Fetal impact of cystic fibrosis transmembrane conductance regulator modulator use during assisted and natural reproduction and partner pregnancy in men with cystic fibrosis

Background: Increasing availability of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapy (HEMT) has improved the quality of life and long-term prognosis for many people with CF. Thus, more people with CF are considering parenthood. Almost all menwith CF (MwCF) are infertile because of congenital bilateral absence of the vas deferens (CBAVD). Based on CF animal models, CBAVD occurs early in gestation and is unlikely to be reversible using HEMT, but assisted reproductive techniques (ARTs) can enable MwCF to father children using the sperm in their testes. Animal reproductive models suggest no HEMT teratogenicity, and the amount of exposure of the fetus to HEMT via absorption of seminal fluid through the vaginal wall is predicted to be negligible, although to ensure no sperm exposure to HEMT, the life span of sperm would require MwCF to discontinue CFTR modulators for approximately 3 months before ART. Because abrupt discontinuation of CFTR modulators may result in health decline, MwCF and their providers must consider all potential risks. There are no published data in MwCF regarding use of HEMT during conception and partner pregnancy. Method(s): Beginning in August 2021, CF center staff in the United States, United Kingdom, and Australia completed a two-page anonymous questionnaire regarding MwCF who used CFTR modulators during ART (sperm retrieval and in vitro fertilization) or natural conception with subsequent partner pregnancy. Result(s): Providers have submitted 34 surveys for MwCF on CFTR modulators whose partner became pregnant after use of ART (n = 32) or natural conception (n = 2). The median age of the samplewas 32 (range 24- 43). Fifteen were homozygous for F508del, median percentage predicted forced expiratory volume in 1 second was 76% (range (22-111%), and median body mass index was 24 kg/m2 (range 18.5-32.1). Twenty-three were taking elexacaftor/tezacaftor/ivacaftor. The median time that MwCF were taking CFTR modulators before partner conception was 18 months (range 0-82). One newly diagnosed man initiated HEMT after sperm retrieval. Four MwCF stopped CFTR modulators before sperm retrieval, one of whom experienced pulmonary decline. None of the 19 MwCF whose condom use during pregnancy was known used condoms. Fetal complications in partners of MwCF included three first-trimester miscarriages, two* COVID, two breech presentation, two* vaginal bleeding, and one vasa previa. None of the complications were deemed definitively related to use of CFTR modulators. One MwCF experienced testicular infection after sperm retrieval#. Postpartum complications included three# infants with hypoxemia requiring neonatal intensive care unit stay, three maternal blood loss, one forceps delivery, and one caesarean section. No congenital anomalies were reported for any infant. (*/# overlap). Conclusion(s): Use of CFTR modulator therapy during partner conception and pregnancy in 34 MwCF has not resulted in higher-than-expected miscarriage rates or congenital anomalies. Providers should consider the risk to the health of MwCF combined with the lack of teratogenicity in animal reproductive models and limited safety data in the human fetus before discontinuing CFTR modulators before ART or natural partner conception. Survey collection is ongoing;results will be updated for presentationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

Creating community and building connection through play: An improvisational response to the coronavirus pandemic

Responding to the call for 'social distancing' people around the world engaged in play together via the internet. While these activities could be seen as a diversion, they can also be understood as, along with wearing masks , essential to people surviving the pandemic. This qualitative study explores the experiences of people who participated in Creating Connection and Building Community Through Play, a series of five synchronous improvisational play sessions on Zoom. The sessions averaged 83 people with a total of 287 individuals from 29 countries participating in one or more sessions. Analysis revealed that virtual activities focused on relationality, improvisation and play provided people with connection and community in the midst of isolation, and that co-creating these experiences was emotionally healing for many. The findings advance our understanding of the importance of adult play for building and maintaining emotional health, creating community, and responding to ongoing challenges. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

Improving Data Quality in Multicenter Trials: Innovative Approaches Utilized within the Wake Forest Nci Community Oncology Research Program Research Base (Wf Ncorp Rb)

