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Lipid nanoparticles (LNPs) are the most versatile and successful gene delivery systems, mainly because of their use in vaccines against Covid-19. LNPs have a well-defined core-shell structure, each region with its own distinctive compositions, suited for a wide range of in-vivo delivery applications. Here, we discuss how a detailed knowledge of LNP structure can guide LNP formulation to improve the efficiency of delivery of their nucleic acid payload. Perspectives are detailed on how LNP structural design can guide more efficient nucleic acid transfection. Views on key physical characterization techniques needed for such developments are outlined including opinions on biophysical approaches both correlating structure with functionality in biological fluids and improving their ability to escape the endosome and deliver they payload.
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Background and aim: During the early stages of the COVID-19 pandemic, nationwide lockdowns caused disruption in the diets, physical activities, and lifestyles of patients with type 2 diabetes. Previous reports on the possible association between race/ethnicity, COVID-19, and mortality have shown that Hispanic/Latino patients with type 2 diabetes who are socioeconomically disadvantaged are disproportionately affected by this novel virus. The aim of this study was to explore stressors associated with changes in diabetes self-management behaviors. Our goal was to highlight the health disparities in these vulnerable racial/ethnic minority communities and underscore the need for effective interventions. Methods and participants: Participants were enrolled in part of a larger randomized controlled trial to compare diabetes telehealth management (DTM) with comprehensive outpatient management (COM) in terms of critical patient-centered outcomes among Hispanic/Latino patients with type 2 diabetes. We conducted a thematic analysis using patient notes collected from two research nurses between March 2020 and March 2021. Two authors read through the transcripts independently to identify overarching themes. Once the themes had been identified, both authors convened to compare themes and ensure that similar themes were identified within the transcripts. Any discrepancies were discussed by the larger study team until a consensus was reached. Results: Six themes emerged, each of which can be categorized as either a source or an outcome of stress. Sources of stress associated with the COVID-19 pandemic were (1) fear of contracting COVID-19, (2) disruptions from lockdowns, and (3) financial stressors (e.g., loss of income). Outcomes of COVID-19 stressors were (1) reduced diabetes management (e.g., reduced diabetes monitoring and physical activity), (2) suboptimal mental health outcomes (e.g., anxiety and depression), and (3) outcomes of financial stressors. Conclusion: The findings indicated that underserved Hispanic/Latino patients with type 2 diabetes encountered a number of stressors that led to the deterioration of diabetes self-management behaviors during the pandemic.
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Background: In the context of aphasia rehabilitation, there is a perceived need for interventions with a reduced linguistic demand targeting well-being. Mind-body and creative arts approaches are holistic and person-centred approaches, primarily relying on means other than verbal exchanges and promoting self-regulation strategies. Aim(s): This mixed-method systematic review aimed to evaluate the availability, feasibility and effectiveness of mind-body and creative arts therapies in promoting well-being for people with aphasia. Eight databases were searched using subject headings and keywords. Full-text screening, critical appraisal and data extraction were conducted independently by two reviewers. A segregated synthesis approach was used (i.e., Revised Effect Direction Plot technique and Thematic Synthesis approach). Findings are presented in a narrative and visual form. Main Contribution: Twenty-two studies were included (Mind-body: n = 11;Creative arts: n = 11). Heterogeneity of study design and quality, intervention type, procedures and dosage, outcomes, and level of offered communication support were identified. Improvements were noted across a wide range of well-being outcomes with more consistent positive results for anxiety and communication. One hundred and twenty-eight findings were extracted and synthesised in three broad themes: positive impact on self, empowering multifaceted experience, and relevance of needs-centred adjustments. Conclusion(s): Provisional findings about the benefits of mind-body and creative arts interventions on aspects of well-being for some individuals with aphasia were identified. However, findings are complex and need to be interpreted cautiously. Facilitators and