Iterative Design of Ionizable Lipids for Intramuscular mRNA Delivery.

Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicles for RNA and have enabled the development of RNA-based drugs such as the mRNA COVID-19 vaccines. Functional delivery of mRNA by an LNP greatly depends on the inclusion of an ionizable lipid, and small changes to these lipid structures can significantly improve delivery. However, the structure-function relationships between ionizable lipids and mRNA delivery are poorly understood, especially for LNPs administered intramuscularly. Here, we show that the iterative design of a novel series of ionizable lipids generates key structure-activity relationships and enables the optimization of chemically distinct lipids with efficacy that is on-par with the current state of the art. We find that the combination of ionizable lipids comprising an ethanolamine core and LNPs with an apparent pKa between 6.6 and 6.9 maximizes intramuscular mRNA delivery. Furthermore, we report a nonlinear relationship between the lipid-to-mRNA mass ratio and protein expression, suggesting that a critical mass ratio exists for LNPs and may depend on ionizable lipid structure. Our findings add to the mechanistic understanding of ionizable lipids and demonstrate that hydrogen bonding, ionization behavior, and lipid-to-mRNA mass ratio are key design parameters affecting intramuscular mRNA delivery. We validate these insights by applying them to the rational design of new ionizable lipids. Overall, our iterative design strategy efficiently generates potent ionizable lipids. This hypothesis-driven method reveals structure-activity relationships that lay the foundation for the optimization of ionizable lipids in future LNP-RNA drugs. We foresee that this design strategy can be extended to other optimization parameters beyond intramuscular expression.

Urology Residency Applications in the COVID-19 Era.

OBJECTIVE: To evaluate urology applicants' opinions about the interview process during the COVID-19 pandemic. MATERIAL AND METHODS: An anonymous survey was emailed to applicants to our institution from the 2019 and 2020 urology matches prior to issuance of professional organization guidelines. The survey inquired about attitudes toward the residency interview process in the era of COVID-19 and which interview elements could be replicated virtually. Descriptive statistics were utilized. RESULTS: Eighty percent of urology applicants from the 2019 and 2020 matches received our survey. One hundred fifty-six people (24% of recipients) responded. Thirty-four percent preferred virtual interviews, while 41% in-person interviews at each program, and 25% regional/centralized interviews. Sixty-four percent said that interactions with residents (pre/postinterview social and informal time) were the most important interview day component and 81% said it could not be replicated virtually. Conversely, 81% believed faculty interviews could be replicated virtually. Eighty-seven percent believed that city visits could not be accomplished virtually. A plurality felt that away rotations and second-looks should be allowed (both 45%). COMMENT: Applicants feel that faculty interviews can be replicated virtually, while resident interactions cannot. Steps such as a low-stakes second looks after programs submit rank lists (potentially extending this window) and small virtual encounters with residents could ease applicant concerns. CONCLUSION: Applicants have concerns about changes to the match processes. Programs can adopt virtual best practices to address these issues.

Family functioning under COVID-19: An ecological perspective of family resilience of Hong Kong Chinese families.

This study tested an ecological model of resilience that illustrated the influence of COVID-19-related stressors (i.e., social and health stressors) and various socio-ecological factors at microsystem (i.e., parent-child conflicts and couple relationship) and exo-system levels (i.e., the utilization of community resources) on family functioning among Chinese families during COVID-19. An anonymous telephone survey was conducted using random sampling method. The sample contained 322 respondents who were co-habiting with their child(ren) and their partner. Hierarchical regression analysis and structural equation modelling were used to examine the differential impacts of various levels of factors and the model that were proposed. Results showed that 13.2% of the households were categorized as at-risk of poorer family functioning. Couple relationship and stressors significantly accounted for much of the variance in family functioning. While stressors had a significant direct effect on family functioning, couple relationship, but not parent-child conflicts or utilization of community resources, significantly mediated and moderated the impact of stressors on family functioning. The findings highlighted the impacts of both individual and ecological factors on family functioning under COVID-19. Importantly, cultural and contextual factors should be considered when adopting ecological model of resilience to examine family functioning in diverse cultural groups.

