The literature paints a complex picture of the association between mortality risk and ICU strain.In this study, we sought to determine if there is an association between mortality risk in intensive care units (ICU) and occupancy of beds compatible with mechanical ventilation, as a proxy for strain.A national retrospective observational cohort study of 89 English hospital trusts . Seven thousand one hundred thirty-three adults admitted to an ICU in England between 2 April and 1 December, 2020 (inclusive), with presumed or confirmed COVID-19, for whom data was submitted to the national surveillance programme and met study inclusion criteria. A Bayesian hierarchical approach was used to model the association between hospital trust level , bed occupancy, and in-hospital all-cause mortality. Results were adjusted for unit characteristics (pre-pandemic size), individual patient-level demographic characteristics , and recorded chronic comorbidities .One hundred thirty-five thousand six hundred patient days were observed, with a mortality rate of 19.4 per 1000 patient days. Adjusting for patient-level factors, mortality was higher for admissions during periods of high occupancy (> 85% occupancy versus the baseline of 45 to 85%) [OR 1.23 : 1.08 to 1.39)]. In contrast, mortality was decreased for admissions during periods of low occupancy (< 45% relative to the baseline) [OR 0.83 (95% PCI 0.75 to 0.94)].Increasing occupancy of beds compatible with mechanical ventilation, a proxy for operational strain, is associated with a higher mortality risk for individuals admitted to ICU. Further research is required to establish if this is a causal relationship or whether it reflects strain on other operational factors such as staff. If causal, the result highlights the importance of strategies to keep ICU occupancy low to mitigate the impact of this type of resource saturation.The online version contains supplementary material available at 10.1186/s12916-021-02096-0. From the first reports of a novel coronavirus SARS-CoV-2) in late 2019, to date, global mortality associated with the resultant disease (COVID-19) has exceeded 1.7 million people  in late . NotablyAvailability of certain resources, such as bed occupancy/availability, is well-established proxies for operational strain . Prior tA better understanding of how operating under such extreme circumstances affects outcomes is crucial for two reasons: firstly, to allow hospitals to adapt practice to improve outcomes, and secondly, to provide policy makers with more accurate information about the potential consequences of allowing health services to be overwhelmed. As such, in this study, we sought to evaluate the extent to which mortality risk in intensive care units (ICUs) during the COVID-19 pandemic in England could be explained by differences in occupancy.Data on all intensive care unit (ICU) admissions across England were extracted from the COVID-19 Hospitalisation in England Surveillance System (CHESS) . InformaAll ICU admissions reported to CHESS between 2 April and 1 December ), demographic characteristics , recorded comorbidities , and a binary indicator for use of mechanical ventilation. Ethnicity was coded as white, Asian (Subcontinent and other), black, mixed, and other; comorbidities were recorded as binary indicator variables, with missing entries assumed to reflect the absence of a comorbidity. The appropriateness of this assumption in CHESS has been previously explored .Trusts are groups of geographically co-located hospitals that function as a single organisational unit within the UK’s national healthcare system. Information extracted from SitRep about each trust comprised: pre-pandemic (January–March 2020) number of beds compatible with mechanical ventilation, the proportion of beds compatible with mechanical ventilation occupied on each day of the study period, and each trust’s geographical region . LinkageThe primary outcome was in-hospital all-cause mortality; patients were followed up until death, discharge, transfer, or a minimum of 90 days from admission. Discharge and transfer were both treated as suggesting that the patient survived.Descriptive summaries were generated as median and interquartile ranges for continuous variables and frequency and percentage incidence for categorical factors. Exploratory analyses included: the relationship of the COVID-19 epidemic curve to bed occupancy at a national level , with a model specified using BRMS V2.14.4) in R (V4.0.3) –21. Furt4.4 in R n = 250); (3) including all individuals with a known outcome but no date whom were excluded in the data cleaning process (n = 10); (4) a random effect for all patient post 16 June 2020 ; (5) adjusting for week of admission; (6) adjusting for trust and region as random effects; (7) additional patient-level factors: time from hospital admission to ICU admission, chronic liver disease and obesity; (8) the residual bed availability in the sustainability and transformation partnership (STPs) to which each trust belongs—STPs are collections of geographically co-located hospital trusts that are meant to operate collaboratively to support one another, and include ambulance providers and community services so as to allow end-to-end integration of care; (9) the weighted average of the indices of multiple deprivation (IMD) corresponding to each patient’s given postcode district , as a proxy for socio-economic status; and (10) separated into the different waves of the pandemic in the UK .As secondary analyses, two potential interactions were assessed: 1) baseline trust size and occupancy and (2) patient age and occupancy (results not reported due to insignificance). We also assessed the association of occupancy on the recorded outcome date with mortality and occupancy expressed in terms of pre-pandemic ICU size. Several sensitivity analyses were carried out , the unadjusted odds ratio (OR) for mortality based on the mechanical ventilator occupancy rate on the day of admission was 1.22  1.06–1.40), relative to the baseline of 45–85%. For low occupancy rates (0–45%), the unadjusted odds ratio was 0.82 (95% PCI 0.73–0.93), relative to the baseline of 45–85%. Following adjustment for patient-level factors , the OR was 1.23 (95% PCI 1.05–1.43) for high occupancy rates and 0.83 (95% PCI 0.73–0.96) for low occupancy rates. Figure The fully adjusted OR for mortality Fig. , using oUsing the alternative definition of occupancy, relative to baseline (i.e. pre-pandemic) capacity instead of the real-time (surge) capacity on the day of admission illustrates that mortality risk given a linear continuous factor was 1.31  beds compatible with mechanical ventilation , increaThe remaining result for which the interpretation is not immediately apparent is that the risk of mortality based on occupancy on the date of recorded outcome is also high; OR 2.29 . There are several plausible explanations, but for the sake of brevity, we will mention just two. The first is based on the same principle as the other results, i.e. as occupancy increases the availability of staff and resources decreases which can indirect contribute to an individual’s mortality risk, and/or there may be a direct effect due to rationing of care or treatment limiting orders. Alternatively, this result could also reflect a specific type of observation bias wherein patients who are likely to survive are kept in ICU and in hospital longer , thus reOur observations are consistent with the aforementioned Belgian and US VA study , 14, excThe strengths of this study are the national cohort of patient-level data with extensive capture of admissions , coupledThe lack of physiological data and minimal clinical intervention data available in the CHESS dataset limits our ability to adjust for individual-level differences in severity and treatment. Thus, we cannot exclude that the observed associations are a result of unmeasured confounding due to differences in severity on admission or variation in natural history due to the evolving treatment strategies that have been used over the course of the pandemic. At present, there is no single research environment that links primary care, secondary care, administrative mortality records, surveillance datasets (e.g. CHESS), routine COVID testing , and national audit data such as that collected by the UK Intensive Care National Audit and Research Centre (ICNARC) which includes some of the necessary information at the patient-level. Notably, there are on-going attempts to link the aforementioned