barriers to these therapies are highlighted with related recommendations for practice. This review poses a demand for further research in the field, implementing rigorous methodology and aphasia-specific support to facilitate inclusion and engagement.Copyright © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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Introduction: Depression and anxiety are prevalent after stroke, persist long-term, and are associated with poor outcomes, including lack of engagement with rehabilitation. Long-term psychological support is a recognised unmet need and a research priority. In previous work with people affected by stroke we co-developed a stroke-specific psychoeducational self-management intervention HEADS: UP, an adaptation of a Mindfulness Based Stress Reduction course. The work reported here aimed to test feasibility and acceptability of HEADS: UP (NCT03956693). Method(s): We recruited stroke survivors (SS) >=3 months post-stroke, with symptoms of mood disorder (Hospital Anxiety and Depression Scale >=8), to participate in one of two non-randomised feasibility studies. Participants could 'enrol' a family member/'other', if desired. Study 1 tested face-to-face delivery of HEADS: UP;data informed optimisation and adaptation of research processes and the intervention. In response to COVID 19, Study 2 tested HEADS: UP Online. Quantitative data (demographics;mood and quality of life outcomes measures (OMs)) and qualitative data were collected pre-/post-intervention. Both studies received ethical approval. Result(s): STUDY 1: SS n=13;aged 63.3 (mean). Feasibility: Completion of paper-based OMs post-intervention n=6 (46.2%);intervention attendance 6.2/9 (median). Acceptability: I find myself . . . on the bus doing [mindfulness]! I realise I am actually doing it! STUDY 2: SS n=9;aged 54.2 (mean). Feasibility: Completion of online OMs: n=9 (100%) post-intervention;intervention attendance: 8.6/9 sessions. Acceptability: I was apprehensive . . . I wasn't sure you could do mindfulness over Zoom . . . but it has worked really, really well Conclusion(s): Stroke survivors found a stroke-specific psychoeducational self-management intervention, HEADS: UP, feasible and acceptable.
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Coordination of Care Since the COVID-19 pandemic unfolded, strains on the healthcare system have been widespread and pervasive (Kumar & Dey, 2020). At times, this crisis has put the oncology patient in a particularly unique position. As oncology care is a time-sensitive endeavor, treatment delays are critical to mitigate against and understand (Du et al., 2022). Delays or interruptions in cancer treatment can lead to progressive symptoms and worsened survival (Kumar & Dey, 2020). In addition, psychological implications for cancer patients are prominent (Dermody & Shuman, 2022). In the beginning of the pandemic, oncology patients who tested positive for COVID-19 were admitted to a respiratory isolation area in the hospital system not specialized in oncology, to provide physical separation from other vulnerable oncology patients in the cancer hospital. As a result, specialized oncologic treatments were not always available, which caused potential delays in necessary interventions. The aim of this project was to create a safe space for oncology patients, with an active COVID-19 infection, who additionally required timely oncologic treatments requiring an inpatient admission (acute leukemia, CAR T-cell administration, stem cell transplant, surgical intervention). The cancer hospital designed a 9-bed HEPA-filtrated area, with five rooms capable of being converted into ICU rooms for critically-ill patients. This area was termed the "Respiratory Isolation Flex Unit (RIFU)." Nursing leadership developed guidelines and policies around its appropriate use to ensure patient safety. Not only was a physical space required to allow for these types of admissions, but appropriate nursing specialty was vital as well. Institutional processes were developed to allow for nursing staff who were specialty trained in chemotherapy, critical care, stem cell transplant, etc. to be available for these patients. Cancer patients with a positive COVID-19 test upon admission were appropriately assigned to the RIFU and able to receive timely treatment, education, and monitoring with specialty trained nursing staff. Nursing staff had positive experiences caring for this unique patient population and collaborated to ensure a consistent "patient first" mentality. These innovative solutions allowed the cancer hospital to rise to the occasion and provide essential oncology treatments during these unprecedented times to patients with active COVID-19 infections. By preventing delays in important treatments and allowing for continued specialized care, we strived to positively impact outcomes and patient experiences.
