenofovir alafenamide and tenofovir disoproxil fumarate adherence, which may support adherence-promoting interventions across a range of HIV care settings.

Promising protein biomarkers in the early diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is an insidious, multifactorial disease that involves the devastation of neurons leading to cognitive impairments. Alzheimer's have compounded pathologies of diverse nature, including proteins as one important factor along with mutated genes and enzymes. Although various review articles have proposed biomarkers, still, the statistical importance of proteins is missing. Proteins associated with AD include amyloid precursor protein, glial fibrillary acidic protein, calmodulin-like skin protein, hepatocyte growth factor, matrix Metalloproteinase-2. These proteins play a crucial role in the AD hypothesis which includes the tau hypothesis, amyloid-beta (Aβ) hypothesis, cholinergic neuron damage, etc. The present review highlights the role of major proteins and their physiological functions in the early diagnosis of AD. Altered protein expression results in cognitive impairment, synaptic dysfunction, neuronal degradation, and memory loss. On the medicinal ground, efforts of making anti-amyloid, anti-tau, anti-inflammatory treatments are on the peak, having these proteins as putative targets. Few proteins, e.g.,Amyloid precursor protein results in the formation of non-soluble sticky Aβ40 and Aβ42 monomers that, over time, aggregate into plaques in the cortical and limbic brain areas and neurogranin is believed to regulate calcium-mediated signaling pathways and thus modulating synaptic plasticity are few putative and potential forthcoming targets for developing effective anti-AD therapies. These proteins may help to diagnose the disease early, bode well for the successful discovery and development of therapeutic and preventative regimens for this devasting public health problem.

Effectiveness of different preventive regimens on Cariogram parameters of high caries risk patients: A randomized controlled trial

Effectiveness of different preventive regimens on Cariogram parameters of high caries risk patients: A randomized controlled trial

Targeting the Pro-survival Protein BCL-2 to Prevent Breast Cancer.

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention. PREVENTION RELEVANCE: This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.

P118: THE ROLE OF HEMOGLOBIN AND HEMOLYSIS ON TRANSCRANIAL DOPPLER VELOCITIES IN CHILDREN WITH SICKLE CELL DISEASE: DATA FROM A NATURAL HISTORY COHORT

Background: Children with sickle cell disease (SCD) are at increased risk of cerebrovascular events that can impact neurocognitive development and quality of life (Colombatti 2016). Transcranial Doppler ultrasound (TCD) is a validated screening tool to identify pediatric SCD patients with the highest risk of stroke, to start on a preventive chronic blood transfusion regimen (Estcourt 2020; Inusa 2019). We aimed to evaluate the distribution of TCD velocities in a pediatric natural history cohort and investigate their correlation with hematological variables and treatments. Methods: We performed a retrospective analysis on data from a prospective pediatric cohort followed from January 1, 2009, to December 31, 2020 (censoring date). We used transcranial Doppler imaging (TCDi) and classified results according to STOP criteria, considering terminal internal carotid artery (TICA) and middle cerebral artery (MCA) time-averaged maximum mean velocities (TAMMVs). Hematological, clinical, and treatment variables were available from the natural history cohort database. Two-sample and Welch t-tests for unequal variances were used to compare mean hemoglobin (Hb) values and hemolysis markers in patients with and without abnormal/conditional TCDi results. Fisher and chi-square tests were used to compare categorical variables. Linear regression models were used to assess the effects of MCA and TICA TAMMVs as continuous variables on Hb. Odds ratios (ORs) for neurological events at different Hb levels were estimated using generalized estimated equations (GEE) with a binomial distribution, logistic function, and exchangeable correlation structure, allowing for correlation among repeated observations for the same patient. Multivariable GEE including characteristics and treatment variables were used to evaluate the association between neurological events and Hb. Results: Of the 182 SCD patients in the cohort, 169 had assessments of cerebral vasculopathy, and 155 had evaluable TCDi (583 exams). The median follow-up of the entire cohort was 79.8 months (range: 2.1–298.6 months) (interquartile range [IQR]: 36.9–126.3 months). The median age at the censoring date was 13.4 years (IQR: 9.1–17.5 years). Patients with abnormal/conditional TCDi results had lower Hb (8.4 vs 8.9 g/dL, P≤0.0001) and higher reticulocyte counts (317,766 vs 262,750/mm3, P≤0.0001), lactate dehydrogenase (843 vs 690 U/L, P=0.0012), and aspartate aminotransferase (61 vs 54 U/L, P=0.0007) compared with patients with normal/low results. We detected an inverse linear correlation between TICA/MCA TAMMVs and Hb (Figure 1A and 1B). Univariate analysis showed significant inverse correlation between abnormal/conditional TCDi results and Hb considered as a continuous variable (OR: 0.484, P<0.001). In the multivariate analysis, the correlation between TCDi results and Hb remained significant; moreover, the risk of presenting abnormal/conditional TCDi results decreased with age (OR: 0.833, P<0.0064). Conclusions: This analysis from our natural history cohort shows a significant inverse correlation between Hb and MCA and TICA velocities, supporting the beneficial effect of higher Hb levels in reducing TAMMV.

