Lipid nanoparticle library towards development next generation genomic medicines

Ionizable amino lipids are a major constituent of the lipid nanoparticles for delivering nucleic acid therapeutics (e.g., DLin-MC3-DMA in ONPATTRO , ALC-0315 in Comirnaty , SM-102 in Spikevax ). Scarcity of lipids that are suitable for cell therapy, vaccination, and gene therapies continue to be a problem in advancing many potential diagnostic/therapeutic/vaccine candidates to the clinic. Herein, we describe the development of novel ionizable lipids to be used as functional excipients for designing vehicles for nucleic acid therapeutics/vaccines in vivo or ex vivo use in cell therapy applications. We first studied the transfection efficiency (TE) of LNP-based mRNA formulations of these ionizable lipid candidates in primary human T cells and established a workflow for engineering of primary immune T cells. We then adapted this workflow towards bioengineering of CAR constructs to T cells towards non-viral CAR T therapy. Lipids were also tested in rodents for vaccine applications using self-amplifying RNA (saRNA) encoding various antigens. We have then evaluated various ionizable lipid candidates and their biodistribution along with the mRNA/DNA translation exploration using various LNP compositions. Further, using ionizable lipids from the library, we have shown gene editing of various targets in rodents. We believe that these studies will pave the path to the advancement in nucleic acid based therapeutics and vaccines, or cell gene therapy agents for early diagnosis and detection of cancer, and for targeted genomic medicines towards cancer treatment and diagnosis.

Psychosocial stressors of parenting and the postpartum period during COVID-19

Objective: Pandemic-related changes produced a major shift for parental roles, responsibilities, and expectations. Our objective was to identify parenting challenges experienced by low-income postpartum mothers during a global pandemic lockdown. Study Design: In this qualitative investigation, we conducted semi-structured interviews with 40 postpartum individuals who gave birth in a single center in Chicago in the first three months of the COVID-19 pandemic (January-March 2020). Interviews addressed issues related to maternal health and well-being, including parental stress, limited access to essential goods, and COVID-related barriers to providing for children. All interviews were conducted via phone, transcribed, and analyzed using the constant comparative method. Results: Of the 40 participants, 50% (n=20) identified as non-Hispanic Black and 38% (n=15) as Hispanic;75% (n=30) were parents of multiple children. The primary parenting-related themes included challenges of parenting multiple children, barriers to self-care, and novel barriers to providing for children (Table). Subthemes within challenges of parenting multiple children include new role as an educator, struggle with entertaining, and time allocation. The barriers to self-care subthemes included lack of free time, changes in self-care and coping strategies, and effects on maternal mental health. The novel barriers to providing for children subthemes included lack of communal support, financial stress, and difficulty obtaining essential needs. Conclusion: Obstetric providers are often a first-line point of contact for postpartum individuals and may benefit from understanding how psychosocial stressors experienced during the pandemic may negatively affect maternal health. Our findings suggest new psychosocial burdens were introduced by the pandemic that challenged individual health and wellbeing during the postpartum period. Findings can inform interventions, which may include enhanced support from the clinical team or connections to community resources, to alleviate postpartum challenges for mothers and their families. [Formula presented]

Kaposi sarcoma of the larynx, an unusual encounter

Kaposi Sarcoma is a low-grade malignant mesenchymal neoplasm commonly associated with acquired immunodeficiency syndrome (AIDS). It primarily affects the cutaneous layer of the face and extremities and also oropharyngeal mucosa. Involvement of the larynx is somewhat unusual, with sparse information in the English literature. Herein, the author reported a case of a 27-year-old gentleman with Human immunodeficiency virus (HIV) on HAART treatment, who presented with progressive dysphonia and globus sensation of 1-month duration. In addition to the multiple purplish raised papules over his right forearm, a similar violaceous lesion was observed arising from the lingual surface of the epiglottis via flexible bedside laryngoscopy. Biopsy of the lesions confirmed the diagnosis of Kaposi Sarcoma. The clinical conundrum of managing this case was well illustrated with the concurrent diagnosis of COVID-19 in him. Detailed counselling on the treatment options of the laryngeal lesion was arranged, involving a multidisciplinary approach. The patient then opted for concurrent chemoradiotherapy. Chemotherapy offers the benefit of laryngeal preservation in Kaposi sarcoma involving the larynx and may be considered as a treatment option in patients with high risk of surgical intervention.

Quality of home spirometry performance amongst adults with cystic fibrosis

Introduction/Aim: Spirometry is usually performed under the supervision of a trained respiratory scientist to ensure acceptability and repeatability of results as outlined by the 2019 American Thoracic Society and European Respiratory Society Statement. With increased telehealth consultations during the COVID-19 pandemic, remote monitoring of lung function is encouraged at Cystic Fibrosis (CF) centres. Evaluate the quality of spirometry performance by adult CF patients with and without observation by a trained respiratory scientist. Methods: An observational, cross-sectional, single-centre study was conducted between February-September 2020. 74 adults from the Royal Prince Alfred Hospital Adult CF clinic were recruited and instructed to perform spirometry without supervision within 24 hours of their remote CF clinic consultation. Spirometry was repeated at their consultation, supervised by a respiratory scientist using video conferencing. The same portable spirometer was used during both encounters. Spirometry grade was recorded from their portable devices and severity of obstruction (mild: FEV1 >80%, moderate: FEV1 50-80%, severe: FEV1 <50%) was obtained from their supervised encounter Results: 15, 30 and 29 participants with mild, moderate and severe obstruction respectively participated in the study (total n=74, mean age 37±11 years, 50% female, completed year 12 62, 83.7%, employed 56, 78%). The majority of patients achieved ATS/ERS grade A (excellent) or B (very good) spirometry quality with (95%) and without supervision (91%) independent of lung function severity or age. Participants with poorer grades (C-F) either experienced technical difficulties with their devices or failed to perform a sufficient number of manoeuvres. No patients required carer assistance to perform spirometry remotely. Remote spirometry was performed at home (60, 84.5%), work (2, 2.8%), or the local general practitioner's (1, 1.4%) clinic. Conclusion: For a large proportion of adult CF patients, unsupervised portable spirometry produces acceptable and repeatable results. On-going monitoring for technical difficulties may be needed.