Exploring the Landscape of Aptamers: From Cross-Reactive to Selective to Specific, High-Affinity Receptors for Cocaine.

We reported over 20 years ago MNS-4.1, the first DNA aptamer with a micromolar affinity for cocaine. MNS-4.1 is based on a structural motif that is very common in any random pool of oligonucleotides, and it is actually a nonspecific hydrophobic receptor with wide cross-reactivity with alkaloids and steroids. Despite such weaknesses preventing broad applications, this aptamer became widely used in proof-of-concept demonstrations of new formats of biosensors. We now report a series of progressively improved DNA aptamers recognizing cocaine, with the final optimized receptors having low nanomolar affinity and over a thousand-fold selectivity over the initial cross-reactants. In the process of optimization, we tested different methods to eliminate cross-reactivities and improve affinity, eventually achieving properties that are comparable to those of the reported monoclonal antibody candidates for the therapy of overdose. Multiple aptamers that we now report share structural motifs with the previously reported receptor for serotonin. Further mutagenesis studies revealed a palindromic, highly adaptable, broadly cross-reactive hydrophobic motif that could be rebuilt through mutagenesis, expansion of linker regions, and selections into receptors with exceptional affinities and varying specificities.

The impacts of migraine on functioning: Results from two qualitative studies of people living with migraine.

OBJECTIVE: To describe the impact of migraine on functioning based on comprehensive data collection, analysis, and reporting of patients' experiences. BACKGROUND: Qualitative research conducted to understand patients' perspectives on living with migraine has often focused on narrow topics or specific groups of patients or has been selectively reported. METHODS: Qualitative interviews with 71 participants were conducted during two concept elicitation studies as part of the Migraine Clinical Outcome Assessment System (MiCOAS) project, an FDA grant-funded program designed to develop a core set of patient-centered outcome measures for migraine clinical trials. Participants self-reported being diagnosed with migraine by a healthcare professional and participated in semi-structured qualitative interviews about their experiences with the symptoms and impacts of migraine. Interview transcripts were coded to identify and define concepts, which were then grouped into broad domains based on conceptual similarities. RESULTS: A total of 66 concepts were identified: 12 for physical functioning, 16 for cognitive functioning, 10 for social role functioning, 19 for emotional and psychological functioning, and 9 related to migraine management. Participants described a complex and varied relationship between migraine attack symptoms and impacts on functioning. Impacts from migraine were further influenced by numerous contextual factors, such as people's individual social environments and the level of day-to-day demand for functioning they face. CONCLUSION: Findings showed that migraine impacted individual functioning in multiple ways and the nature of these impacts was dependent on social-contextual factors. The results are being used in the development of core measures designed to improve our understanding of the burden of migraine and the efficacy of migraine therapies. The results also offer new insights and raise new questions about migraine experience that can be used to guide future research.

Pediatric COVID-19 Hospitalizations During the Omicron Surge.

BACKGROUND: Treatment recommendations for children hospitalized with COVID-19 during the winter 2021-2022 omicron variant surge included remdesivir and dexamethasone for hypoxia and remdesivir for patients at risk of severe illness, including those with comorbidities. The omicron variant caused many otherwise-healthy children without hypoxia to be hospitalized for common viral syndromes like croup. This study aimed to characterize children hospitalized with COVID-19 during the omicron surge and describe their management and clinical trajectory. METHODS: This single-center retrospective study included patients under 19 years old with a COVID-19 discharge diagnosis on the Pediatric Hospital Medicine service in January and February 2022. Hypoxia was defined by sustained oxygen saturation greater than 90%. Primary outcome was return to emergency department or readmission within 14 days. Secondary outcomes were length of stay, multisystem inflammatory syndrome within 6 weeks, and death. RESULTS: During the study time frame, 111 children were hospitalized with COVID-19, including 35 who had an incidental COVID-19 result. In the remaining 76 patients, the median length of stay was 1.9 days (1.0 - 3.3). Eight patients (11%) returned to the emergency department or were readmitted within 14 days of discharge; 3 of the emergency department visits were related to ongoing COVID-19 infection. Of the 10 patients with croup, 1 received remdesivir due to prolonged illness, and none returned to the emergency department or were readmitted. DISCUSSION: Most children hospitalized with COVID-19 were young, previously healthy and unvaccinated for COVID-19 due to age-based ineligibility. Hypoxia was the most common indication for use of remdesivir/corticosteroids (25%). Return to the emergency department for ongoing COVID-19 symptoms was uncommon (4%). Patients with croup, a presentation seen more commonly with the omicron variant than previously, appeared to do well without remdesivir.