datasets, e.g. . HoweverAlthough direct analysis to address the above issues is not possible for the reasons outlined previously, it is still worth noting that several studies from the UK suggest that any potential differences in severity on admission are unlikely to explain the observed association between occupancy and mortality. For example, a study using linked CHESS data from the first wave of the pandemic did not find between centre variation in severity scores (e.g. mean APACHE-II) to be associated with mortality risk . MoreoveCharacterisation of operational strain as a function of surge occupancy likely fails to fully reflect the complexity of using non-specialist staff and other resource allocation issues present when ‘creating’ new ICU beds, which could be the underlying causal explanation for the increased mortality risk observed during periods of high occupancy. Notably, previous research has identified a detrimental impact of insufficient (adequately trained) nursing and medical consultant staff on patient mortality risk in intensive care units , and staDespite the more recent identification of several effective treatments for severe COVID-19, as bed saturation in ICUs again became an issue from November 2020 to January 2021, mortality rates increased across England to rates similar to that seen during the 1st wave . NotablyThe results presented in this study are especially relevant given the identification of variants of concern with increased risk of transmission and mortality , as wellThe results of this study suggest that increasing occupancy of beds compatible with mechanical ventilation, a proxy for operational strain, is associated with a higher mortality risk for individuals admitted to ICU. Further research is required to establish if this is a causal relationship or whether it reflects strain on other operational factors such as staff/residual confounding not addressed due to the lack of physiological severity data. If causal, the result highlights the importance of strategies to keep ICU occupancy low to mitigate the impact of this type of resource saturation, rather than waiting for arbitrary thresholds to be triggered, especially given the observation that average exposure  to this operational risk factor is also associated with mortality risk.Additional file 1:. eMethods, Figures S1-8, & Tables S1-6. eMethods – Additional detail on data handling and modelling methods. Fig S1. - Application of inclusion and exclusion criteria to raw data. Fig S2. - Unadjusted mortality rate in the ICU, alongside the total, confirmed COVID and non-COVID national-level occupancies (Top) and percentages of the study cohort in each of the three main ICU occupancy bins used in the primary model (Bottom) across the duration of the study. Fig S3. - Trust-level missingness at varying inclusion thresholds. Fig S4. - Seven-day rolling averages for Age (Top) and Number of Comorbidities (Bottom) across the duration of the study. Fig S5. - Trust-Level Ventilator Bed Occupancy (Based on Surge Capacities) Across England. Fig S6. - Marginal posterior densities for linear population level coefficients in the model, for mechanically ventilated bed occupancy binned as described in the main text, comorbidities, sex and week of admission. Fig S7. - Marginal posterior densities for group level ethnicity intercepts. Fig S8. - The interaction between the baseline availability of beds supporting mechanical ventilation, and occupancy on the day of ICU admission. Table S1. - Marginal posterior densities for occupancy under sensitivity analyses. Table S2. - Comparison of prior choices via their effect on primary model OR estimates. Table S3. - Marginal posterior densities for mortality ORs when occupancy is utilised at each individual’s final outcome date, rather than their date of admission to ICU. Table S4. - Marginal posterior densities for mortality ORs when occupancy is taken as the mean or median occupancy achieved during each patient’s stay. Table S5. - Marginal posterior densities for mortality ORs when occupancy is defined as a ratio relative to baseline capacity. Table S6. - Marginal posterior densities for mortality ORs including baseline bed availability and interaction with occupancy.


Protective behaviors such as mask wearing and physical distancing are critical to slow the spread of COVID-19, even in the context of vaccine scale-up. Understanding the variation in self-reported COVID-19 protective behaviors is critical to developing public health messaging. The purpose of the study is to provide nationally representative estimates of five self-reported COVID-19 protective behaviors and correlates of such behaviors. In this cross-sectional survey study of US adults, surveys were administered via internet and telephone. Adults were surveyed from April 30-May 4, 2020, a time of peaking COVID-19 incidence within the US. Participants were recruited from the probability-based AmeriSpeak® national panel. Brief surveys were completed by 994 adults, with 73.0% of respondents reported mask wearing, 82.7% reported physical distancing, 75.1% reported crowd avoidance, 89.8% reported increased hand-washing, and 7.7% reported having prior COVID-19 testing. Multivariate analysis  indicates that women were more likely to report protective behaviors than men, as were those over age 60. Respondents who self-identified as having low incomes, histories of criminal justice involvement, and Republican Party affiliation, were less likely to report four protective behaviors, though Republicans and individuals with criminal justice histories were more likely to report having received COVID-19 testing. The majority of Americans engaged in COVID-19 protective behaviors, with low-income Americans, those with histories of criminal justice involvement, and self-identified Republicans less likely to engage in these preventive behaviors. Culturally competent public health messaging and interventions might focus on these latter groups to prevent future infections. These findings will remain highly relevant even with vaccines widely available, given the complementarities between vaccines and protective behaviors, as well as the many challenges in delivering vaccines. The United States is currently experiencing the largest COVID-19 epidemic in the world with 20% of the world’s cases and the most COVID-19 deaths . EvidencVarious public health agencies including the WHO  and CentDespite these calls for COVID-19 protective behaviors, little is known about uptake of these practices, and how these behaviors vary by demographic and other individual and community characteristics . It is uThis analysis explores these questions by investigating protective behaviors in a national sample of the US adult population. We use a national probability-based survey linked to aggregate level data on COVID-19 hotspots and state adopted non-pharmaceutical interventions (NPIs) related to COVID-19. In particular, we explore prevalence of COVID-19 protective behaviors and individual and contextual-level correlates of protective behaviors and NPIs across the US, particularly among subgroups of greatest vulnerability.Survey data were collected from a cross-sectional sample of 994 US adults drawn from AmeriSpeak®, a probability-based non-institutionalized panel of over 45,000 panel members designed to be representative of the US household population. Randomly selected households were sampled using area probability and address-based sampling, with known selection probabilities from the NORC National Sample Frame . SampledThe panel provides sample coverage of approximately 97% of the US household population. Prior methodology comparisons indicate that the resulting AmeriSpeak sample broadly replicates the US Census American Community Survey sample on key demographic measures, including sex, age, race/ethnicity, education, marital status, employment, income, region, and home Internet access , 16. TheFive key COVID-19 protective behaviors. Respondents were queried about their COVID-19 protective behaviors to include: “Wearing a mask when leaving home,” “Keeping a 6-foot radius when interacting with people you do not live with,” “Limiting interactions with others to groups of 10 or less” and “Washed/sanitized hands more than usual.” Respondent were also asked if they had been tested (no/yes) for COVID-19. COVID-19 related items were taken from NIH’s PhenX Toolkit COVID-19 Protocols, specifically from the work of Cawthon and colleagues [lleagues .Respondent-level background