In-Hospital Delirium and Disability and Cognitive Impairment After COVID-19 Hospitalization.

Importance: Older adults who are hospitalized for COVID-19 are at risk of delirium. Little is known about the association of in-hospital delirium with functional and cognitive outcomes among older adults who have survived a COVID-19 hospitalization. Objective: To evaluate the association of delirium with functional disability and cognitive impairment over the 6 months after discharge among older adults hospitalized with COVID-19. Design, Setting, and Participants: This prospective cohort study involved patients aged 60 years or older who were hospitalized with COVID-19 between June 18, 2020, and June 30, 2021, at 5 hospitals in a major tertiary care system in the US. Follow-up occurred through January 11, 2022. Data analysis was performed from December 2022 to February 2024. Exposure: Delirium during the COVID-19 hospitalization was assessed using the Chart-based Delirium Identification Instrument (CHART-DEL) and CHART-DEL-ICU. Main Outcomes and Measures: Primary outcomes were disability in 15 functional activities and the presence of cognitive impairment (defined as Montreal Cognitive Assessment score <22) at 1, 3, and 6 months after hospital discharge. The associations of in-hospital delirium with functional disability and cognitive impairment were evaluated using zero-inflated negative binominal and logistic regression models, respectively, with adjustment for age, month of follow-up, and baseline (before COVID-19) measures of the respective outcome. Results: The cohort included 311 older adults (mean [SD] age, 71.3 [8.5] years; 163 female [52.4%]) who survived COVID-19 hospitalization. In the functional disability sample of 311 participants, 49 participants (15.8%) experienced in-hospital delirium. In the cognition sample of 271 participants, 31 (11.4%) experienced in-hospital delirium. In-hospital delirium was associated with both increased functional disability (rate ratio, 1.32; 95% CI, 1.05-1.66) and increased cognitive impairment (odds ratio, 2.48; 95% CI, 1.38-4.82) over the 6 months after discharge from the COVID-19 hospitalization. Conclusions and Relevance: In this cohort study of 311 hospitalized older adults with COVID-19, in-hospital delirium was associated with increased functional disability and cognitive impairment over the 6 months following discharge. Older survivors of a COVID-19 hospitalization who experience in-hospital delirium should be assessed for disability and cognitive impairment during postdischarge follow-up.

Associations of Social Support With Physical and Mental Health Symptom Burden After COVID-19 Hospitalization Among Older Adults.

BACKGROUND: Despite significant support system disruptions during the coronavirus 2019 (COVID-19) pandemic, little is known about the relationship between social support and symptom burden among older adults following COVID-19 hospitalization. METHODS: From a prospective cohort of 341 community-living persons aged ≥60 years hospitalized with COVID-19 between June 2020 and June 2021 who underwent follow-up at 1, 3, and 6 months after discharge, we identified 311 participants with ≥1 follow-up assessment. Social support prehospitalization was ascertained using a 5-item version of the Medical Outcomes Study Social Support Survey (range, 5-25), with low social support defined as a score ≤15. At hospitalization and each follow-up assessment, 14 physical symptoms were assessed using a modified Edmonton Symptom Assessment System inclusive of COVID-19-relevant symptoms. Mental health symptoms were assessed using Patient Health Questionnaire-4. Longitudinal associations between social support and physical and mental health symptoms, respectively, were evaluated through multivariable regression. RESULTS: Participants' mean age was 71.3 years (standard deviation, 8.5), 52.4% were female, and 34.2% were of Black race or Hispanic ethnicity. 11.8% reported low social support. Over the 6-month follow-up period, low social support was independently associated with higher burden of physical symptoms (adjusted rate ratio [aRR], 1.26; 95% confidence interval [CI], 1.05-1.52), but not mental health symptoms (aRR, 1.14; 95% CI, 0.85-1.53). CONCLUSIONS: Low social support is associated with greater physical, but not mental health, symptom burden among older survivors of COVID-19 hospitalization. Our findings suggest a potential need for social support screening and interventions to improve post-COVID-19 symptom management in this vulnerable group.

Rationale, Design, and Characteristics of the VALIANT (COVID-19 in Older Adults: A Longitudinal Assessment) Cohort.