АНТИГЕРПЕТИЧНА ДІЯ СОЛЕЙ ЦЕРІЮ IN VITRO

Compounds based on cerium are highly promising objects in biotechnology regarding their high biological activities such as antiviral, antibacterial, antifungal, neuro- and radioprotective action, and antioxidant activity. On their basis is possible to develop compositions capable of activating the systems of cellular and humoral immune defence and use them for the prevention and therapy of viral diseases, which makes it achievable to use them for the development of potential antiherpetic agents. Despite the success of their application in biotechnological fields, the mechanism of their action on biological objects requires detailed research. The work aimed to verify in vitro anti-HSV-1/2 activity of trivalent and tetravalent cerium salts (1 mM – 0.01 nM) according to the preventive and therapeutic regimen. Methods: virological, cytological, statistical. Results. The therapeutic regime was noneffective. In the preventive regime, salt (NH4)2Ce(NO3)6 in vitro forms antiviral resistance in the range of investigated concentrations, while the salt CeCl3·7Н2О forms a non-linear, sinusoidal-like concentration-dependent anti-HSV-1/2 response of cells. Conclusions. Cerium salts (III and IV) can cause the formation of a state of antiviral resistance in the model system MA-104 - HSV-1/2 during their previous 24 h of contact with test cells. Cerium salt (IV) provides 50% inhibition of the cytopathic action of HSV-1/2 at a concentration of 1 μM. It is assumed that the shown antiviral activity of cerium salts may be due to their effect on the interferon system and the formation of antiviral resistance in cells.

Efficacy of 5 mg Olanzapine in the Prevention and Treatment of Carboplatin-Induced Nausea and Vomiting in the Chinese Population

To investigate the efficacy and safety of low-dose 5 mg olanzapine triple regimen for prevention of carboplatininduced nausea and vomiting in Chinese population. 56 patients with malignancies were treated with carboplatin (area under the curve≥5) chemotherapy. All patients received a triple antiemetic regimen of 5 mg olanzapine combined with 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The primary endpoint of the study was total control in the overall phase (0-120 h), acute phase (0-24 h) and delayed phase (25-120 h) in all patients. Secondary endpoints were total protection and complete response in the overall phase, acute phase and delayed phases. The impact of chemotherapy-induced nausea and vomiting on the quality of life was assessed by the functional living index-emesis. Olanzapine related side-effect was also recorded. The primary end points total control in the overall phase, acute phase and delayed phases were 62.50 % (35/56), 87.50 % (49/56) and 64.28 % (36/56) respectively. These end points total protection in the overall phase, acute phase and delayed phases were 82.14 % (46/56), 96.42 % (54/56) and 83.92 % (47/56) respectively. The complete response rate in the overall phase, acute phase and delayed phases were 91.07 % (51/56), 98.21 % (55/56) and 91.07 % (51/56) respectively. There was no effect on life-quality (score≥108) assessed by functional living index-emesis was 62.50 %.The most common olanzapine-related side effects were Grade I-II somnolence and weakness. The 5 mg olanzapine based triplet antiemetic regimen is effective and safe in the prevention carboplatin-induced nausea and vomiting in the Chinese population.