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Introduction: HEADS: UP is a psychoeducational self-management intervention to help stroke survivors cope with symptoms of anxiety and depression. During COVID 19 the HEADS: UP (Helping Ease Anxiety and Depression after Stroke) pilot randomised controlled trial (protocol: NCT04985838) was adapted at short notice for online delivery. The Project Advisory Group (PAG) or Patient and Public Involvement and Engagement group comprising 5 stroke survivors, a family member, and 2 stroke health professionals provided first-hand experience and advice to help develop resources required to enable stroke survivors negotiate the technology and 'get online'. Method(s): The PAG met 4-6 weekly online with HEADS: UP researchers;interim contact was by phone and email. They tested, advised, and offered personal reflections on/experiences of i) research processes e.g. online screening/recruitment, data collection and ii) intervention delivery e.g. suitability of Zoom for weekly HEADS: UP sessions, and accessibility of an online community platform, Padlet. Result(s): The PAG helped improve accessibility of pre-existing HEADS: UP research and intervention materials e.g. study Welcome Packs. Their 'hands-on' experiential approach also informed development of novel resources e.g. How to use Padlet. PAG members reported benefiting from their reciprocal relationship with researchers: "Everything changed after COVID . . . working online with HEADS: UP made me feel . . . important!" Their input enabled participants to successfully navigate online screening/ recruitment, complete research questionnaires online, and take part in the online course (if randomised to the intervention). Conclusion(s): The PAG's first-hand experience and advice enhanced HEADS: UP online research processes and intervention delivery for stroke survivor participants.
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Introduction: Social media has emerged as a useful and potentially costeffective recruitment route for clinical trials particularly during the COVID-19 pandemic. This paper presents recruitment results and lessons learned from using social media for recruitment to the HEADS: UP Helping Ease Anxiety and Depression after Stroke Online randomised control trial. Method(s): We recruited UK-based community-dwelling stroke survivors with self-reported anxiety and depression. Our recruitment strategy included community networks and social media platforms. Result(s): Recruitment over 22 weeks resulted in 120 leads (5.5/week), with social media, primarily Facebook and Twitter, contributing 38 leads (31.7%;1.7/week). We enrolled 64 participants (female n=36 (56.3%), mean age 56.3 yrs, SD=11.2 ), with 28 (43.8%;female n=15 (53.6%), mean age 53.0 yrs, SD=11.3) recruited through social media. Facebook generated 21 (75%) of 28 social media participants, with Twitter contributing 8 (28.6%), including one participant from both Facebook and Twitter (3.6%). Facebook allowed for recruitment from stroke community groups and contact with key group members who posted regularly on our behalf, aiding credibility. Twitter provided the opportunity to recruit without gatekeepers, but required considerable researcher time and effort spent networking (i.e. Following, Liking, requesting Retweets) and developing new content to post, which stretched our limited resources. Conclusion(s): Social media was an effective, integral strategy for recruitment. However, substantial resources were required to develop content and manage our online presence. Future research could benefit from costing researcher time into funding applications and investing time in identifying and making contacts within population-specific pages or groups.
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The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for the treatment of COVID-19. The potential of 3CLpro-inhibitors to select for drug-resistant variants needs to be established. Therefore, SARS-CoV-2 was passaged in vitro in the presence of increasing concentrations of ALG-097161, a probe compound designed in the context of a 3CLpro drug discovery program. We identified a combination of amino acid substitutions in 3CLpro (L50F E166A L167F) that is associated with a >20× increase in 50% effective concentration (EC50) values for ALG-097161, nirmatrelvir (PF-07321332), PF-00835231, and ensitrelvir. While two of the single substitutions (E166A and L167F) provide low-level resistance to the inhibitors in a biochemical assay, the triple mutant results in the highest levels of resistance (6× to 72×). All substitutions are associated with a significant loss of enzymatic 3CLpro activity, suggesting a reduction in viral fitness. Structural biology analysis indicates that the different substitutions reduce the number of inhibitor/enzyme interactions while the binding of the substrate is maintained. These observations will be important for the interpretation of resistance development to 3CLpro inhibitors in the clinical setting. IMPORTANCE Paxlovid is the first oral antiviral approved for treatment of SARS-CoV-2 infection. Antiviral treatments are often associated with the development of drug-resistant viruses. In order to guide the use of novel antivirals, it is essential to understand the risk of resistance development and to characterize the associated changes in the viral genes and proteins. In this work, we describe for the first time a pathway that allows SARS-CoV-2 to develop resistance against Paxlovid in vitro. The characteristics of in vitro antiviral resistance development may be predictive for the clinical situation. Therefore, our work will be important for the management of COVID-19 with Paxlovid and next-generation SARS-CoV-2 3CLpro inhibitors.