variables. Age was collected as a continuous variable and categorized as 18–30, 31–59, and 60 and older. We measured biological sex , race/ethnicity , non-Hispanic Black (Black), non-Hispanic Other/Mixed (Other/Mixed), non-Hispanic Asian (Asian), Hispanic, years of education , employment (not employed = 0 and employed = 1), income (below state median income = 0 and above state median income = 1), personal lifetime history of CJI (yes/no to a self-reported conviction for a misdemeanor or felony crime or incarceration in jail or prison), personal lifetime history of non-medical opioid use (yes/no to use of opioids or prescription pain medication illicitly obtained or used in a way not prescribed by a doctor) and self-reported political party affiliation .Local contextual variables. Based on the respondent’s home address we measured the US Census region of the respondent’s home . Next, we included a county-level dichotomous COVID-19 hotspot variable based on whether the county was identified as an emerging statistical hotspot for all days during the survey period. Specifically, we implemented Local Indicators of Spatial Association (LISA) analyses [analyses  on populanalyses  data foranalyses .We included a state policy count measure indicating whether the state implemented one or more NPI policies a priori hypotheses about their relationships with COVID-19 protective behaviors and all variables were retained regardless of statistical significance. All analyses  used data weighted to national census benchmarks, taking into account selection probabilities [Multivariable logistic regression models were conducted for each outcome . Variables were selected for inclusion in the multivariable models based on d region) and non-d region). MissingThe survey was completed by 994 of those invited from the larger AmeriSpeak panel (24%) with 17 respondents (2%) excluded from the analysis due to missing data, producing a final sample of 977 respondents. AmeriSpeak has been designed to address response rate and sampling issues through sample weights and non-response adjustments , 25–27. COVID-19 testing was infrequent at the time of the survey ; only 7.7% of respondents reported having been tested and of those a 10.0% positivity rate.As seen in Almost all respondents reported taking at least one protective behavior to reduce COVID-19 risk. As seen in As seen in Social distancing was more common among older respondents 31–59 , and those age 60 and over  compared to younger respondents 18–30 years old. In addition, Black race , incomes below their state median , CJI history , non-medical opioid use  and affiliation with the Democratic Party , were all associated with social distancing.COVID-19 testing was significantly independently associated with Black race , Asian race , incomes below their state median , individuals with justice involvement histories  and Democratic Party affiliation .US adults report high uptake of at least some COVID-19 protective behaviors, though uptake of multiple measures at once was more modest. Respondents reported low overall rates of COVID-19 testing. This finding was expected, given the strong geographic clustering of COVID-19 cases at this phase of the pandemic and the limited availability of testing nationwide.Demographic characteristics, economic and social circumstance, and political values are all associated with specific protective behaviors. Older respondents and respondents affiliating with the Democratic Party reported higher uptake of such practices ; while mCJI populations and respondents with Republican political affiliation were more likely to have been COVID-19 tested. Individuals with CJI experience may have been more likely to be tested due to involuntary confinement with others, congregate living in jails and prisons or due to contact with community-based system that required such testing. Republican political affiliation may have used COVID-19 testing as an alternative to other preventive behaviors such as the use of face coverings, which are less acceptable among this sub-population.Diverse demographic factors, including age and gender, have been found to affect the general adoption of public health preventive practices , 29. In This study’s US sample displayed a slightly different pattern. Older respondents reported higher rates of protective behaviors, perhaps reflecting early and clear public awareness of the sharp age gradients in COVID-19 morbidity and mortality. We found no consistent relationship between education and protective behaviors. However, we found that females were more likely to use facial coverings and restrict themselves to groups of 10 or less.Individuals with OUD are particularly vulnerable to COVID-19 infection and worse outcomes from the disease, including hospitalization and death . We did A model to help with building on our results in future research are socio-physical models. Socio-physical models have been used to interpret the interactions of complex social systems such as public opinions, behavior of crowds and collective decision making . Socio-pBuilding on ‘vaccination game’ research, which gives a mathematical framework to account for this interrelated behavior not only for epidemiologic dynamics but also for the voluntary mitigation risk behavior of individuals who face pandemics , can alsOther next steps based on our research include using tailored and community-specific engagement to assist with the deployment of COVID-19 prevention interventions. This is critically important given that Black/African Americans, Hispanic/Latinx community members and other minoritized populations historically have either had limited or delayed access to prevention interventions , 38. TheThis analysis did not allow for causal or other temporal inferences with cross-sectional data. Our data were also collected during a particular early period in the COVID-19 pandemic and patterns of protective practices may have shifted over time. While fifteen percent of our sample reported histories of either opioid misuse or CJI, our household study did not include individuals presumably at the highest risk . We also lack measures of COVID protective behaviors and risk-factors among individuals with current or very recent histories of CJI involvement or opioid use; something that will be examined in detail through the NIH’s RADx-UP initiative . We alsoAs with other household surveys, this study displayed a modest response rate. Nevertheless, the AmeriSpeak panel’s response rate of 37% is one of the highest for comparable national probability-based household panels . We weigWhile social desirability and other response biases are possible in our self-report survey, reliable and valid estimates of risky behaviors is possible with surveys , includiOur data suggest that most American adults have adopted at least some protective behaviors to reduce the risk of COVID-19 transmission and infection. We also find uneven take-up of such measures. Younger adults, low-income respondents, those with CJI histories, and those identifying themselves as Republican were less likely to report protective behaviors. These findings are important for prevention. They will remain highly relevant as vaccines become available, given the complementarities between vaccines and protective behaviors, as well as the many challenges in delivering vaccines.We found little relationship between the emergence of local hotspots or state public health policies with respondents’ protective behaviors. Low prevalence of protective behaviors may have accelerated local disease spread. One or both of these factors may have necessitated more aggressive state measures. Alternatively, respondents’ protective behaviors may not be very responsive to local public policies and epidemiological conditions.At this writing, millions of Americans are starting to receive COVID-19 vaccines. However, vaccines alone may be insufficient to halt the current pandemic, at least in the near term , which mThroughout, nationally representative surveys can help accomplish these tasks. Such research can help monitor how protective behaviors and vaccine hesitance vary across the US, particularly among those groups at greatest risk. It can also assist in the development of focused epidemiological surveillance, and the testing of public health messaging and other COVID-19 prevention interventions.S1 Appendix(DOCX)Click here for additional data file.S1 Data(CSV)Click here for additional data file.S2 Data(XLSX)Click here for additional data file.