Экстренная профилактика клещевого энцефалита у детей: ретроспективный анализ и случаи из практики

The purpose — to conduct a retrospective analysis of the effectiveness of anti-tick borne immunoglobulin (IgG) and technologically processed antibodies to interferon gamma (ТOАIG) (аnaferon for children) for the emergency prevention of tick-borne encephalitis (TBE) in children. Material and methods. The analysis of medical documentation of patients with TBE who received various emergency prevention: anti-tick-borne IgG in the dose of 0.1 ml/kg i/m once (n = 626) or ТОАIG during 21 days (n = 354) or anti-tick-borne IgG together with ТОАIG (n = 56). The comparison group consisted of 351 patients with TBE who were admitted to the clinic and had not received any prevention. In groups of children who received various emergency prevention regimens, blood was examined by PCR method for the TBE virus at 1, 2 and 6 months after a tick bite. Results. Both the children affected by ticks and among those who got ill were predominantly 7 to 17 years old, 76.1 and 93%, respectively. Among the patients with TBE, 77.6% had not received any prevention, and 22.4% had different emergency prevention tactics. When prescribing anti-tick-borne IgG to children affected by ticks infected with the TBE virus, infection developed in 27.3% of cases (n = 93); when taking ТОАIG — in 1.7% (n = 3), and when using anti-tick-borne IgG and ТОАIG together — in 8.9% of cases (n = 5). The implementation of ТОАIG resulted in only 3 cases of asymptomatic acute (inapparent) infection identified by PCR results. After the introduction of anti-tick-borne IgG to 93 children, a half of them developed manifest forms of TBE, including 16.1% — meningeal forms and 5.4% — forms with focal neurological symptoms and brain edema. When anti-tick-borne IgG was used together with ТОАIG, fever form was observed in 40% (n = 2) and inapparant form in 60% (n = 3) of cases. The article presents 4 cases of severe focal cerebrospinal forms of tick-borne encephalitis associated with the ineffectiveness of the anti-tick-borne IgG for preventive purposes. Conclusions. The maximum effectiveness (98.3%) for emergency prevention was shown by an immunomodulator ТОАIG (anaferon for children), while 21.5% of children (20 cases out of 93) developed clinical forms of tick-borne neuroinfection with CNS damage syndromes and the number of non-patients was 72.7%.

Imported malaria in Switzerland, (1990–2019): A retrospective analysis

BackgroundMalaria is a life-threatening, mosquito-borne parasitic disease, caused by Plasmodium spp. It is a major public health issue. Malaria in Switzerland is primarily “imported” by infected international travellers, migrants, and asylum-seekers. MethodWe investigated the epidemiology and characteristics of imported malaria in Switzerland in the period between 1990 and 2019 using data from the Swiss Federal Office of Public Health (BAG). We also obtained traveller statistics from the World Tourism Organization (UNWTO). ResultsDuring the last thirty years a total of 8′439 malaria cases and 52 deaths were reported in Switzerland. The main origin of infection was West Africa, followed by Central Africa and East Africa. The profile of malaria in migrants in Switzerland has changed, reflecting variation in migrant flows. The estimated risk of malaria in travellers sank significantly over the time frame of the study (p < 0.001, 95% CI -0.076 to −0.043). ConclusionsTravel medicine should focus on West Africa, the main source of malaria in Switzerland. Despite most cases and all but one death being caused by Plasmodium falciparum, Plasmodium vivax remains a threat for travellers and is associated with complex prevention and therapy regimens. Public health authorities need to pre-empt the need for malaria screening, prevention and treatment based on the profile of migrant waves from malaria endemic areas including Eritrea and Afghanistan arriving in Europe.

RETROSPECTIVE STUDY OF MORBIDITY AND MORTALITY OF AFRICAN PENGUINS (SPHENISCUS DEMERSUS) UNDER MANAGED CARE IN NORTH AMERICA: 2007-2018.