Introduction: Efficient and comprehensive trial oversight and data management ensures valid, robust outcomes necessary to inform health policy and improve patient outcomes. This is particularly challenging in the context of multicenter trials. The format of this session will include four introductory presentations (15 min each), followed by 30-min panel discussion/Q&A focusing on recent experiences and innovative approaches utilized within the Wake Forest NCI Community Oncology Research Program Research Base (WF NCORP RB). Since 2017, WF has managed 15 studies with approximately 3000 patient and 1000 provider/stakeholder accruals across 1000 potential participating community oncology practices within the United States and Puerto Rico. These practices often operate differently from academic medical centers, with varying patient capacity, provider number and level of engagement, use of advanced practice providers, and services offered. In addition, practices within this network have heterogeneous utility of electronic health records (EHRs) and display a wide range of clinical research staffing models. The COVID-19 pandemic has highlighted the need for streamlining research visits and maximizing telehealth technologies when applicable, particularly for intervention non-therapeutic clinical trials. As such, research expectations must be standardized to ensure quality trial conduct and data collection across diverse practices. Recently, the WF NCORP RB has taken many steps to improve efficiency and data quality across our studies. This session will discuss a comprehensive approach to data quality and management across the lifespan of a trial. This starts with consent/ recruitment strategies and general oversight/ monitoring of our portfolio of trials. WF RB now utilizes REDCap for all data capture, as this allows direct data entry for site personnel and participant entered patient-reported outcomes using surveys. In addition, REDCap facilitates data monitoring, query, and auditing strategies. We will also introduce a team-based approach to adjudicate complex outcomes. Talk 1 (15 min): Specifically, Karen Craver, our RB administrator, will discuss approaches to obtain robust data as a result of strong screening and recruitment. She will provide an overview on how we survey practice research staff within the Landscape assessment and brief, pre-trial interest surveys to identify optimal target populations during the planning stage. We utilize our internal EHR to create custom screening reports to identify potential participants and generalize these for other practices to customize and use as a screening tool within their clinic. The RB has integrated remote consenting in part due to the pandemic, but we realize the need to continue offering flexibility in consent modality moving forward. Talk 2 (15 min): Emily Dressler, lead Biostatistician, will discuss oversight of the RB portfolio using dynamic reports within Tableau. These reports update daily and provide a comprehensive assessment of all ongoing and completed studies. RB personnel can filter reports to create custom results subset by timeframe, practice or set of practices, trial type, and/or other demographic characteristics. This has greatly reduced the request for study-specific accrual reports and has standardized our reporting across studies. She will also discuss the rationale for transitioning to REDCap, including strengths and weaknesses for integrating in multicenter studies. Talk 3 (15 min): Bill Stanfield, lead data manager, will demonstrate our utilization of the REDCap Data Resolution Workflow and Data Quality modules to efficiently manage data collection, data quality, and audits. He will show how REDCap can be used to seamlessly communicate with research staff to obtain missing or late data, verify out of range values, and then validate and lock responses for analysis. Talk 4 (15 min): Glenn Lesser, WF NCORP multiple principal investigator (mPI), will discuss a team approach to adjudicating cancer treatment information that often consists of combination of surgery, radiation, chemotherapy, or immunotherapy/targeted agents. This remains a particularly challenging problem in large trials enrolling patients with multiple types of cancer who may be treated with a wide spectrum of standard therapeutic regimens. This diversity limits both the effectiveness of automated reviews of remote data entries and the study-specific training of data management staff at sites. Data are pulled in real time from multiple forms within REDCap and collated into participant-level summaries of treatment, starting with the time of baseline assessment and sorted sequentially for each drug administration or event. A multidisciplinary team of data managers, biostatisticians, and clinicians meet to adjudicate each participant as data collection completes. Particularly for trials with multiple cancer types or treatment regimens, our experience with this approach has shown it identifies significant data gaps in treatment, with at least 75% of entries requiring clarification from research staff prior to finalizing and locking data. This process highlighted the challenge of real-time adjudication of treatment data in patients receiving multiple anti-cancer agents, given at varying doses and schedules, and in multiple combinations and/or phases over an individual patient's course of therapy. Panel (30 min): We will conclude with a panel discussion and Q&A. The panel will contribute additional perspective on implications of these strategies in the conduct of multilevel cancer care delivery research studies. We will also incorporate perspectives from NCORP community sites implementing these strategies. Panelists will discuss the broad applicability of these strategies for diverse trials, with attention to size/ complexity, database vendor, and patient population.