What is the association of a COVID-19 diagnosis and mobility and physical function among community-living middle-aged and older Canadians during the initial pandemic lockdown in 2020?This cohort study of 24 114 participants found that community-living middle-aged and older adults with confirmed, probable, or suspected COVID-19 had nearly 2-fold higher odds of worsening mobility and physical function compared with adults without COVID-19, although most participants with COVID-19 had mild to moderate disease and were not hospitalized.These findings suggest that individuals with mild and moderate COVID-19 who were predominantly not hospitalized experienced deficits in functional mobility compared with those without COVID-19. This cohort study evaluates the association of mild to moderate COVID-19 with change in mobility and physical function in a population-based sample of adults aged 50 years or older in Canada. The association of COVID-19 not requiring hospitalization with functional mobility in community-dwelling adults above and beyond the impact of the pandemic control measures implemented in 2020 remains to be elucidated.To evaluate the association between a COVID-19 diagnosis and change in mobility and physical function of adults in Canada aged 50 years or older during the initial pandemic lockdown.This population-based cohort study used data from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 study. This study was launched on April 15, 2020, and the exit questionnaires were completed between September and December 2020. Prepandemic data from the first CLSA follow-up (2015-2018) were also used. Respondents included middle-aged and older community-dwelling participants residing in Canadian provinces. Data were analyzed from February to May 2021.The assessment for self-reported COVID-19 status was adapted from the Public Health Agency of Canada and the Centers for Disease Control and Prevention case definition available at the time of data collection; cases were classified as confirmed or probable, suspected, or non–COVID-19.Changes in mobility since the start of the COVID-19 pandemic were assessed using global rating of change in mobility scales at the COVID-19 exit questionnaire. Participant-reported new onset of difficulty in 3 physical function tasks was also examined.Among 51 338 participants at baseline, 21 491 participants (41.9%) were 65 years or older and 26 155 participants (51.0%) were women and 25 183 (49.1%) were men. Of 2748 individuals with confirmed or probable or suspected COVID-19, 113 (94.2%) were not hospitalized. Individuals with confirmed or probable COVID-19 had higher odds of worsening mobility in terms of ability to engage in household activity , physical activity , and standing up after sitting in a chair  compared with adults without COVID-19 during the same pandemic time period. Similar results were found for suspected COVID-19 status .This cohort study among older adults in Canada found that receiving a COVID-19 diagnosis was significantly associated with worse mobility and functioning outcomes even in the absence of hospitalization. These findings suggest that interventions may be needed for individuals with mild to moderate COVID-19 who do not require hospitalization. Even less is known about mobility and function in nonhospitalized samples of community-dwelling older adults.5The World Health Organization (WHO) declared COVID-19 a pandemic on March 11, 2020, and as of December 2021, there have been more than 262 million confirmed cases and more than 5.2 million deaths globally.9 There is also some emerging research to suggest that even mild to moderate COVID-19 can have negative ongoing functional associations for nonhospitalized patients.11 However, a major criticism of this early work is the use of convenience sampling  and lack of control or comparison groups. In addition, the associations of preexisting sociodemographic and health characteristics in community-dwelling individuals with changes in mobility and functioning from COVID-19 remain to be elucidated. We hypothesized that individuals with confirmed or probable and suspected COVID-19 will be more likely to report worsening of mobility and physical function compared with those without COVID-19. The purpose of this study was to examine the association between a COVID-19 diagnosis and change in mobility and physical function among middle-aged and older adults who were enrolled in the Canadian Longitudinal Study on Aging (CLSA) COVID-19 study.Mobility is well recognized as an essential component of well-being and an important determinant of healthy aging. A developing body of literature has shown that patients with severe COVID-19 who survived hospitalization report ongoing symptoms and physical limitations up to several months after discharge.STROBE) reporting guideline for cohort studies.This cohort study was approved by the Hamilton Integrated Research Ethics Board and by research ethics boards of all the participating institutions across Canada. Informed consent was obtained from the participants. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology . Participants were recruited from across the 10 provinces and are followed-up every 3 years. Individuals residing in Canada’s 3 territories, on First Nation reserves, or in long-term care facilities, as well as members of the armed forces, those who were unable to communicate in English or French, and those with severe cognitive deficits were not eligible to participate in the study. A core set of information was collected from all participants by questionnaire. The first follow-up assessments were completed among 48 893 participants from 2015 to 2018. Further details on the CLSA study design and methods have been described elsewhere.In response to the onset of the COVID-19 pandemic, the CLSA launched the COVID-19 Questionnaire Study on April 15, 2020, to investigate the epidemiologic characteristics of COVID-19 among middle-aged and older adults. Of 51 338 CLSA participants, 42 700 were invited to participate. Overall, 42 511 participants were eligible to participate in the CLSA COVID-19 Study, of whom, 28 457 agreed (66.9%), and 24 114 (56.7%) completed the exit survey (September-December 2020)  and the results were positive. Probable cases included (1) participants who had exposure to a confirmed COVID-19 case and a body temperature greater than 38 °C or reported cough, who were tested for COVID-19, but the results were inconclusive; or (2) participants who reported having close contact with a confirmed COVID-19 case with either body temperature greater than 38 °C or reported cough; or (3) participants who were told by a health care practitioner that they had COVID-19 but they did not have a confirmatory test. We included this definition because early in the pandemic, testing was restricted to returning travelers, close contacts of known cases, and hospitalized patients. Suspected cases of COVID-19 included participants who reported exposure to a probable COVID-19 case and had 2 or more symptoms, including fever, cough, runny nose, sore or scratchy throat, headache, chills or shivering, muscle and/or joint aches and pains, loss of smell, or difficulty breathing. In the analysis, COVID-19 status was grouped as confirmed or probable, suspected, and no COVID-19. The exact timing of COVID-19 diagnosis in relation to mobility decline was not assessed in this study.Assessment for self-reported COVID-19 diagnosis was based on data collected from all COVID-19 study questionnaires administered from baseline to exit, and was adapted from the Public Health Agency of Canada and the Centers for Disease Control and Prevention case definitions available at the time of data collection.Changes in mobility since the start of the COVID-19 pandemic were assessed using global rating of change in mobility scales in the COVID-19 exit questionnaire. Consistent with the International Classification of Functioning, Disability and Health definition, participants were asked to report changes in their mobility in 3 domains: ability to move around the home, engage in housework, and engage in physical activity on a 5-point Likert scale ranging from 1 indicating much worse to 5, much better. In this analysis, each outcome was dichotomized into either worse or not worse. Self-reported physical function for 3 specific functional tasks was assessed at CLSA first follow-up and the COVID-19 exit survey. Participants were asked to report whether or not they experienced difficulty in standing up after sitting in a chair, walking up and down a flight of stairs without assistance, and walking 2 to 3 neighborhood blocks. Participants who experienced difficulty were further probed about the degree of difficulty, with response options being a little difficult, somewhat difficult, and very difficult , dwelling type , living area , smoking , physical activity (adequate or low activity), nutritional intake (high risk or not at risk), and number of chronic conditions from 10 disease categories, including musculoskeletal, respiratory, cardiovascular, endocrine-metabolic, neurological, gastrointestinal, genitourinary, ophthalmologic, renal, and cancer, which were added and categorized as less than 3 or 3 or more conditions. Race and ethnicity was self-reported, and it was included as a covariate in the sensitivity analysis.16 Based on the World Health Organization’s age-specific recommendations, adequate physical activity was classified as engaging in at least 150 minutes of moderate-intensity or at least 75 minutes of vigorous-intensity physical activity per week.17 Nutritional behavior was assessed using the Seniors in the