Currently, more than 20% (51/240) of zoos and aquariums accredited by the Association of Zoos and Aquariums house African penguins (Spheniscus demersus) in their collections. The African penguin Species Survival Plan (SSP) veterinary advisors regularly collect information from those facilities to characterize morbidity and mortality for this species and to collate preventative medicine and treatment regimens. These efforts resulted in more than 10 yr of collection of management data across the SSP, representing the care and management of more than a thousand birds. The most common morbidities reported included those of dermatologic (27%, 125/452 institutions) and musculoskeletal or neurologic (18%, 82/452 institutions) disease, while the most common causes of mortality were respiratory diseases (20%, 65/323 deaths) and systemic or multifactorial conditions (19%, 62/323 deaths). Aspergillosis cases accounted for 69% (45/65 deaths) of respiratory-related mortality and avian malaria cases comprised 31% (19/62 deaths) of mortality related to systemic diseases. Mortality was most commonly reported in geriatric birds, or those older than 15 yr of age (34%, 111/323 deaths). Reproductive related mortality was only defined in female birds, while other causes of death were more evenly distributed between sexes. Utilizing the SSP data to determine morbidity and mortality trends within this population provides important information to veterinary and animal care teams, allowing them to provide enhanced levels of care to the penguins housed at their institutions. By recognizing the most important diseases and causes of death in this species, management and healthcare resources can target conditions with the highest impact on the population.

Preventing Ischemic Cerebrovascular Events in High-Risk Patients With Non-disabling Ischemic Cerebrovascular Events Using Remote Ischemic Conditioning: A Single-Arm Study

Background: Secondary stroke prevention after a high-risk, non-disabling ischemic cerebrovascular event needs to be enhanced. The study was conducted to investigate whether remote ischemic conditioning (RIC) is effective in preventing recurrent ischemic events within 3 months.Methods: This was a four-center, single-arm, open-label Phase IIa futility trial (PICNIC-One Study). Adult patients (≥18 years of age) who had an acute minor ischemic stroke (AMIS) with a National Institutes of Health Stroke Scale score ≤ 3 or a transient ischemic attack (TIA) with moderate-to-high risk of stroke recurrence (ABCD score ≥ 4) within 14 days of symptom onset were recruited. Patients received RIC as adjunctive therapy to routine secondary stroke prevention regimen. RIC consisted of five cycles of 5-min inflation (200 mmHg) and 5-min deflation of cuffs (45 min) on bilateral upper limbs twice a day for 90 days.Results: A total of 285 patients met the study criteria, of which 167 provided signed informed consent and were enrolled. Data from 162 were analyzed with five subjects excluded. Recurrent AIS/TIA occurred in 6/162 (3.7%) patients within 3 months, with no occurrence of hemorrhagic stroke. The top three adverse events were upper limb pain (44/162, 27.2%), petechia (26/162, 16.0%), and heart palpitation (5/162, 3.1%). About 68 (42.0%) subjects completed ≥ 50% of 45-min RIC sessions.Conclusions: RIC is a safe add-on procedure and it has a potential benefit in reducing recurrent cerebrovascular events in patients with high-risk, non-disabling ischemic cerebrovascular events as the risk of stroke/TIA events is lower than expected; however, its compliance needs to be improved. Our study provides critical preliminary data to plan a large sample size, randomized controlled clinical study to systematically investigate the safety and efficacy of RIC in this population.

Weight-Based Aspirin Dosing May Further Reduce the Incidence of Venous Thromboembolism Following Primary Total Joint Arthroplasty

Obesity poses a challenge to thromboembolic prophylaxis following total joint arthroplasty (TJA). The purpose of this study is to evaluate a weight-based aspirin dosing regimen for prevention of venous thromboembolism (VTE) following TJA.This is a retrospective observational study of 2403 patients who underwent primary total hip or knee arthroplasty at one institution. A weight-based aspirin dosing regimen for VTE prophylaxis was administered to 1247 patients: patients weighing ≥120 kg received 325 mg aspirin twice daily (BID) and those weighing <120 kg received 81 mg aspirin BID for 4 weeks. In total, 1156 patients in the comparison cohort received 81 mg aspirin BID. VTE and gastrointestinal bleeding events were identified through chart review at 42 days and 6 months postoperatively. A multivariable logistic regression was performed to adjust for covariates.The weight-based aspirin cohort had a significantly lesser incidence of VTE at 42 days (P = .03, relative risk [RR] 0.31, 95% confidence interval 0.12-0.82) and 6 months (P = .03, RR 0.38, 95% confidence interval 0.18-0.80). There was no difference in VTE incidence between total hip arthroplasty and total knee arthroplasty cases (P = .8). There was no difference in gastrointestinal bleeding events between the cohorts at 42 days (P = .69) or 6 months (P = .92). Subanalysis of patients weighing ≥120 kg demonstrated a significant difference between the cohorts with a VTE incidence of 3.48% and 0% in the 81 mg and weight-based cohorts, respectively (P = .02).Patients prescribed a weight-based aspirin regimen had significantly fewer VTEs after TJA compared to historical controls with an RR reduction of 69% at 6 weeks and 62% at 6 months postoperatively. This suggests the need to factor patient weight when determining postoperative VTE prophylaxis with aspirin.