SARCOPENIA: FEATURES OF PATHOGENESIS, DIAGNOSIS, TREATMENT AND REHABILITATION IN COVID-19 PATIENTS.

A global problem in all countries is the aging of the population due to the lengthening of the life span. The number of age-related diseases, including sarcopenia, rises with increasing age. People of the elderly and senile age were especially vulnerable in terms of the number of infections, the severity of the course of the disease, the number of deaths, for 2 years of the COVID-19 pandemic. The pandemic requires restrictive measures on the movement of citizens up to the introduction of a lockdown. This entails a decrease in physical activity and a rapid progression of sarcopenia, which worsens the prognosis of COVID-19 in this category of citizens, not only in the acute stage of the disease, but also in the following months due to an exacerbation of cardiovascular diseases, kidney diseases.Copyright © 2022 Stavropol State Medical University. All rights reserved.

Literacy and international development

Literacy is a complex and dynamic phenomenon that varies across history, language, and geography. The present review considers the roles of literacy in an international development perspective. First, an overview is provided of the history and definitions of literacy, considering its evolution from a dichotomous concept (literate/illiterate) to a continuum of writing, reading, and numeracy across the life span. Second, key contemporary aspects of literacy are described, including the effects of language of instruction policies, technology, and emergent crises on literacy acquisition in low-and-middle income countries. In conclusion, considerations and recommendations for literacy promotion are linked to broader issues in educational planning and international development. © 2023 Elsevier Ltd. All rights reserved.

Current pandemic COVID-19 vaccine strategies and development: a comprehensive review

The coronavirus disease-19 pandemic with the characteristics of asymptomatic condition, long incubation period and poor treatment has influenced the entire globe. Coronaviruses are important emergent pathogens, specifically, the recently emerged sever acute respiratory syndrome coronavirus 2, the causative virus of the current COVID-19 pandemic. To mitigate the virus and curtail the infection risk, vaccines are the most hopeful solution. The protein structure and genome sequence of SARS-CoV-2 were processed and provided in record time;providing feasibility to the development of COVID-19 vaccines. In an unprecedented scientific and technological effort, vaccines against SARS-CoV-2 have been developed in less than one year. This review addresses the approaches adopted for SARS-CoV-2 vaccine development and the effectiveness of the currently approved vaccines.Copyright © 2023, Finlay Ediciones. All rights reserved.

History of childhood mistreatment and the psychological health consequences of COVID-19 for older adults.

OBJECTIVES: We examine the associations between childhood mistreatment (emotional abuse, physical abuse, sexual abuse, and emotional neglect) and older adults' changes in depressive symptoms from before to during the COVID-19 pandemic (September 2018-June 2020). METHODS: Using a community-based sample of older adults in North Florida (N = 581), we used ordinary least-squares regression to estimate associations between childhood mistreatments and depressive symptoms in June 2020, controlling for baseline symptoms and demographic characteristics. Additional models tested whether emotion regulation and social support attenuated associations between childhood mistreatments and depressive symptoms. RESULTS: Older adults exposed to emotional neglect in childhood saw a greater increase in depressive symptoms than those who did not experience childhood mistreatment. Those reporting childhood physical abuse had higher baseline depressive symptoms, but they did not increase during the pandemic. These associations remained stable after controlling for emotion regulation and social support, coping resources thought to contribute to linkages between childhood mistreatment and psychological health in adulthood. CONCLUSION: Childhood mistreatment might inform the psychological consequences of major stressors in later life. Thus, early life interventions for children experiencing mistreatment could be especially important for long-term psychological health outcomes and responses to major stressful events. Identifying older people with histories of childhood mistreatment could also help clinicians gauge patients' risk of psychological decline during times such as the COVID-19 pandemic and tailor psychological health interventions.

Time-varying associations between loneliness and physical activity: Evidence from repeated daily life assessments in an adult lifespan sample.