Community: Risk Evaluation for Eating and Nutrition tool.18 Using previously validated cutoff of a score less than 32 was identified as high risk.18The Physical Activity Scale for Elderly was used to assess participants’ physical activity levels.Descriptive statistics for all participants were presented as frequency and percentage. CLSA first follow-up data were used to impute a variable that was not assessed in the COVID-19 baseline and exit surveys, and COVID-19 baseline data were used to impute a variable that was not assessed in the COVID-19 exit survey. Multivariable logistic regression models were used to examine the association between COVID-19 status and change in mobility and physical function outcomes. All multivariable models were adjusted for the prepandemic covariates, since they are known to be associated with increased risk of COVID-19 and poor functional mobility outcomes. Unadjusted and adjusted odds ratios (aORs) and 95% CIs were reported. Statistical analyses were conducted using SAS software version 9.4 (SAS Institute). The proportion of worsening of the mobility and function outcomes among the COVID-19 exposure groups were similar under conditions of missing covariates and in the complete case scenario  were aged 65 years or older, 26 155 (51.0%) were women, and 25 183 (49.1%) were men. According to self-report, 47 105 participants (92.7%) were of European ethnic background and 3718 participants (7.3%) were of non-European ethnic background, including Southeast Asian, South Asian, West Asian, Chinese, Japanese, Korean, Black, Latin American, Filipino, Indigenous populations . DescripDuring the COVID-19 pandemic, more than 1 in 4 participants (5976 participants [25.2%]) reported worsening ability to engage in physical activity (1349 participants [5.7%] reported much worse ability), 2111 participants (8.9%) reported worsening ability to move around in their home (338 participants [1.4%] reported much worse ability), and 2022 participants (8.6%) reported worsening ability to engage in housework (336 participants [1.6%] reported much worse ability). Compared with rates reported at the first CLSA follow-up, 3639 participants (15.2%) reported new difficulty in standing up after sitting in a chair, 2489 participants (10.4%) reported new difficulty walking up and down a flight of stairs without assistance, and 2656 participants (11.1%) reported new difficulty walking 2 to 3 neighborhood blocks.Compared with individuals without COVID-19, individuals with probable or confirmed COVID-19 had nearly 2-fold higher odds of reporting worsening ability to engage in household activity  and participate in physical activity , after adjusting for covariates. Similarly, individuals with suspected COVID-19 were also 2-fold as likely to report worsening ability to move around in the home , engage in housework activity , and participate in physical activity  compared with individuals without COVID-19 .After adjusting for covariates, individuals with confirmed or probable COVID-19 were more likely to experience worsening difficulty standing up after sitting in a chair , as were those with suspected COVID-19 . Furthermore, individuals with suspected COVID-19 were also more likely to experience worsening difficulty with walking up and down a flight of stairs  and walking 2 to 3 neighborhood blocks  compared with those without COVID-19 . We alsoThis cohort study is the first study, to our knowledge, to evaluate the associations of confirmed, probable, or suspected COVID-19 with the mobility and functioning of a community-based sample of middle-aged and older adults. Our results showed that community-dwelling individuals who reported confirmed, probable, or suspected COVID-19 had higher odds of worsening mobility since the start of the pandemic and worsening physical function since the CLSA first follow-up compared with those without COVID-19. Importantly, in a population-based study with a built-in comparison group, these findings highlight the burden of mild to moderate COVID-19 not requiring hospitalization on physical health in community-living people.20 Anecdotal reports, patient accounts on social media, and some preliminary research with convenience samples, have suggested that many patients who experience even mild COVID-19 have persistent and troublesome symptoms, including impaired physical function after their initial illness.21 There is an ongoing effort by both health professionals and patients alike to recognize long COVID as a long-term condition and to increase access to treatments and rehabilitative care.24 Our findings confirm that individuals with COVID-19 who did not require hospitalization were more likely than those without COVID-19 to experience worsening of overall mobility since the start of the pandemic and a deterioration in physical function at the COVID-19 exit survey compared with the CLSA first follow-up. Research suggests certain coronaviruses can cause inflammatory damage to the central nervous system tissue.25 Studies conducted in individuals with severe acute respiratory syndrome and Middle East respiratory syndrome reported prolonged fatigue, sleep disturbances, and changes in cognition after recovery from infection.28 Similar symptoms have been reported by individuals after COVID-19.30 Some evidence suggests that the SARS-CoV-2 can cause neuroinflammation and inflammation in other parts of the body, resulting in neuronal degeneration and release of proinflammatory cytokines, which may explain the subsequent chronic fatigue and functional mobility impacts experienced by many individuals after COVID-19.30 It is also possible that public health recommendations for quarantine and self-isolation for individuals who have test results positive for COVID-19 restricted physical activity and may have exacerbated the mobility and physical function decline.32Although there is a growing body of research showing that hospitalized patients with COVID-19 experience problems with physical functioning up to 6 months after discharge, there is still a dearth of literature on nonhospitalized patients with less severe illness.34 and our findings indicate that these risk factors are also negatively associated with physical health outcomes in community-dwelling individuals, some of whom may have mild to moderate COVID-19. Therefore, older adults in these subgroups who may become ill with COVID-19 should be prioritized when planning interventions. Taken together with previous work, our results suggest a need for approaches to effectively restore functional mobility to predisease levels after COVID-19. It is recommended that approaches that promote gradual activity and enhance social, cultural, and financial support may help with managing post–COVID-19 conditions.35Further, our results showed that sociodemographic risk factors and having 3 or more chronic conditions were associated with a decline in mobility and/or functioning. These risk factors have been associated with severe COVID-19 and its complications,The strengths of this study include the timing of data collection in the midst of the COVID-19 pandemic. Additionally, our use of a large sample of community-living adults to examine changes in function and mobility relative to a COVID-19 diagnosis make our findings more nationally generalizable.36 Thus, it is important to note that the low number of hospitalizations in our study is not a reflection that participants were turned away from hospitalization and sent home, but rather a reflection of the CLSA sample of community-dwelling middle aged and older adults.Our study has several limitations that should be considered when interpreting the findings. COVID-19 status was classified based on self-reports, and not all cases were confirmed with testing. The number of participants with confirmed or probable COVID-19 was small, which may have resulted in lower statistical power to examine associations for this group. Furthermore, the exact timing of COVID-19 diagnosis in relation to mobility decline or duration of functional mobility deficits was not assessed in our study. Functional mobility was not assessed using performance-based tests and therefore the mobility outcomes may be prone to recall bias. Additionally, individuals at risk of experiencing worsening of mobility may be more likely to withdraw from the study, which may underestimate the associations. A greater proportion of participants who did not participate in the COVID-19 study were older and had lower income, which may impact the validity of our findings. Additionally, this study did not include individuals residing in long-term care institutions, who were more often hospitalized with COVID-19 and whose change in function or mobility associated with a COVID-19 diagnosis may be different than that experienced by community-dwelling older adults. In Canada, health measures taken by the governments and hospitals included creating additional critical care beds; in regions where hospitals were overwhelmed with COVID-19 admissions, some critical care patients were transferred to other hospital locations with increased capacity.In this population-based cohort study of community-dwelling middle-aged and older adults, we found that mild to moderate COVID-19 was associated with worsening mobility and difficulties in physical functioning. In view of the large number of adults diagnosed with COVID-19 worldwide, there is a need to further understand the longer-term impacts of the illness and to consider the development and implementation of effective intervention and management approaches to address any persistent deficits in mobility and functioning among those living in the community.