Provision of Decentralized TB Care Services: A Detect-Treat-Prevent Strategy for Children and Adolescents Affected by TB.

In this review, we discuss considerations and successful models for providing decentralized diagnosis, treatment, and prevention services for children and adolescents. Key approaches to building decentralized capacity for childhood TB diagnosis in primary care facilities include provider training and increased access to child-focused diagnostic tools and techniques. Treatment of TB disease should be managed close to where patients live; pediatric formulations of both first- and second-line drugs should be widely available; and any hospitalization should be for as brief a period as medically indicated. TB preventive treatment for child and adolescent contacts must be greatly expanded, which will require home visits to identify contacts, building capacity to rule out TB, and adoption of shorter preventive regimens. Decentralization of TB services should involve the private sector, with collaborations outside the TB program in order to reach children and adolescents where they first enter the health care system. The impact of decentralization will be maximized if programs are family-centered and designed around responding to the needs of children and adolescents affected by TB, as well as their families.

Association of multiple preventive therapies postdischarge and long-term health outcomes after acute myocardial infarction

Statins, beta-blockers, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers have been advocated by guidelines as secondary prevention medications to improve the long-term outcomes of post-acute myocardial infarction (AMI) patients. However, adequate drug adherence has always been challenging, and different treatment regimens may lead to divergent outcomes that remain unclear under current myocardial infarction (MI) care standards. This study investigated the association between use of different preventive regimens post-AMI and patients' long-term outcomes. This cohort study used data files from the Taiwan National Health Insurance Research Database. A total of 77 520 people who were hospitalized with AMI between 2002 and 2015 were assessed. On the basis of medication possession ratio (MPR) to individual medications, eight treatment groups were examined in this study. Receiving therapy was defined as MPR ≥40%. We investigated the association between different treatment groups and all-cause mortality in 24 months. Overall, 51 322 patients with ST-elevation MI and 26 198 with non-ST-elevation MI were included in the study. Patients received all three preventive medications show the lowest mortality in 24 months follow-up periods among all treatment groups. Patients who did not usage of any of these three preventive medications had the highest mortality in 24 months (adjusted hazard ratio, 1.78; 95% CI, 1.64-1.93). This mortality rate had the same pattern across the three cohort generations (2002-2005, 2006-2010, and 2011-2015). In this large population-based real-world study, usage of three preventive therapies post-MI was associated with the lowest rate of all-cause mortality.

Chemotherapy-associated cardiomyopathy: Mechanisms of toxicity and cardioprotective strategies.

To describe the proposed mechanisms of chemotherapy-associated cardiomyopathy (CAC) and potential cardioprotective therapies for CAC including a comprehensive review of existing systematic analyses, guideline recommendations, and ongoing clinical trials. A literature search of MEDLINE was performed (from 1990 to June 2020) using the following search terms: anthracycline, trastuzumab, cardiomyopathy, cardiotoxicity, primary prevention, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta blocker, dexrazoxane (DEX) as well as using individual names from select therapeutic categories. Existing English language systematic analyses and guidelines were considered. The mechanisms of CAC are multifaceted, but various cardioprotective therapies target many of these pathways. To date, anthracyclines and HER-2 targeted therapies have been the focus of cardioprotective trials to date as they are the most commonly implicated therapies in CAC. While traditional neurohormonal antagonists (ACEIs, ARBs, and beta blockers) and DEX performed favorably in many small clinical trials, the quality of available evidence remains limited. Hence, major guidelines lack consensus on an approach to primary prevention of CAC. Given the uncertain role of preventive therapy, monitoring for a symptomatic or asymptomatic decline in LV function is imperative with prompt evaluation should this occur. Numerous ongoing randomized controlled trials seek to either confirm the findings of these previous studies or identify new therapeutic agents to prevent CAC. Clinical implications are derived from the available literature as well as current guideline recommendations for CAC cardioprotection. At this time, no single therapy has a clear cardioprotective benefit in preventing CAC nor is any therapy strongly recommended by current guidelines. Additional studies are needed to determine the optimal preventative regimens.

Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children

Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84–99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.

Real-World Data of the Hemostatic Efficacy of Recombinant Human Factor VIIa Eptacog Beta for Acute Bleeding Events in Patients with Hemophilia a and B with Inhibitors

Introduction: Activated prothrombin complex concentrate (FEIBA, Takeda) and recombinant factor VIIa (rFVIIa, Novoseven, NovoNordisk) remain the primary bypassing agents (BPA) available for bleeding management in patients with hemophilia and inhibitors. Eptacog beta [rFVIIa-B, Coagulation factor VIIa (recombinant)-jncw, Sevenfact, HEMA Biologics & LFB] is a recombinant human FVIIa approved by the FDA in 2020 for the treatment of acute bleeding events in adult and adolescent patients ≥12 years old with hemophilia A or B with inhibitors. rFVIIa-B demonstrated hemostatic efficacy of 86% in a phase 3, randomized cross-over study of 465 mild/moderate bleeding events in 27 patients with hemophilia A and B with inhibitors. The purpose of this study is to report real-world data on the hemostatic efficacy of rFVIIa-B for acute bleeding management in patients with hemophilia A and B with inhibitors.Methods: This is a retrospective chart-review of individuals ≥12 years of age with severe hemophilia A (factor VIII <1%) or hemophilia B (factor IX <1%) with an active inhibitor from 3 U.S. hemophilia treatment centers who utilized rFVIIa-B for acute bleed management.Results: Seven bleeds were treated among the 3 patients identified. Patient characteristics and bleeding events are summarized in Table 1. The 3 patients were 12, 13, and 31 years of age. Two patients had hemophilia A and 1 patient had hemophilia B. The 2 patients with hemophilia A were on emicizumab prophylaxis per standard dosing regimens for bleeding prevention. The individual patient with hemophilia B had a history of anaphylaxis at inhibitor development and received on-demand BPA for acute bleeding events. All 7 bleeds consisted of hemarthroses with the knee being the primary site in 57% of the bleeds. Five of the 7 bleeds (71%) received a severe bleeding dose of 210-225 microgram per kilogram (mcg/kg) for the initial rFVIIa-B dose followed by 70-75 mcg/kg for subsequent doses. Final dosing regimens were dependent on available vial sizes. rFVIIa-B resulted in complete resolution of all bleeds (100%) at a median of 4 doses (range 1-8 doses) and a median of 24 hours (range 3-48 hours). There were no failures in bleeding resolution following treatment. No adverse events with infusions were reported including infusion-related reactions, hypersensitivity reactions, thrombosis, or thrombotic microangiopathy.Conclusions: Administration of rFVIIa-B in the real-world setting appears to demonstrate hemostatic efficacy in a cohort of pediatric and adult patients with hemophilia A and B with inhibitors and may serve as an alternative human rFVIIa therapy for the management of acute bleeds in this population. Further post-marketing studies are warranted to expand the indication to younger children (<12 years of age) and to continue to monitor drug efficacy and adverse events in a larger population of patients over time including individuals on non-factor therapies such as emicizumab. [Display omitted] DisclosuresBatsuli: Bio Product Laboratory: Honoraria; Kedrion: Honoraria. Tran: HEMA Biologics: Honoraria. Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Sidonio: Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Biomarin: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Genentech: Consultancy, Research Funding.

The Role of Hemoglobin and Hemolysis on Transcranial Doppler Velocities in Children with Sickle Cell Disease: Data from a Natural History Cohort