Physical activity is a behavior that promotes physical and mental health; yet physical activity has decreased during the COVID-19 pandemic. To promote health during times of challenge, it is important to identify potential barriers to this key health behavior, such as loneliness. This brief report extends previous research on physical activity and loneliness that mainly focused on between-person differences to examine their time-varying associations at the within-person level using repeated daily life assessments. From April 2020 to August 2020, data were collected from a sample of 139 community-dwelling Canadian adults (M age = 40.65 years, SD = 18.37; range = 18-83 years). Each evening for 10 consecutive days, participants reported their loneliness, number of steps, and minutes of moderate-to-vigorous physical activity. Results revealed that, in line with our hypotheses, on days when participants reported more loneliness they also engaged in less moderate-to-vigorous physical activity than on less lonely days (estimate = -0.24, p = 0.007); there was a significant negative association between loneliness and daily number of steps (estimate = -18.42, p = 0.041). In contrast, at the between-person level, overall loneliness was not associated with overall physical activity engagement after accounting for within-person differences and control variables (age, sex, day in study). From an intervention perspective, our findings suggest that it is promising to tackle loneliness on a day-to-day basis to increase physical activity one day at a time. This may be especially relevant during times mandating social-distancing, but also at other times when individuals experience greater feelings of loneliness.

Perceived Changes in Social Connectedness Across the Life Course: A Mixed Method Approach.

Social connection is important across the life course, but overall levels have been declining. The COVID-19 pandemic presented a unique context to examine social connectedness and adaptive capacity in times of social adversity. We used a parallel mixed method design to collect online survey data from a representative U.S. sample (N = 359). Applying an exploratory sequential approach, we used a general linear model multivariate approach to repeated measures to test for differences in participants' perceptions of social connectedness by time and age category and qualitative analysis to gain insights about disrupted social contexts. Results indicated that social connectedness decreased after mitigation restrictions for all age groups, but individuals in emerging and late adulthood felt the greatest impact. Two themes emerged: differing emotional responses to altered communication and intentionality of maintaining and/or creating social connections. Experiences of social connectedness need to be understood as a function of life stage and developmental timing.

Co-creating inclusive spaces and places: Towards an intergenerational and age-friendly living ecosystem.

Introduction: Evolving aging societies, ongoing digitalisation and circumstances of COVID-19 are changing living conditions for growing older. There is an increased urgency to view public health with a focus on integrating people of all ages into the matrix of opportunities afforded in their communities. This study initiates the conceptualization of an intergenerational, age-friendly living ecosystem (AFLE) to enhance public health planning. Methodology: A participatory study was conducted using a multi-methods approach. Six virtual co-creation sessions (n = 35-50 participants), alongside a mainly open-ended INTERGEN survey designed specifically for this study (n = 130) were conducted to conceptualize multilevel ideas for building intergenerational age-friendly places using Bronfenbrenner's ecological systems model. At the height of COVID-19, virtual applications (Zoom, Moodboard) and case studies, creative methods (drawing, photography, storytelling and spotlight sessions) were applied to engage academic and non-academic participants between ages 5 - 80+ years, across eight countries. Sessions were video-recorded with visual themes captured by a graphic facilitator. The survey covered issues of multigenerational interactions; intergenerational and age-friendly place features; place safety; and necessary stakeholders required for creating intergenerational and age-friendly places. Data were reflexively analyzed using a team approach to thematic analysis. Results: Findings present both the thematic analysis of Virtual Co-creation Camps (VCCs) and the INTERGEN survey results. These findings are addressed in three overarching categories that highlight the necessary characteristics of AFLEs as suggested by the VCC participants and survey respondents: (i) Sensory factors: feeling and emotion as starting points for physical design; (ii) Physical and digital factors in designing AFLE spaces and places; and (iii) Socio-cultural factors: tackling ageism and exclusion as part of the solution. Discussion: The analysis resulted in a pathway toward enhanced understandings on how multi-generations can better interact with fluctuating organizational domains (industry, voluntary, academic and public sectors) in urban and rural settings to facilitate intergenerational connectivity. Through processes of co-creation, an AFLE proof of concept and roadmap for public health planning was developed to support and provide opportunities for people as they age to reap the socioeconomic benefits of their local and virtual communities and help them become well integrated, valued and contributory members of society.