Prevalence of inflammatory bowel disease has been on the rise in recent years, especially in pediatric populations. This study aimed to provide precise identification and stratification of pediatric patients with diagnosed ulcerative colitis (UC) according to the severity of their condition and the prediction for standard treatment according to the specific expression of candidate miRNAs. We enrolled consecutive, therapeutically naïve, pediatric UC patients with confirmed pancolitis. We examined formalin-fixed paraffin-embedded specimens of colonic tissue for the expression of 10 selected candidate miRNAs. We performed receiver operating characteristic curve analysis, using area under the curve and a logistic regression model to evaluate the diagnostic and predictive power of the miRNA panels. Sixty patients were included in the final analysis. As a control group, 18 children without macroscopic and microscopic signs of inflammatory bowel disease were examined. The combination of three candidate miRNAs  enabled accurate detection of pediatric UC patients and controls. A panel of four candidate miRNAs  was associated with severity of UC in pediatric patients and a combination of three miRNAs  was associated with early relapse of the disease. Nine patients out of the total were diagnosed with primary sclerosing cholangitis (PSC) simultaneously with ulcerative colitis. A panel of 6 candidate miRNAs  identified those patients with PSC. Specific combinations of miRNAs are promising tools for potential use in precise disease identification and severity and prognostic stratification in pediatric patients with ulcerative pancolitis. Inflammatory bowel disease (IBD) is a chronic complex disorder of the digestive system caused by multiple factors, including genetics, epigenetics, gut microbiota, environmental factors and altered immune system, although the precise mechanisms underlying the pathogenesis of this disease remain unclear ,2,3. OwiAlthough prevalence of the disease peaks in the fourth and fifth decades of life, a substantial number of patients have onset of IBD during early childhood ,7. SigniSubjects were enrolled at the Department of Pediatrics, University Hospital Brno, Czech Republic. Eligible subjects consisted of children having been diagnosed with UC (only pancolitis) according to relevant guidelines ,14  on the Quantstudio 6 Real-Time PCR System  and we used miR-16-5p as an endogenous control for data normalization. The relative expression levels of target genes were normalized against beta-actin using the 2-ΔCT method.Total RNA was isolated from formalin-fixed paraffin-embedded biopsy tissues from rectosigmoideum using ALL Prep DNA/RNA FFPE kit . Synthesis of complementary DNA (cDNA) was conducted using miRCURY LNA RT Kit . miRCURY LNA miRNA PCR Assays (primer mix) for the following miRNAs were used for quantitative real-time reverse transcription analysis (qRT-PCR): miR-16-5p, miR-21-5p, miR-142-3p, miR-146a-5p, miR-192-5p, miR-194-5p, miR-200b-3p, miR-223-3p, miR-375-3p, miR-4284 and let-7i-5p . qRT-PCR was performed using the SensiFAST™ SYBRp-value < 0.05 was considered significant. All statistical analyses were performed using MedCalc statistical software Version 19.1 , JMP software 14.0.0  and GraphPad Prism version 8.2.0 . To identify the most robust miRNA panel for the diagnosis of UC patients, the adaptive LASSO model was applied to the qPCR data using JMP 14.0.0 .We performed receiver operating characteristic (ROC) curve analysis and used area under the curve (AUC) values to evaluate the diagnostic power of the miRNA panel. For ROC analysis, we used a risk score calculated by a logistic regression model. The categorical factors were analyzed by Fisher’s exact test or chi-squared test and continuous factors were analyzed by Mann–Whitney U test. Spearman’s correlation coefficient was used to determine statistical dependence between variables. All statistical tests were two-sided and A total of 60 patients with complete clinical data and with a sufficient amount of material from colonic tissue for further analysis were included in the final analysis. The basic demographic and clinical characteristics of patients are shown in As a controls, we used a group of 18 children without macroscopic and microscopic signs of IBD. The control group consisted of 12 girls (66.7%) and 6 boys (33.3%), with mean age of 14.6 years.Differences in expression of selected 10 miRNAs in patients with mild and moderate UC (based on PUCAI score) and healthy controls are depicted in In the Supplementary materials, we provide the expression of 10 selected miRNAs , ROC curTo identify the most robust miRNA panel for the diagnosis of UC patients, the adaptive LASSO model was applied to the qPCR data using JMP 14.0.0 . Three candidate miRNAs  were distinguished for accurate identification of pediatric UC patients . A risk In the quest to find the most robust miRNA panel for identifying UC severity, an adaptive LASSO model was applied to the qPCR data using JMP 14.0.0 . Four candidate miRNAs  were prioritized for identifying severity of UC in pediatric patients .We built a risk score for quantifying the severity of the UC patients as follows: logit (risk score) = 6.99 − 8.32 × miR-200b-3p + 2.45 × miR-223-3p + 5.61 × miR-375-3p + 2.50 × miR-146a-5p.Endeavoring to stratify patients according to their response to the standard therapeutic regime, we identified in the same manner three specific miRNAs (upregulated miR-21-5p and downregulated miR-192-5p and miR-194-5p) that appear to be associated with early disease relapse, where early relapse was assessed as a significant worsening of the patient’s condition during the first year of treatment  .To determine the most robust miRNA panel for the identification of patients with UC and primary sclerosing cholangitis, an adaptive LASSO model was applied to the qPCR data using JMP 14.0.0 . Four upregulated  and two downregulated (miR-192-5p and miR-194-5p) miRNAs were identified .A knowledge of non-coding RNAs, mainly regarding miRNAs, has grown rapidly in recent years, mostly since the development of next-generation sequencing. Expression levels of miRNAs are closely related to many vital cellular processes and their regulation, as miRNAs act as fine-tuners of those processes. By complementary binding to the 3′-untranslated region of their target mRNA, miRNAs destabilize or activate the degradation of their target mRNA and thus preclude its translation. Being involved in a complex regulatory network consisting of not only other miRNAs but also of many other regulatory molecules, some miRNAs can regulate multiple pathways even as other miRNAs are simultaneously regulated by several pathways. Thus, a complex network exists and is involved also in IBD. Evidence on the involvement of miRNAs in the development of IBD is based mostly on studies performed on the adult population. Studies performed on cohorts of pediatric patients are rather sparse and of limited reliability, as most of the studies work with several dozen patients at most. Despite all the limitations, the results are mutually confirming , at leasMost of the previously published studies were focused on differentiating IBD cases from healthy controls, thus identifying so-called diagnostic biomarkers. We tested, also, the ability of chosen miRNAs to differentiate UC cases from healthy patients, which was feasible using a combination of let-7i, miR-223 and miR-4284. There exist, however, many more specific clinical challenges, such as responsiveness to therapy, prediction of relapse, differentiation of IBD subtypes and preventing overtreatment. We therefore focused our effort also on other biomarker aspects and successfully identified a combination of miR-375, miR-146a, miR-223 and miR-200b that was able to identify patients with a more severe course of the disease. Moreover, we identified that the upregulation of miR-21 and downregulation of miR-192 and miR-194 are indicative of early relapse after treatment and more precisely relapse within 1 year after administering treatment. In order to find a biomarker discerning patients with IBD associated with PSC (PSC-IBD), we showed for the first time that a combination of 3 upregulated miRNAs  