BACKGROUND: Most older adults hospitalized with COVID-19 survive their acute illness. The impact of COVID-19 hospitalization on patient-centered outcomes, including physical function, cognition, and symptoms, is not well understood. To address this knowledge gap, we collected longitudinal data about these issues from a cohort of older survivors of COVID-19 hospitalization. METHODS: We undertook a prospective study of community-living persons age ≥ 60 years who were hospitalized with COVID-19 from June 2020-June 2021. A baseline interview was conducted during or up to 2 weeks after hospitalization. Follow-up interviews occurred at one, three, and six months post-discharge. Participants completed comprehensive assessments of physical and cognitive function, symptoms, and psychosocial factors. An abbreviated assessment could be performed with a proxy. Additional information was collected from the electronic health record. RESULTS: Among 341 participants, the mean age was 71.4 (SD 8.4) years, 51% were women, and 37% were of Black race or Hispanic ethnicity. Median length of hospitalization was 8 (IQR 6-12) days. All but 4% of participants required supplemental oxygen, and 20% required care in an intensive care unit or stepdown unit. At enrollment, nearly half (47%) reported at least one preexisting disability in physical function, 45% demonstrated cognitive impairment, and 67% were pre-frail or frail. Participants reported a mean of 9 of 14 (SD 3) COVID-19-related symptoms. At the six-month follow-up interview, more than a third of participants experienced a decline from their pre-hospitalization function, nearly 20% had cognitive impairment, and burdensome symptoms remained highly prevalent. CONCLUSIONS: We enrolled a diverse cohort of older adults hospitalized with COVID-19 and followed them after discharge. Functional decline was common, and there were high rates of persistent cognitive impairment and symptoms. Future analyses of these data will advance our understanding of patient-centered outcomes among older COVID-19 survivors.

Anti-PEG antibodies alter the mobility and biodistribution of densely PEGylated nanoparticles in mucus.

UNLABELLED: Antibodies that specifically bind polyethylene glycol (PEG) can lead to rapid elimination of PEGylated therapeutics from the systemic circulation. We have recently shown that virus-binding IgG can immobilize viruses in mucus via multiple low-affinity crosslinks between IgG and mucins. However, it remains unclear whether anti-PEG antibodies in mucus may also alter the penetration and consequently biodistribution of PEGylated nanoparticles delivered to mucosal surfaces. We found that both anti-PEG IgG and IgM can readily bind nanoparticles that were densely coated with PEG polymer to minimize adhesive interactions with mucus constituents. Addition of anti-PEG IgG and IgM into mouse cervicovaginal mucus resulted in extensive trapping of mucus-penetrating PEGylated nanoparticles, with the fraction of mobile particles reduced from over 95% to only 34% and 7% with anti-PEG IgG and IgM, respectively. Surprisingly, we did not observe significant agglutination induced by either antibody, suggesting that particle immobilization is caused by adhesive crosslinks between mucin fibers and IgG or IgM bound to individual nanoparticles. Importantly, addition of corresponding control antibodies did not slow the PEGylated nanoparticles, confirming anti-PEG antibodies specifically bound to and trapped the PEGylated nanoparticles. Finally, we showed that trapped PEGylated nanoparticles remained largely in the luminal mucus layer of the mouse vagina even when delivered in hypotonic formulations that caused untrapped particles to be drawn by the flow of water (advection) through mucus all the way to the epithelial surface. These results underscore the potential importance of elucidating mucosal anti-PEG immune responses for PEGylated therapeutics and biomaterials applied to mucosal surfaces. STATEMENT OF SIGNIFICANCE: PEG, generally considered a 'stealth' polymer, is broadly used to improve the circulation times and therapeutic efficacy of nanomedicines. Nevertheless, there is increasing scientific evidence that demonstrates both animals and humans can generate PEG-specific antibodies. Here, we show that anti-PEG IgG and IgM can specifically immobilize otherwise freely diffusing PEG-coated nanoparticles in fresh vaginal mucus gel ex vivo by crosslinking nanoparticles to the mucin mesh, and consequently prevent PEG-coated nanoparticles from accessing the vaginal epithelium in vivo. Given the increasing use of PEG coatings to enhance nanoparticle penetration of mucosal barriers, our findings demonstrate that anti-PEG immunity may be a potential concern not only for systemic drug delivery but also for mucosal drug delivery.

Nanoparticles coated with high molecular weight PEG penetrate mucus and provide uniform vaginal and colorectal distribution in vivo.