Effect of an Intensive Nurse Home Visiting Program on Adverse Birth Outcomes in a Medicaid-Eligible Population: A Randomized Clinical Trial

Mortality, morbidity, and childhood developmental challenges can all result fromadverse birth outcomes. In regard to these outcomes, the United States exhibits significant racial and socioeconomic inequities, and effective interventions targeting lowincome pregnant people are necessary. A recommendation for expanding home visiting programs has been provided with the hope of improving newborn andmaternal outcomes, and substantial federal funding is granted to these programs via theMaternal, Infant, and Early Childhood Home Visiting program. The Nurse-Family Partnership program is a nurse home visiting service targeting nulliparous low-income families during pregnancy and early childhood. The state of South Carolina's preterm birth rate in 2016 was the sixth highest in the United States, which motivated the state to offer program services to Medicaid-eligible nulliparous women through aMedicaid waiver. This study's objective was to determine effects of intensive nurse home visiting programs on the composite outcome of small for gestational age, low birth weight, preterm birth, and perinatal mortality. This randomized clinical trial assigned participants in a 2:1 ratio to either a control group or an intervention group, which was offered access to the program. The control group was offered a list of community-based resources available to them, and all participants received usual care for South Carolina. Inclusion criteria were nulliparous pregnancy of less than 28 weeks' gestation, income-eligible for Medicaid during pregnancy, and residence in a program-served county. Self-referral, or referral through schools, clinicians, and Medicaid led patients to 1 of 9 program-implementing sites. The intervention, which consisted of a prenatal and early childhood home visiting program, was carried out by nurses conducting home visits with participants from pregnancy through the first 2 years of the child's life. The nurses used activities tailored to the clients' strengths, preferences, and risks via educational tools, motivational interviews, goal setting related to prenatal health, health assessments, maternal life course, and child health and development. Utilization of health care was encouraged when needed, coupled with referrals to health and social services. Ideal visits ranged from weekly 60- to 90-minute sessions for 4 weeks following enrollment and then every other week leading up to delivery. Nurse training encouraged flexible support of clients for more or fewer visits as necessary, with services provided in both Spanish and English, with other translation options. Enrollment for the study began on April 1, 2016, but concerns for the COVID-19 pandemic led to a recruitment halt on March 17, 2020. However, 95% of the target recruitment goal had already occurred, and the remaining home visits were conducted via telehealth. A total of 3319 patients were eligible and opted for enrollment. Upon time of enrollment, 18% of participants were younger than 19 years, with 54.8% of them between 19 and 24 years old. Self-reported race and ethnicity statistics were reported as 55.2% non-Hispanic Black, and 22.4% had not completed high school. Body mass index of greater than 30 kg/m2 was present in 34.5%, and smoking 3 months before pregnancy was reported in 25.8% of participants. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Predictive Value of Red Cell Distribution Width at Admission as A Marker Of ICU Requirement in COVID-19 Infection

Introduction: COVID-19 is a global pandemic disease first identified in Wuhan, China in late 2019. As of March 2022, over 450 million cases and 6 million deaths have been reported across the world, with the confirmed numbers probably being a fraction of the real numbers. Red Cell Distribution width (RDW) is a measure of anisocytosis, that is, variation in the circulating red blood cell volume. It is a nonspecific marker of acute illness. Increased RDW is suggestive of dysfunctional erythropoiesis and/or shortened RBC lifespan. Hence, it is a good predictor of clinical outcome in many disorders. Aims & Objectives: AIMS: To prove association of RDW with COVID-19 infection requiring ICU stay in a tertiary care hospital. OBJECTIVE(S): Primary Objective: To assess the predictive value of RDW on admission with requirement of ICU as a marker of severity in COVID-19 patients. Secondary Objectives: To compare RDW to other markers commonly used in COVID-19 infection, such as D-Dimer and CRP. Material(s) and Method(s): Patients over 18 years of age getting admitted at COVID ward or ICU at P.D. Hinduja Hospital, Mumbai were included in the study. RDW, CRP and D-dimer values of Ward group and ICU group patients were noted and compared. Result(s): 234 patients were screened and 190 patients were included in the final study. RDW was found to have significant association with ICU requirement (p = 0.0066). Further, an RDW value of 13 or more is found to be 85% sensitive for predicting ICU requirement. RDW of 16 or more is found to be 80% specific for predicting requirement of ICU stay. Regarding secondary objectives, RDW was found to have significant correlation with D-Dimer (p = 0.0005) but not with CRP (p = 0.12). Conclusion(s): RDW can be a potentially useful marker for risk stratification in COVID-19. A value of RDW more than 16 is associated with a significant risk of ICU requirement in COVID-19 disease. Further studies may be indicated to find a statistically significant correlation between RDW values and mortality in COVID- 19.