High attack rate in a Tong Lau house outbreak of COVID-19 with subdivided units in Hong Kong.

Poor housing conditions are known to be associated with infectious diseases such as high Coronavirus disease 2019 (COVID-19) incidences. Transmission causes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in poor housing conditions can be complex. An understanding of the exact mechanism of transmission can help to pinpoint contributing environmental issues. Here, we investigated a Hong Kong COVID-19 outbreak in early 2021 in four traditional Tong Lau houses with subdivided units. There are more than 80 subdivided units of less than 20 m2 floor area each on average. With a total of 34 confirmed COVID-19 cases, the outbreak had an attack rate of 25.4%, being one of the highest attack rates observed in Hong Kong, and ranked among the highest attack rates in reported outbreaks internationally. Tracer gas leakage and decay measurements were performed in the drainage system and in the subdivided units to determine the transport of infectious aerosols by the owner-modified sophisticated wastewater drainage pipe networks and the poor ventilation conditions in some subdivided units. The results show that the outbreak was probably due to multiple transmission routes, i.e. by the drainage pipe spread of stack aerosols, which is enhanced by poor ventilation in the subdivided units.

Telemedicine in urogynaecology during COVID-19 in Hong Kong: An assessment of Chinese patients' acceptability using a validated questionnaire.

AIMS: There is no urogynaecology teleconsultation services available in Hong Kong's public health system. This cross-sectional study aimed to assess Chinese womens' acceptance of teleconsultations during the COVID-19 pandemic using the validated Telemedicine Perception Questionnaire (TMPQ). MATERIALS AND METHODS: One hundred and fifty-one patients attending our urogynaecology clinic between February and March 2021 were recruited for an in-person interview. Patients who could not comprehend the questionnaire due to neurological or psychiatric conditions were excluded. TMPQ is a 17-item, five-point Likert scale questionnaire developed to assess the acceptability of telemedicine. Scores range from 17 to 85; a higher score reflects a more positive overall perception of telemedicine. Additional questions on demographics, medical history, Internet access and transport arrangements were included. RESULTS: Mean age was 67.5 ± 11.3 years. Mean TMPQ score was 53.93 ± 8.49. Younger age, higher education, employment, prior telecommunication platform usage, lower travelling costs and interest in telemedicine were associated with a higher TMPQ score (P < 0.05). Multiple linear regression analysis found age (ß = -0.132, 95% CI (confidence interval): -0.225 to -0.04), interest in telemedicine (ß = 10.169, 95% CI: 8.073-12.266) and post-operative status (ß = 4.743, 95% CI: 1.172-8.314) significantly predicted TMPQ score (adjusted R2  = 0.427). CONCLUSIONS: Our study found that the acceptability of telemedicine in Hong Kong was weak and identified patient groups that showed favourable attitudes. Future research directions would be to perform pilot studies to assess any change in perception after using telemedicine so that this service can be provided to patient groups who would benefit most, ensuring effective use of public resources.

Predominance of antibody-resistant SARS-CoV-2 variants in vaccine breakthrough cases from the San Francisco Bay Area, California.