AIM: We previously reported that nanoparticles (NPs) coated with 10 kDa PEG were mucoadhesive. Here, we demonstrate that by increasing the surface density, PEG with molecular weight (MW) as high as 40 kDa can be used as a mucoinert NP surface coating. MATERIALS & METHODS: We compared two sets of reaction conditions for coating model polystyrene NPs with 10 kDa PEG and used optimized conditions to coat NPs with PEG as high as 40 kDa in MW. We then characterized NP transport in human cervicovaginal mucus ex vivo. We further administered PEG-coated NPs to the mouse cervicovaginal tract and colorectum to assess mucosal distribution in vivo. RESULTS & CONCLUSION: We demonstrate here that PEG with MW as high as 40 kDa can be densely grafted to the surface of NP to prevent interactions with mucus. NP coated with 10-40 kDa PEG rapidly diffused through human cervicovaginal mucus ex vivo, and uniformly lined the mouse colorectal and vaginal epithelium in vivo.

Enema ion compositions for enhancing colorectal drug delivery.

Delivering drugs to the colorectum by enema has advantages for treating or preventing both local and systemic diseases. However, the properties of the enema itself are not typically exploited for improving drug delivery. Sodium ions are actively pumped out of the lumen of the colon, which is followed by osmotically-driven water absorption, so we hypothesized that this natural mechanism could be exploited to drive nanoparticles and drugs to the colorectal tissue surface. Here, we report that sodium-based, absorption-inducing (hypotonic) enemas rapidly transport hydrophilic drugs and non-mucoadhesive, mucus penetrating nanoparticles (MPP), deep into the colorectal folds to reach virtually the entire colorectal epithelial surface. In contrast, isotonic and secretion-inducing (hypertonic) vehicles led to non-uniform, poor surface coverage. Sodium-based enemas induced rapid fluid absorption even when moderately hyper-osmolal (~350 mOsm) compared to blood (~300 mOsm), which suggests that active sodium absorption plays a key role in osmosis-driven fluid uptake. We then used tenofovir, an antiretroviral drug in clinical trials for preventing HIV, to test the effects of enema composition on local and systemic drug delivery. We found that strongly hypotonic and hypertonic enemas caused rapid systemic drug uptake, whereas moderately hypotonic enemas with ion compositions similar to feces resulted in high local tissue levels with minimal systemic drug exposure. Similarly, moderately hypotonic enemas provided improved local drug retention in colorectal tissue, whereas hypertonic and isotonic enemas provided markedly reduced drug retention in colorectal tissue. Lastly, we found that moderately hypotonic enema formulations caused little to no detectable epithelial damage, while hypertonic solutions caused significant damage, including epithelial sloughing; the epithelial damage caused increased systemic drug absorption and penetration of MPP into colorectal tissue, a potential advantage in certain drug delivery applications. In summary, we illustrate that enema composition can be adjusted to maximize local versus systemic drug delivery, and that mildly hypotonic, sodium-based vehicles can provide uniform drug and MPP delivery in the colon that maximizes local drug concentrations.

Liposome-based mucus-penetrating particles (MPP) for mucosal theranostics: demonstration of diamagnetic chemical exchange saturation transfer (diaCEST) magnetic resonance imaging (MRI).

Mucus barriers lining mucosal epithelia reduce the effectiveness of nanocarrier-based mucosal drug delivery and imaging ("theranostics"). Here, we describe liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, e.g., the diaCEST MRI contrast agent barbituric acid (BA). We observed that polyethylene glycol (PEG)-coated liposomes containing ≥7 mol% PEG diffused only ~10-fold slower in human cervicovaginal mucus (CVM) compared to their theoretical speeds in water. 7 mol%-PEG liposomes contained sufficient BA loading for diaCEST contrast, and provided improved vaginal distribution compared to 0 and 3mol%-PEG liposomes. However, increasing PEG content to ~12 mol% compromised BA loading and vaginal distribution, suggesting that PEG content must be optimized to maintain drug loading and stability. Non-invasive diaCEST MRI illustrated uniform vaginal coverage and longer retention of BA-loaded 7 mol%-PEG liposomes compared to unencapsulated BA. Liposomal MPP with optimized PEG content hold promise for drug delivery and imaging at mucosal surfaces. FROM THE CLINICAL EDITOR: This team of authors characterized liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, such as barbituric acid (a diaCEST MRI contrast agent) and concluded that liposomal MPP with optimized PEG coating enables drug delivery and imaging at mucosal surfaces.