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COVID-19 , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Enzyme Inhibitors , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2/geneticsABSTRACT
Background: TLR7/8 are immune receptors expressed in megakaryocytes which detects single-stranded RNA viruses such as SARS-CoV- 2. There is increasing evidence that in addition to raised platelet counts, severe infection with SARS-CoV- 2 increases the risk of venous, arterial and microvascular coagulation. Aim(s): To determine if ssRNA viruses are capable of increasing thrombopoeisis through direct interaction with megakaryocytes. Method(s): Cells were incubated with and without Gardiquimod (GDQ), a specific agonist of TLR7/8 in cord blood derived (CBMKs) and mouse bone marrow derived megakaryocytes (mMKs). TLR7/8-/- iPSC derived megakaryocytes (iPSC-MKs) were produced using CRISPR Cas9 editing of iPSCs and forward programming using an doxycyclin inducible cassette. GFP labelled SARS-CoV- 2 virus was incubated with the TLR7/8-/- iPSC- MKs and wild-type iPSC-MKs. Result(s): Incubation with GDQ increased platelet production in CBMKs and mMKs, and increased platelet function. Increased platelet counts were seen in mice treated with GDQ, and mice infected with influenza. Incubation with GDQ induced increased expression of IL1beta in the parental iPSC-MKs, however in the TLR7-/- and TLR7/8-/- MKs, no increased expression was observed. There was a significant increase in platelet production from the parental iPSC-MKs in response to incubation with GDQ, which was not seen in the TLR7-/- and TLR7/8-/- MKs. Incubation of the GFP-labelled SARS-CoV- 2 virus with wild-type MKs did not lead to a significant increase in fluorescence. Only very low level viral sequences were found in the cells post-incubation demonstrating that penetration within the MKs is unlikely to be of significance. Studies are ongoing to ascertain whether SARS-CoV- 2 induces outside in signalling leading to changes in transcription within the MKs (such as elevation of IL1beta). Conclusion(s): TLR7/8 agonists, including ssRNA genome viruses, increase platelet production and functionality from megakaryocytes. SARS-CoV- 2 does not appear to penetrate and significantly replicate within MKs, however incubation with megakaryocytes did show elevated expression of IL1beta. (Figure Presented).
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AIM: People may differ in their vaccine-related beliefs (i.e. efficacy, safety, purpose), with a host of factors influencing these differences. This can produce homogeneous groups of individuals who share certain beliefs, attitudes and opinions not only towards vaccines but science and medicine in general. This study aims to characterise distinct subgroups and identify ideal targets for tailored public health interventions to reinforce favourable vaccine beliefs. METHODS: Latent class analysis was used to derive unique profiles using the 2019 Gallup survey of 140 countries. We modelled a composite of vaccine beliefs and regressed this on class membership and relevant covariates. RESULTS: Patterns of item endorsement indicated a well-fitting five-class model, with classes distinguished based on whether individuals sought personal knowledge about science, medicine and health; trusted science and scientists; and reported confidence in the health care system. The lowest levels of vaccine beliefs were reported by a class lacking trust and confidence and the highest levels were reported by a class endorsing trust, confidence and desiring medical and scientific knowledge. Country-level income was moderately related to class membership, and vaccine beliefs were higher in lower-income countries. CONCLUSIONS: Findings suggest that public health campaigns can focus on improving trust in science and medical providers. Efforts to improve vaccination rates can only be achieved when individuals trust science, view the work of scientists as beneficial and hold favourable views towards health care providers. Individuals will then accrue the necessary wisdom to make good health care decisions that affect not only themselves but also their fellow citizens.