Background: Children with sickle cell disease (SCD) are at increased risk of cerebrovascular events that can impact neurocognitive development and quality of life (Colombatti 2016). Transcranial Doppler ultrasound (TCD) is a validated screening tool to identify pediatric SCD patients with the highest risk of stroke to start on a preventive chronic blood transfusion regimen (Estcourt 2020; Inusa 2019). High TCD velocities are an indication to start disease-modifying treatments or consider disease-curative options in children with SCD (Khemani 2019). However, real-world pediatric data on the correlation between hematological variables and TCD results are scarce (Salama 2020). We aimed to evaluate the distribution of TCD velocities in a pediatric natural history cohort and investigate their correlation with hematological variables and treatments.Methods: We performed a retrospective analysis on data from a prospective pediatric cohort followed from January 1,2009, to December 31, 2020 (censoring date). Standard care includes annual TCD from 2 years of age. We used transcranial Doppler imaging (TCDi) and classified results according to STOP criteria, considering terminal internal carotid artery (TICA) and middle cerebral artery (MCA) time-averaged maximum mean velocities (TAMMVs). Only complete exams with right and left measures available for both vessels were included. Hematological, clinical, and treatment variables were available from the natural history cohort database. Patients were divided according to genotype: HbSS/HbSβ 0 or HbSC/HbSβ +.Two-sample and Welch t-tests for unequal variances were used to compare mean hemoglobin (Hb) values and hemolysis markers in patients with and without abnormal/conditional TCDi results. Fisher and chi-square tests were used to compare categorical variables. Linear regression models were used to assess the effects of MCA and TICA TAMMVs as continuous variables on Hb. Odds ratios (ORs) for neurological events at different Hb levels were estimated using generalized estimated equations (GEE) with a binomial distribution, logistic function, and exchangeable correlation structure, allowing for correlation among repeated observations for the same patient. Multivariable GEE including characteristics and treatment variables were used to evaluate the association between neurological events and Hb.Results: Of the 182 SCD patients in the cohort, 169 had assessments of cerebral vasculopathy, and 155 had evaluable TCDi (583 exams). The median follow-up of the entire cohort was 79.8 months (range: 2.1-298.6 months) (interquartile range [IQR]: 36.9-126.3 months). The median age at the censoring date was 13.4 years (IQR: 9.1-17.5 years); 130 were HbSS/HbSβ 0, and 25 were HbSC/HbSβ +. Basic demographic characteristics of the cohort are in Table 1. The distribution of TCDi results was significantly different between genotypes (P<0.0001): in the HbSC/HbSβ + group (70 exams), 14 were normal (20.0%), and 56 were low (80.0%); in the HbSS/HbSβ 0 group (513 exams), 8 were abnormal (1.6%), 56 were conditional (10.9%), 311 were normal (60.6%), and 138 were low (26.9%). Only 37/138 (26.8%) low TCDi results were confirmed as stenosis at the nearest MRA. Patients with abnormal/conditional TCDi results had lower Hb (8.4 vs 8.9 g/dL, P≤0.0001) and higher reticulocyte counts (317,766 vs 262,750/mm 3, P≤0.0001), lactate dehydrogenase (843 vs 690 U/L, P=0.0012), and aspartate aminotransferase (61 vs 54 U/L, P=0.0007) compared with patients with normal/low results.We detected a linear correlation between TICA/MCA TAMMVs and Hb (Figure 1A and 1B). Univariate analysis showed significant inverse correlation between abnormal/conditional TCDi results and Hb considered as a continuous variable (OR: 0.484, P<0.001). In the multivariate analysis, the correlation between TCDi results and Hb remained significant; moreover, the risk of presenting abnormal/conditional TCDi results decreased with age (OR: 0.833, P<0.0064).Conclusions: This analysis from our natural history cohort shows a significant inverse correlation between Hb and MCA and TICA velocities, supporting the beneficial effect of higher Hb levels in reducing TAMMV. Disease-modifying therapies increasing Hb and reducing hemolysis could be helpful in reducing TAMMV in children with SCD.Funding: This study was supported by Global Blood Therapeutics. [Display omitted] DisclosuresAgodoa: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Beaubrun: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Biffi: BlueBirdBio: Consultancy, Other: Advisory Board. Colombatti: Global Blood Therapeutics: Research Funding; Addmedica: Consultancy; Forma Therapeutics: Consultancy; Novartis: Consultancy; NovoNordisk: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; BlueBirdBio: Research Funding.