and 3 downregulated miRNAs  is typical for PSC-IBD patients.Although IBD’s exact pathogenesis remains unclear, its inflammatory nature is evident also from miRNAs that are repeatedly identified as deregulated in IBD patients of either subtype . PotentiIn our study, we have successfully validated results and confirmed biomarker potential in several miRNAs identified in studies of similar design. Moreover, to the best of our knowledge, we have evaluated for the first time in a Central European representative population of children with ulcerative pancolitis expression of selected miRNAs and their association with key clinical questions. Our study cohort is relatively homogenous, consisting exclusively of well-described pancolitic disease patients, thus avoiding any inconsistency stemming from an uneven range of the disease among patients. The results demonstrate that the specific combinations of expressed miRNAs in colonic mucosa are associated with important clinical parameters for more precise diagnosis, prediction of prognosis and clinical outcome. The uniqueness of our study lies in an unusually large study cohort. No previous study has been carried out on more than 20 patients with UC, and therefore, the reliability of the information has been somewhat limited. Independent validation of the results on a cohort including as many as 78 pediatric patients has never been published to date. Moreover, we have identified miRNAs and their combinations that not only can differentiate patients from controls but also patients with early relapse of the disease. This is of great diagnostic and prognostic importance. Due to our stratification of patients is based solely on the PUCAI score, however and that score itself has some diagnostic limitations, our results should be verified on a cohort described more precisely by other clinical and endoscopic (Mayo score) parameters.In addition, unique is the identification of patients with PSC-IBD. Although typical for middle-aged males, this condition also affects children. In the majority of the childhood cases, it is associated with IBD, typically with UC, while association with CD is less common ,37. The As current therapeutic options do not allow for early identification of patients who would not profit from a standard therapy either for non-responsiveness or for other causes, identification of potential biomarkers is of utmost interest for physicians. It should be noted, though, that the miRNAs validated in our study and successfully confirmed as deregulated are involved in inflammation as such, and therefore, do not reflect specific IBD changes other than overall inflammation of the gut. Moreover, this study validates previously published results. The main limitation of our study is a lack of the CD patients cohort disabling determination of the specificity of tested biomarkers.While this study undeniably brings value to the existing knowledge, independent validation in combination with profiling that uses such currently available high-throughput techniques as next-generation sequencing would be even more significant.In conclusion, we independently verified the biomarker potential of miRNAs feasible for assessing detection and prognosis and discovered that their combinations could distinguish not only UC patients from controls without signs of IBD but even more specific conditions such as disease severity, early relapse and even association with PSC. A larger cohort of patients with not only UC but also CD and a study based on expression profiling using high-throughput platforms and independent validation is greatly needed in this field.


Drug delivery to tumor sites using nanotechnology has been demonstrated to overcome the drawbacks of conventional anticancer drugs. Altering the surface shape and geometry of nanocomposites alters their chemical properties, which can confer multiple attributes to nanocarriers for the treatment of cancer and their use as imaging agents for cancer diagnosis. However, heterogeneity and blood flow in human cancer limit the distribution of nanoparticles at the site of tumor tisues. For targeted delivery and controlled release of drug molecules in harsh tumor microenvironments, smart nanocarriers combined with various stimuli-responsive materials have been developed. In this review, we describe nanomaterials for smart anticancer therapy as well as their pharmaceutical aspects including pharmaceutical process, formulation, controlled drug release, drug targetability, and pharmacokinetic or pharmacodynamic profiles of smart nanocarriers. Inorganic or organic-inorganic hybrid nanoplatforms and the electrospinning process have also been briefly described here. Nanoparticles with sizes ranging from tens to hundreds of nanometers in at least one of their dimensions demonstrate a large surface-area-to-volume ratio and quantum effects. Their large surface area enables them to have chemical reactivity for the attachment of multifunctional moieties . NanomatNanocarriers for biomedical applications are typically larger than single molecules, such as water or glucose, and smaller than bacteria or cells. They can protect enclosed small-molecule drugs or imaging agents with relatively high loading efficiency. The concept involving the accumulation of nanoparticles around cancerous tissue with leaky vasculature due to enhanced permeability and retention (EPR) effect has been prevalent since the 1980s . NanoforHowever, the distribution of nanomedicines at the site of tumor tissues in humans with passive targeting using the EPR effect is limited. Penetration or accumulation of drugs in bulk tumors varies in humans due to interstitial fluid pressure . In ordeWhen injected into the blood circulation of the body, nanoparticles smaller than 5.5 nm in their hydrodynamic diameter are primarily eliminated via renal clearance, but particles larger than 7 nm in their diameter cannot be easily eliminated by urinary excretion . The sizIn this review, we categorize smart nanocarriers for anticancer therapy as polymer-based nanocarriers, lipid-based nanocarriers, inorganic nanocarriers, and hybrid nanocarriers. The electrospinning technique for the production of nanofibers in bulk is also introduced. Finally, we discuss the future directions of smart nanocarriers for effective cancer treatment.Owing to cell proliferation and angiogenesis, the blood vessels inside the tumors are abnormally shaped, and the endothelial cells have large fenestrations that are not aligned or organized . Due to Based on the understanding of the characteristics of the tumor microenvironment, “smart” nanocarriers have been developed in order to overcome pathophysiological barriers. They are expected to offer high accuracy, selectivity, and high sensitivity for the targeted delivery of loaded drugs in a predictable or controlled manner. Aspects such as the penetration of cytotoxic drug-loaded nanocarriers into solid tumors, intracellular drug delivery, and reaching a concentration within the therapeutic window at the target site also aid in reversing multidrug resistance ,35. Targ3O4, and DOX were prepared for delivery by utilizing the EPR effect at the tumor site. Cystamine-modified gelatin released DOX, which was in response to glutathione (GSH) and matrix metalloproteinase (MMP). Since the amount of GSH and MMP is overexpressed in cancer tissues compared to that in normal tissues, the developed microemulsion can control the release of DOX in cancer tissues. Controlled drug releases induced by GSH and MMP improved tumor therapy and drug monitoring using T2 magnetic resonance imaging (MRI) were possible due to the properties of Fe3O4. While the drug release was regulated by enzymes, monitoring the drug concentration was important for determining the efficiency and prognosis of cancer treatment. Core-satellite nanomedicines for accurate real-time monitoring of enzyme-induced drug release were also developed [The anticancer DDS that can react with enzymes and control the release of DOX was developed by using cystamine-modified gelatin . Oil-in-eveloped . This naDepending on the constituent materials, organic nanocarriers for anticancer therapy are broadly classified as polymer-based nanoformulations, lipid-based nanoformulations, and protein-based or virus-based nanoparticles.Synthetic and natural polymers have been applied for controlling the fluidity of liquids, film coating in pharmaceutical formulations, controlled drug release, targeted drug delivery, improvement of the bioavailability (BA) of drugs, and biomedical implants . ComparePolymeric nanoparticles are nanometer-sized particles composed of polymers that are exploited as carriers of therapeutic agents for invasive and non-invasive routes of delivery . Such sySurfactants in the aqueous solution aggregate in response to certain concentration and temperature conditions to form micelles. Micelles within the particle diameter range in which drug-loaded micelles are expected to accumulate in the tumor tissue via the EPR effect can be selected for cancer therapy. The size and physical properties of micelles can be controlled by adjusting molecular weight, chemical composition, and component ratio.