The mediating role of loneliness on relations between face-to-face and virtual interactions and psychological well-being across age: A 21-day diary study

Lack of social interaction is associated with a heightened sense of loneliness and, in turn, poorer psychological well-being. Despite the prevalence of communicating with others virtually even when physically alone, whether the social interaction-loneliness-well-being relationship is different between face-to-face and virtual interactions and between younger and older adults is relatively understudied. This 21-day diary study examined this question among younger (n = 91;M-age = 22.87) and older (n = 107;M-age = 64.53) Hong Kong participants during the early stage of the COVID-19 pandemic (March-May 2020). We found significant indirect effects of shorter face-to-face interaction time on poorer psychological well-being via a heightened sense of loneliness at the within-person level only among younger adults and at the between-person level only among older adults. Independent of loneliness, spending more time with others on virtual interactions was associated with better psychological well-being only among older adults. Taken together, while the mechanisms may be different across age groups, face-to-face interaction remains an effective way to reduce loneliness and enhance psychological well-being even at times when it is discouraged (e.g., pandemic). Although virtual interaction does not reduce loneliness, its positive impact on older adults' well-being sheds light on the utility of promoting technological acceptance in late adulthood.

Trajectories of resilience and mental distress to global major disruptions.

The COVID-19 pandemic has resulted in a major societal disruption, raising the question of how people can maintain or quickly regain their mental health (i.e., be resilient) during such times. Researchers have used the pandemic as a use case for studying resilience in response to a global, synchronously starting, and chronic set of stressors on the individual and societal level. Our review of this recent literature reveals that mental distress trajectories during the pandemic largely resemble mental distress responses to individual-level macro-stressors, except for a lower prevalence of recovery trajectories. Results suggest more resilient responses in older adults, but trajectories are less consistent for younger and older ages compared with middle-aged adults. We call for more research integrating state-of-the-art operationalizations of resilience and using these to study resilience over the lifespan.

Optimising filter lifespan in critically ill patients with SARS-CoV-2 receiving renal replacement therapy: An observational study in a district general hospital

Introduction: Acute kidney injury (AKI) and need for renal replacement therapy (RRT) is a known complication of SARS-Coronovirus-2 (SARS-CoV-2) in critically ill patients. 1 Early evidence suggested SARS-CoV-2 patients have increased incidence of filter cartridge failure on RRT.2,3 Frequent filter changes can lead to reduced therapy delivery, increased cost and anaemia. To mitigate this, our intensive care unit developed a new protocol for patients with SARS-CoV-2 requiring RRT to balance the benefits of preserving filter lifespan and risks of anticoagulation associated bleeding. Objectives: To investigate whether an increased citrate dose and an adjusted RRT prescription would increase the filter lifespan for patients with SARS-CoV-2. Methods: We performed a retrospective observational study looking at all patients admitted to our Level 3 critical care unit since the pandemic in March 2020 to date. Data was collected from Ward Watcher, a Scottish Intensive Care Society Audit Group (SICSAG) database and the CAREVUE electronic patient records. We introduced a modified RRT prescription for continuous venovenous haemodiafiltration (CVVHDF) with a citrate dose of 4mmol/l, increasing the dialysate flow rate to 1500ml/hr to mitigate the risk of increased citrate load. Results: During the period for data collection, the unit had 106 patients with SARS-CoV-2 of whom 15 required RRT. The median duration spent on RRT was 188 hours (range 24-677). Eight patients were managed exclusively on the adjusted protocol. The average lifespan of a filter in SARSCoV-2 patients on the standard protocol was 37 hours compared to 45 (range 6-70) hours using the adjusted protocol. The median number of filters per patient per RRT day on the adjusted protocol was 0.3 (range 0.2 -1). It also allowed more therapy to be delivered with patients spending on average 79% of the day on RRT. There were no adverse bleeding outcomes and no documented evidence of citrate toxicity or acid-base disturbances Conclusion: This small study showed an increase in filter life for patients on an increased citrate dose protocol of CVVHDF without any adverse outcomes. This results in cost savings and more appropriate resource usage during a pandemic without increased bleeding risk. Another suggested measure to reduce frequent filter malfunctions was that centres returned to using heparin anticoagulation, but this is known to have increased bleeding risk.4.