Acute Myeloid Leukemia Patients in Complete Remission with Positive Measurable Residual Disease Prior to Allogeneic Transplant Have Worse Outcomes, Similar to Active Disease Regardless of Conditioning Regimen Intensity and Post-Transplant Cyclophosphamide Administration

IntroductionAllogenic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) is a curative option in patients with intermediate/high risk disease who achieve morphologic complete remission (CR) after induction chemotherapy. Patients in CR but with positive measurable residual disease (pMRD) prior to HCT had high relapse risk(RR) (67% vs 65%) and low 3 year overall survival (OS) (26% vs 23%),similar to those with active disease in a single institution study (Araki et.al; Volume 34, Feb 1,2016, JCO). However, this study included only patients who received myeloablative conditioning (MAC) and included both peripheral blood and marrow grafts. A single institution retrospective study showed that use of MAC compared to reduced intensity conditioning (RIC) improved 3 year RR(19% v 67%; P < .001) and OS( 61% v 43%; P = .02) in patients with pMRD/CR(determined by molecular analysis of limited gene mutational panel)(Hourigan et.al. Volume 38, April 20,2020, JCO). We analyzed a cohort of AML patients that underwent either MAC or RIC followed by peripheral blood stem cell grafts and post-transplant cyclophosphamide (PTCy) based GVHD prevention regimen at our institution to determine the effect of pMRD on transplant outcomes.Methods:To evaluate the impact of pMRD on transplant outcomes, we analyzed AML patients who underwent HCT at Levine Cancer Institute between June 2014 and April 2020 with MRD testing performed within 1 month prior to HCT. MRD testing was performed at University of Washington by using multiparametric flow cytometry (MPC). The overall sensitivity of the assay is conservatively estimated as 0.1%. In our institution, all patients received MAC (Bu/Flu) or RIC (Bu/Flu or Flu/Cy/TBI) regimens followed by peripheral blood stem cell grafts and identical PTCy-based GVHD prophylaxis regimens that included tacrolimus and mycophenolate. Patient and transplant related characteristics were presented via descriptive statistics. Corresponding P-values were determined using Fisher's exact test for categorical variables and nonparametric Mann-Whitney U test for continuous variables. Relapse-free survival (RFS) and OS were estimated using the Kaplan Meier method. All statistical tests were two sided, and a P-value < 0.05 was considered statistically significant.ResultsFrom June 2014 to April 2020, 105 patients with AML underwent HCT. Eighty-three patients with MRD results were included in the final analysis - 52 (63%) with negative MRD (nMRD)/CR, 16 (19%) with pMRD/ CR and 15 (18%) with active disease (no CR). Baseline characteristics were similar except for presence of significantly greater number of high risk patients, based on ASTCT disease classification in the active disease group compared to pMRD/CR and nMRD/CR cohorts( 87% vs 19% vs 0%, P =< 0.001). Median follow up for the entire cohort was 32.7 months. RFS was superior in patients with nMRD/ CR compared to pMRD/ CR or active disease (56.4% vs 19.4% vs 35%, P= 0.005). In addition, OS was superior in nMRD/ CR compared to pMRD/CR or active disease (56.7% vs 35.2% vs 40%, P= 0.014). The use of MAC compared to RIC did not improve RFS (0% vs 32%, P= 0.018) and OS (0% vs 44%, P= 0.071) in pMRD/CR cohort. The use of MAC or RIC did not significantly impact RFS (69% vs 52%, P=0.729) or OS (61% vs 53%, P=0.739) in nMRD/CR patients.Conclusion:Our study validates the previous data that prognosis of patients with pMRD/CR (determined by MPC) prior to HCT is not significantly better than those having active disease. The outcomes were poor regardless of conditioning regimen intensity and PTCy based GVHD prophylaxis used at our institution. These patients might benefit from additional chemotherapy or targeted treatments to achieve nMRD prior to HCT and/or maintenance therapy post HCT. Patients with nMRD/CR disease had similar outcomes with MAC or RIC. This finding suggests that less aggressive conditioning regimens incorporating PTCy could be considered in a subset of patients with nMRD/CR, thereby sparing them from complications associated with MAC. Prospective trials are needed to further study these findings. [Display omitted] DisclosuresCopelan: Amgen: Consultancy. Grunwald: Astellas: Consultancy; Karius: Consultancy; PER: Other; Gilead: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy; PRIME: Other; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Trovagene: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Janssen: Research Funding; Blueprint Medicines: Consultancy; Sierra Oncology: Consultancy; Med Learning Group: Other; Cardinal Health: Consultancy; MDEdge: Other; Agios: Consultancy.