Associations between vaccine breakthrough cases and infection by different SARS coronavirus 2 (SARS-CoV-2) variants have remained largely unexplored. Here we analysed SARS-CoV-2 whole-genome sequences and viral loads from 1,373 persons with COVID-19 from the San Francisco Bay Area from 1 February to 30 June 2021, of which 125 (9.1%) were vaccine breakthrough infections. Vaccine breakthrough infections were more commonly associated with circulating antibody-resistant variants carrying ≥1 mutation associated with decreased antibody neutralization (L452R/Q, E484K/Q and/or F490S) than infections in unvaccinated individuals (78% versus 48%, P = 1.96 × 10-8). Differences in viral loads were non-significant between unvaccinated and fully vaccinated cases overall (P = 0.99) and according to lineage (P = 0.09-0.78). Symptomatic vaccine breakthrough infections had comparable viral loads (P = 0.64), whereas asymptomatic breakthrough infections had decreased viral loads (P = 0.023) compared with infections in unvaccinated individuals. In 5 cases with serial samples available for serologic analyses, vaccine breakthrough infections were found to be associated with low or undetectable neutralizing antibody levels attributable to an immunocompromised state or infection by an antibody-resistant lineage. Taken together, our results show that vaccine breakthrough infections are overrepresented by antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may be as efficient in spreading COVID-19 as unvaccinated infections, regardless of the infecting lineage.

Aerosol transmission of SARS-CoV-2 due to the chimney effect in two high-rise housing drainage stacks.

Stack aerosols are generated within vertical building drainage stacks during the discharge of wastewater containing feces and exhaled mucus from toilets and washbasins. Fifteen stack aerosol-related outbreaks of coronavirus disease 2019 (COVID-19) in high-rise buildings have been observed in Hong Kong and Guangzhou. Currently, we investigated two such outbreaks of COVID-19 in Hong Kong, identified the probable role of chimney effect-induced airflow in a building drainage system in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We injected tracer gas (SF6) into the drainage stacks via the water closet of the index case and monitored tracer gas concentrations in the bathrooms and along the facades of infected and non-infected flats and in roof vents. The air temperature, humidity, and pressure in vertical stacks were also monitored. The measured tracer gas distribution agreed with the observed distribution of the infected cases. Phylogenetic analysis of the SARS-CoV-2 genome sequences demonstrated clonal spread from a point source in cases along the same vertical column. The stack air pressure and temperature distributions suggested that stack aerosols can spread to indoors through pipe leaks which provide direct evidence for the long-range aerosol transmission of SARS-CoV-2 through drainage pipes via the chimney effect.

Risk and resilience of vulnerable families in Hong Kong under the impact of COVID-19: an ecological resilience perspective.

PURPOSE: Hong Kong has experienced four waves of COVID-19 since the first case was confirmed in January 2020. Several studies have highlighted the psychological impacts of the outbreak in Hong Kong but have largely ignored the protective factors that contribute to resilience among vulnerable families. This study adopted an ecological resilience framework to explore the impact of this epidemic on members of families with youth with a delinquent tendency/mental health concerns and the ecological protective factors for these vulnerable families. METHODS: Random sampling based on a sampling frame provided by one of the largest local social service organizations in Hong Kong led to the recruitment of 407 respondents who were interviewed using a battery of standardized questionnaires. RESULTS: The results showed that 30.6% and 11.5% of respondents reported a moderate and a severe level of psychological distress, respectively, almost double the percentages reported in a previous study conducted in Hong Kong before the COVID-19 outbreak. Around 36.6% of respondents indicated they had encountered financial problems and almost 40% indicated aggravated financial circumstances since the outbreak. Hierarchical regression analysis revealed that financial stress was the strongest predictor of psychological distress. Structural equation modeling indicated that family support, indoor leisure activities and community resources significantly mediated the negative influence of COVID-19-related stressors on psychological distress of family members. CONCLUSION: Family leisure activities, family support, community spirit and mutual help within the context of social-distancing restrictions may need to be promoted to benefit vulnerable families in Hong Kong under the COVID-19 epidemic.

Telemedicine During COVID-19 and Beyond: A Practical Guide and Best Practices Multidisciplinary Approach for the Orthopedic and Neurologic Pain Physical Examination.