ETAVOPIVAT TREATMENT FOR UP TO 12 WEEKS IN PATIENTS WITH SICKLE CELL DISEASE IS WELL TOLERATED AND IMPROVES RED BLOOD CELL HEALTH

Background: Etavopivat, an investigational, once-daily, selective, activator of erythrocyte pyruvate kinase (PKR) increases PKR activity, resulting in decreased 2,3-DPG and increased ATP in red blood cells (RBCs) of healthy volunteers and patients (pts) with sickle cell disease (SCD).1,2 Aims: We report results of an open-label (OL) extension cohort from a Phase 1 study (NCT03815695) designed to characterize the safety and clinical activity of etavopivat at a maximal pharmacodynamic dose in pts with SCD. Methods: 15 pts were enrolled to receive etavopivat 400 mg once daily for 12 wks, followed by a 4-wk follow-up. Assessments included safety, pharmacokinetics, pharmacodynamics, RBC health parameters and systemic markers of SCD pathophysiology. Results: Of 15 pts (age 32.3 ±10.1 yr;HbSS/SC n=13/2), 14 completed 12-wks of treatment (tx);1 pt discontinued tx after ∼2 wks. Etavopivat 400 mg once daily was generally well tolerated. Adverse events (AEs) reported during tx and follow-up were commonly low grade (Gr) and consistent with pts' SCD. Gr1-2 AEs in >2 pts (n [%]) were sickle cell pain events (9 [60%]);headache (5 [33%]);and upper respiratory tract infection (3 [20%]). The Gr3-4 AE in >1 pt was sickle cell vaso-occlusion (VOC;4 [27%]). On-tx serious adverse events (SAEs;1 pt each) were Gr3 VOC post Gr3 COVID (not tx-related) and Gr3 left femoral deep vein thrombosis (possibly related, resulting in tx discontinuation as stated above). SAEs (1 pt each) during the 4-wk follow-up were Gr3 acute chest syndrome + Gr3 VOC, Gr3 non-cardiac chest pain and Gr3 syncope (all unrelated). Observed increases in ATP and decreases in 2,3-DPG were durable over 12 wks of etavopivat tx. Etavopivat tx normalized hemoglobin (Hb)S-oxygen affinity to that of HbA. Etavopivat tx over 12 wks improved overall sickle RBC health, demonstrated by a reduction in point of sickling as well as improved measures of deformability and hydration of sickle RBCs (all P<0.01;Figure). Etavopivat tx over 12 wks was associated with a sustained significant increase in Hb compared with baseline (BL;P<0.0001), with mean maximal increase of 1.5 (range 0.7-2.3) g/dL. Ontx increase in Hb >1g/dL was achieved in 11 (73%) pts, for whom the mean maximal Hb increase was 1.8 (1.2-2.3) g/dL. Absolute reticulocytes, indirect bilirubin and lactate dehydrogenase significantly decreased from BL and were sustained over the 12wk period (all P<0.05), indicative of increased RBC lifespan and decreased hemolysis. Several markers of disease activity significantly decreased from BL during daily etavopivat tx, including the inflammatory marker tumor necrosis factor-α , which decreased by 35% (P<0.001). Based on preliminary exploratory analysis with an aggregate duration of etavopivat exposure of 3.32 pt-yrs in the OL cohort, a decrease in the trend for VOC Hospitalizations was observed: annualized historical and on-tx VOC Hospitalization rates were 0.93 and 0.30, respectively;the 1 on-tx VOC Hospitalization was COVID-related. Summary/Conclusion: Etavopivat 400 mg once daily for up to 12 wks demonstrated a tolerable safety profile and showed improvements in various markers of RBC health in pts with SCD. Rapid and sustained increases in Hb were associated with decreases in reticulocyte counts and markers of hemolysis, supporting increased sickle RBC lifespan and improved anemia. Together, these results support further evaluation of etavopivat in the Phase 2/3 Hibiscus Study (NCT04624659) currently enrolling pts. (Figure Presented).