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Introduction: Mood disorder is a significant problem following stroke, affecting survivors (approximately 33%) up to 5 years post-stroke. Mindfulness Based Stress Reduction (MBSR) group-based courses are effective in helping people self-manage symptoms of anxiety and depression. In earlier co-creation work we developed HEADS: UP (Helping Ease Anxiety and Depression after Stroke), a 9-week stroke-specific MBSR course designed to mitigate effects of stroke which make mastery of MBSR skills challenging. Methods: In two non-randomised mixed-methods feasibility studies we further adapted HEADS: UP: face-to-face (study 1);online, in response to COVID-19 restrictions (study 2). We used community networks and social media to recruit stroke survivors (SS) with self-reported anxiety and depression. Quantitative and qualitative data were collected pre-/ post-intervention. Both studies received ethical approval. Results: We enrolled 21 community-dwelling participants. Study 1: 13 SS (female n=4, 30.8%;mean age 63.3 years). Study 2: 9 SS (female n=5, 55.6%;mean age 54.2 years). Qualitative data informed changes to research processes and HEADS: UP course materials. Participants found the course accessible and beneficial, “It's helped dramatically;I can't explain how much.” Conclusions: Stroke survivors found a stroke-specific psychological self-management intervention, HEADS: UP (face-to-face, online) acceptable, feasible and beneficial. (Table Presented).
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Background: Social media can be a useful tool in clinical trial recruitment strategy and could become increasingly important as established recruitment methods may be impaired by the COVID-19 pandemic, i.e. flyers, posters. The HEADS: UP randomized control trial utilised multiple social media platforms to access and recruit stroke survivors alongside additional, non-social media routes in response to COVID-19 pandemic restrictions. Aim: To assess the effectiveness of recruitment to the HEADS: UP clinical trial through social media. Methods: We recruited community-dwelling stroke survivors (SS) with self-reported anxiety and depression using community networks and social media. Social media recruitment allowed for direct communication with potential participants through the development of Twitter (@ HeadsUpStroke), YouTube and Reddit accounts. Facebook posts were shared on the researchers' personal accounts and UK-based stroke organization Facebook pages and groups. Results: Recruitment lasted 16 weeks and resulted in 120 leads (7.5/ week). Where recruitment source was known, social media contributed 36 leads (2.3/week). We enrolled 64 participants (female n=36, mean age 56.3 years) of which 28 were recruited through social media (43.8%;female n=15;mean age 53.0 years). Facebook was the most effective route (n=21, 75%). The least effective route was Reddit. One lead contacted the primary investigator using LinkedIn, a platform we had not included in our strategy. Costs totaled £50 (£1.79/enrolled social media participant). Conclusions: The use of social media for recruitment of stroke survivors to a psychological self-management intervention trial was both effective and low-cost, significantly contributing to overall recruitment and supplementing established research methods.
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Although household food insecurity (HFI) has been associated with depressive symptoms in youth and young adults (YYA) with youth-onset diabetes, little is known about the association of HFI with other mental health comorbidities. We examined the association of HFI with stress and anxiety symptoms among YYA with diabetes using cross-sectional data from the SEARCH Food Security Cohort study (assessments conducted 2018-2020;n = 1030, age =23.8± 0.3, female =58.8%, type 1 diabetes (T1D) = 881, type 2 diabetes (T2D) =149) . HFI was defined as 3+ affirmations on the USDA Household Food Security Survey Module. The Generalized Anxiety Disorder (GAD-7) and Cohen's Perceived Stress Scale (PSS-14) were used to assess outcomes of anxiety (score range 0-21) and stress (score range 0-56) , higher scores indicating greater anxiety or stress. Linear regression models were adjusted for age, sex, race/ethnicity, site, diabetes duration, parental education, income, and whether assessment was completed pre/post the coronavirus pandemic. Analyses were stratified by diabetes type. HFI was present in 17.3% of T1D and 35.6 % of T2D. Moderate/severe anxiety symptom scores (range 10-21) were found in 27.5 % (mean=6.9, s.d. =5.5) of T1D and 40.9% (mean=8.4, s.d. =6.5) of T2D. Mean stress scores were 26.7 (s.d.=6.3) for T1D and 27.9 (s.d.=6.3) for T2D. In T1D, HFI was associated with higher anxiety (β=4.8, p=<0.0001) and stress (β=4.9, p=<0.0001) symptom scores compared to those with food security adjusted for covariates. Among T2D, HFI was associated with greater anxiety symptoms (β=2.8, p=0.0247) but no association was observed with stress. These findings suggest that assessing and alleviating HFI may help improve stress and anxiety among YYA with diabetes, and further study is warranted to determine associations over time.