BACKGROUND: The COVID pandemic has impacted almost every aspect of human interaction, causing global changes in financial, health care, and social environments for the foreseeable future. More than 1.3 million of the 4 million cases of COVID-19 confirmed globally as of May 2020 have been identified in the United States, testing the capacity and resilience of our hospitals and health care workers. The impacts of the ongoing pandemic, caused by a novel strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have far-reaching implications for the future of our health care system and how we deliver routine care to patients. The adoption of social distancing during this pandemic has demonstrated efficacy in controlling the spread of this virus and has been the only proven means of infection control thus far. Social distancing has prompted hospital closures and the reduction of all non-COVID clinical visits, causing widespread financial despair to many outpatient centers. However, the need to treat patients for non-COVID problems remains important despite this pandemic, as care must continue to be delivered to patients despite their ability or desire to report to outpatient centers for their general care. Our national health care system has realized this need and has incentivized providers to adopt distance-based care in the form of telemedicine and video medicine visits. Many institutions have since incorporated these into their practices without financial penalty because of Medicare's 1135 waiver, which currently reimburses telemedicine at the same rate as evaluation and management codes (E/M Codes). Although the financial burden has been alleviated by this policy, the practitioner remains accountable for providing proper assessment with this new modality of health care delivery. This is a challenge for most physicians, so our team of national experts has created a reference guide for musculoskeletal and neurologic examination selection to retrofit into the telemedicine experience. OBJECTIVES: To describe and illustrate musculoskeletal and neurologic examination techniques that can be used effectively in telemedicine. STUDY DESIGN: Consensus-based multispecialty guidelines. SETTING: Tertiary care center. METHODS: Literature review of the neck, shoulder, elbow, wrist, hand, lumbar, hip, and knee physical examinations were performed. A multidisciplinary team comprised of physical medicine and rehabilitation, orthopedics, rheumatology, neurology, and anesthesia experts evaluated each examination and provided consensus opinion to select the examinations most appropriate for telemedicine evaluation. The team also provided consensus opinion on how to modify some examinations to incorporate into a nonhealth care office setting. RESULTS: Sixty-nine examinations were selected by the consensus team. Household objects were identified that modified standard and validated examinations, which could facilitate the examinations.The consensus review team did not believe that the modified tests altered the validity of the standardized tests. LIMITATIONS: Examinations selected are not validated for telemedicine. Qualitative and quantitative analyses were not performed. CONCLUSIONS: The physical examination is an essential component for sound clinical judgment and patient care planning. The physical examinations described in this manuscript provide a comprehensive framework for the musculoskeletal and neurologic examination, which has been vetted by a committee of national experts for incorporation into the telemedicine evaluation.

The use of personal protective equipment in clinical ophthalmology during corona virus disease-2019: a review of international guidelines and literature.

PURPOSE OF REVIEW: The use of nonpharmaceutical interventions can prevent viral spread in COVID-19 pandemic and PPE forms a crucial part of this strategy. However, there are discrepancies in existing guidelines and a lack of consensus among ophthalmic communities. This review aims to identify general consensus and provides recommendation of PPE for most common ophthalmological scenarios. With a global shortage of PPE, extended use and reuse strategies are also discussed. RECENT FINDINGS: In this review, guidelines and resources were selected, based on a three-tier process. The first-tier resources were from international infection control organizations. The second-tier resources were from ophthalmological professional associations and colleges. The third-tier resources involved a PubMed search using the keywords 'COVID-19; coronavirus; personal protective equipment' performed on 1 May 2020. Non-English guidelines and literatures were excluded. SUMMARY: On the basis of our methodology, we included a total of 30 documents, including 5 resources from tier 1, 14 resources from tier 2 and 15 from tier 3. Different levels of protection are necessary. Whenever performing an aerosol generating procedure, maximum protection should be ensured, this includes FFP3 respirator, fluid resistant gown, goggles or face-shield and disposable gloves. Similar protection should be used for handling COVID-19-positive/suspected case but the use of FFP2 respirator is acceptable. During routine outpatient clinic in cases of negative triage, it is recommended to use ASTM III surgical mask, plastic apron, disposable gloves and eye protection with goggles or face-shield. Lastly, patients should be encouraged to wear surgical masks whenever possible.