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Background: Korero mai, or storytelling, has long been a part of human nature and within all cultures. To tell or to hear a story can bring to life the challenges we face, tune our moral compass, connect us to others or realise a truth. Encouraging storytelling has a role in exploring well-being matters. Storytelling provides a reflective and a creative space to consider our well-being through the lens of our experiences of the COVID-19 pandemic both professionally and personally. Objectives: To bring together a diverse group of psychiatrists and trainees to tell a story of their choice to shine a light on members' positive outcomes or experiences during the pandemic, the challenges they have faced and their stories of overcoming. Methods: Four to six storytellers will have 10 minutes each to tell their story. Stories may include music, art or multimedia productions. The Chair will contribute to the session by weaving their own and other stories together. Storytellers are anticipated to have some time to talk among themselves about the stories presented. Findings: The creative flow and personal nature of the stories in the symposium will allow attendees a reflective space to consider the often-complex matter of member well-being. The same symposium format was presented at the Royal Australian and New Zealand College of Psychiatrists (RANZCP) Congress in 2019 and 2021. Conclusion: Diversity in the College membership brings a richness to our profession. By providing a forum for members to tell their stories, this symposium hopes to bring creativity, truth and light to the difficult matter of how we manage our occupations and lives via our stories we all carry within.
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Background: Iwi Maori (Maori people) are the Indigenous people of Aotearoa. Some estimates predict that Maori have been occupying the lands of Aotearoa for more than 1000 years. After claiming sovereignty in 1835 with He Whakaputanga (Declaration of Independence) following annexing international interests, Maori signed the Treaty of Waitangi (Te Tiriti o Waitangi) 5 years later to ensure independence, protection, ongoing prosperity and justice. Maori were prosperous, trading, had a strong economy and thriving in all areas of life. Maori knowledge systems and language were mainstream and many Pakeha who settled embraced all aspects of Maori culture including te reo Maori. Our history tells us that Te Tiriti was not honoured and this had catastrophic effects on Maori existence. By the late 1890s the Maori population had nearly been wiped out by infectious illnesses, loss of lands and the encroaching effects of assimilation, colonial shift in power and the disempowerment of Maori. Access to health care is a human right and was protected under treaty rights but successive governments have failed to address inequities. Moving forward to 2021, the Ministry of Health recently announced a new health structure and the establishment of a Maori Health Authority (MHA) to independently advise, commission health services for iwi Maori. Many see this change as transformative and a true act of Tino Rangatiratanga (self-determination). The act of re-Indigenising our health systems landscape may find the solutions to restoring equity. Objectives: To provide a personal reflection of the proposed new health care system reforms with a particular focus of the historical socio-cultural context of Aotearoa and illustrate why these reforms are important and transformative. I want to demystify the ideas and rationale for de-colonisation. I also want to consider the implications for Maori health and the enormous expectations others may have towards Maori solutions and the anticipated critics of the new system. Methods: I will briefly review the historical context of Maori in Aotearoa, the causes of poor mental health (MH) outcomes, why equity is important and why things need to change. I will discuss the most recent independent health reviews, which provides the basis of the new health reforms. Understanding Indigenous concepts like Tino Rangatiratanga and Mana Motuhake will be articulated. Understanding the concept of health and wellness from a Maori perspective will be discussed. Findings: Maori MH incidence and prevalence rates for most health conditions continue to be disproportionately higher than the dominant culture. Like Indigenous Australians, youth suicide rates for Maori remain the highest in the modern world, and other health crises such as COVID-19 can perpetuate these outcomes. Healthcare systems (in Australia and New Zealand), health structures and those in the positions of influence continue to underperform. The new proposed health reforms put Maori health leaders in the frontline in decision-backing processes and delivery: 'Ma Maori, mo Maori - By Maori, for Maori'. Conclusion: The enduring effects of colonisation continue to create inequitable health outcomes for Maori in Aotearoa. The new health reforms proposed may generate needed ideological, philosophical and culturally mandated shifts which align with the intent of Te Tiriti o Waitangi and the achievement of Tino Rangatiratanga and Mana Motuhake. There is now a process to re-empower Maori to find their own solutions to poor health outcomes, to rediscover lost knowledge and indigenise our healthcare system. The effects of the new system should be given time to make a difference.
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The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for the treatment of COVID-19. The potential of 3CLpro-inhibitors to select for drug-resistant variants needs to be established. Therefore SARS-CoV-2 was passaged in vitro in the presence of increasing concentrations of ALG-097161, a probe compound designed in the context of a 3CLpro drug discovery program. We identified a combination of amino acid substitutions in 3CLpro (L50F E166A L167F) that is associated with > 20x increase in EC50 values for ALG-097161, nirmatrelvir (PF-07321332) and PF-00835231. While two of the single substitutions (E166A and L167F) provide low-level resistance to the inhibitors in a biochemical assay, the triple mutant results in the highest levels of resistance (6- to 72-fold). All substitutions are associated with a significant loss of enzymatic 3CLpro activity, suggesting a reduction in viral fitness. Structural biology analysis indicates that the different substitutions reduce the number of inhibitor/enzyme interactions while the binding of the substrate is maintained. These observations will be important for the interpretation of resistance development to 3CLpro inhibitors in the clinical setting.
Subject(s)
COVID-19 , Virus DiseasesABSTRACT
Following the COVID-19 outbreak of March 2020, states imposed mandatory "lockdowns," forcing schools throughout the country to move to virtual learning platforms. With this unprecedented shift came many unforeseen challenges for school officials, including assessing what First Amendment rights students retain in virtual learning platforms. Falling into an unusual gray area where students are technically "in school" because they are attending school-run classes, and yet off campus as they are doing so from the privacy of their homes, school officials have little guidance from the currently established student speech categories to make these determinations. While this issue originally arose out of the unique circumstances surrounding the COVID-19 pandemic, schools will likely continue to face this problem in the future, whether by the uncertain prospect of further school closings as new COVID-19 variants emerge or by schools and students continuing to take advantage of the convenience and safety provided by online platforms. This Note focuses on the intersection of existing student First Amendment rights both on and off campus and the constitutional protections afforded to speech and expression within the home. Ultimately, this Note concludes that there is no one-size-fits-all test that can be applied to all aspects of the virtual learning platform. While schools arguably must have some authority to limit student expression within virtual learning platforms, that authority must be balanced with students' First Amendment rights. The two central problems posed by virtual learning platforms, virtual backgrounds and physical backgrounds, require a unique solution to balance protection of students' rights and respect for a school's authority. This Note argues that schools should wield far more authority over students' virtual backgrounds and less authority over their physical backgrounds. To control physical backgrounds, school officials must presume students are entitled to First Amendment protection over student expression subject to only few exceptions in specific categories of speech. Virtual backgrounds, on the other hand, do not exist outside of the virtual class, and thus do not implicate the same First Amendment and privacy concerns. This bifurcated solution thus accounts for the nature of virtual learning environments and balances school authority with not only students' First Amendment rights but also students' privacy rights, students' autonomy, and the authority of students' parents to control their homelife. © 2021 Boston University Law Review. All rights reserved.
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U.S. non-citizen residents are burdened by inequitable access to socioeconomic resources, potentially placing them at heightened risk of COVID-19-related disparities. However, COVID-19 impacts on non-citizens are not well understood. Accordingly, the current study investigated COVID-19 mortality disparities within New York (NYC) and Los Angeles (LAC) to test our hypothesis that areas with large proportions of non-citizens will have disproportionately high COVID-19 mortality rates. We examined ecological associations between March 2020-January 2021 COVID-19 mortality rates (per 100,000 residents) and percent non-citizens (using ZIP Code Tabulation Areas (ZCTA) for NYC and City/Community units of analysis for LAC) while controlling for sociodemographic factors. Multiple linear regression analyses revealed significant positive associations between the percentage of non-citizen residents and COVID-19 mortality rates in NYC (95% CI 0.309, 5.181) and LAC (95% CI 0.498, 8.720). Despite NYC and LAC policies intended to provide sanctuary and improve healthcare access for non-citizen residents, communities with larger proportions of non-citizens appear to endure higher COVID-19 mortality rates. The challenges that non-citizens endure-e.g., inequitable access to public benefits-may discourage help-seeking behaviors. Thus, improved health surveillance, public health messaging, and sanctuary policies will be essential for reducing COVID-19 mortality disparities in communities with large shares of non-citizens.