® was approved by the FDA in 2007 as a polyethylene glycol (PEG)-PLA-based polymeric micelle, which is a carrier of PTX and is effective in treating breast cancer and lung cancer [2000, oleic acid, and DOX were used to manufacture micelles. Oleic acid forms an ion pair with the DOX amine group at pH 7.4. As oleic acid becomes protonated at pH 5 or lower pH, the ion pair is unpaired, and the micelle becomes unstable, resulting in the release of DOX. Upon examining the release profile of DOX for 24 h, approximately 30% and 60% of DOX were released at pH 7 and pH 5, respectively. When the tumor size was compared to that of the control group, the micelles comprising the ion-pair of DOX with oleic acid were significantly smaller. In the case of micelles without the ion-pair of DOX and oleic acid, an anticancer effect was observed; however, the difference was not significant when free DOX was used. These observations suggest that the ion pair of DOX and oleic acid releases DOX in response to pH. Xiao et al. developed boronate cross-linked micelles (BCM) that demonstrated an extremely long tumor retention period. BCM showed much better stability than the non-crosslinked micelles [Polymeric micelles can be modified for stimuli responsiveness and active targeting for cancer drug delivery. Depending on the manufacturing method, they can be used as a carrier of hydrophilic or hydrophobic drugs, specifically in chemotherapy. GeneXol-PMg cancer ,72. Antig cancer . DSPE-PEmicelles . FurtherDendrimers exhibit a regular branched structure comprising symmetric small molecules around the core and polymeric branch units . DependiPolymeric dendrimers made from polyamidoamine are expected to enhance the water solubility of hydrophobic drugs, which are enclosed in the internal space or bound to a functional group on the surface of the dendrimers . The surLipid-based nanoformulations have been used as nanocarriers for chemotherapeutics as well as vaccine adjuvant-delivery systems . In addiLiposomes, which are biodegradable vesicles with lipid bilayers composed mainly of phospholipids, have been clinically used as delivery vehicles for drugs such as DOX and daunorubicin . LipophiMethods such as thin-film hydration, sonication, extrusion, and microfluidic mixing are used for manufacturing liposomes ,93,94. A® significantly inhibited the release of DTX at pH 1.2 of the gastric environment. In contrast, docetaxel was quickly released at pH 6.8 without any statistically significant difference when compared to the release from non-coated liposomes. The oral BA of free docetaxel was 1.91 ± 0.232%  cells and to prolong the circulation half-life of loaded drugs, PEG was incorporated into the liposomal membrane . The lip± 0.232% . Interesmaxt (AUC(0-t)) of 5-FU SLNs was 5-fold higher (54.7 ± 3.2) than that of the free 5-FU (15.5 ± 1.9). The tumor size was evaluated for 30 days. The tumor size of the group that was administered SLN was significantly smaller (approximately 200 mm3) than that of the untreated group (approximately 350 mm3).Solid lipid nanoparticles (SLNs), which are spherical nanoparticles composed of lipids that possess a solid lipid core matrix, have also been investigated for cancer treatment with active nanomedicine development in order to overcome the limitations of conventional anticancer drugs . SLNs haVirus-based nanoparticles (VNPs) are being examined in many studies and are a great candidates for the development of smart therapeutics because of their virus-specific advantages such as cell penetration, strong gene expression, possible opportunities for engineering, and modification of functional groups ,103. AmoIn this century, advances in synthetic chemistry have provided tools for synthesizing a wide range of inorganic nanoparticles. Owing to their inherent properties, we can exploit their traits and use them as drug delivery agents as well as imaging representatives. Their robust infrastructure allows us to encapsulate more than one functional component with different capabilities, which enhances the potency of the system. Owing to advantages such as non-toxicity, biocompatibility, hydrophilicity, and high stability over organic materials, they are widely used in the field of drug delivery .Inorganic nanoparticles derived from metals, such as gold, silver, iridium, and platinum, which show phenomenal resistance towards oxidation;3O4 and Gd2O3;Magnetic nanoparticles (MNPs) are mainly derived from 3d and 4f metals, such as FeFluorescent nanoparticles such as silicon-based quantum dots and lanthanide-based upconversion nanoparticles ,111.Common inorganic nanoparticles can be classified into three distinct categories:Although significant efforts have been made to use them as imaging agents and for enhanced radiotherapy and other biomedical applications in oncological systems, their usage as drug delivery vehicles has garnered little interest. Low toxicity, high cellular uptake, and nonimmunogenic response have contributed to their use in the field of DDS. For particles with sizes within the nano region, especially those based on inorganic materials, distinct properties have been observed compared to their bulk counterparts. In the field of biological sciences, the amount of magnetism exerted by nanocomposites, as well as their sizes, shapes, and other optical properties, can substantially alter the expected outcome .The immunoferritin method, mercury-based method, techniques involving uranium, and immunocolloidal methods involving gold have been reported earlier for antibody markers. Since then, the market for the biomedical industry has grown and is vastly dictated by bio-conjugated compounds incorporating inorganic metals ,115,116.The synthesis of inorganic nanoparticles involves many techniques, including hydrothermal methods, microwave-assisted methods, laser ablation, template synthesis, spark discharge, and sputtering. This is mainly applicable to dry particles and nanoparticles disseminated in the liquid phase. Nano-sizes in materials can also be achieved by reducing the size from micro to nano at the atomic level .Owing to their inherent properties, iron oxide nanoparticles (INP) are highly used when it comes to DDSs associated with MNPs. Giorgia Pastorin et al. have reported studies showing the release of sorafenib from INP coated with PVA-LDH and PEG-LDH and synthesized by using ammonia as a base. X-ray spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, transmission electron microscopy, scanning electron microscopy (SEM), dynamic light scattering, high-performance liquid chromatography, UV-visible spectrophotometry, thermogravimetric analysis, and vibrating sample magnetometry have been used for characterization. In the cytotoxicity assay performed against normal 3T3 fibroblast cells, no toxicity was observed after 72 h with different concentrations of nanoparticles. While mediating anticancer activities against HepG2 cells in acidic media, the nanoparticles showed significant cytotoxicity, making sorafenib-loaded and surface-modified INPs potent candidates for magnetic DDS .In 2019, Rostamizadeh et al. demonstrated the efficiency of MNPs coated with PEGylated curcumin in cancer therapeutics . They ex2 was used as a catalyst. In this case, 5FU was used as the drug. The double emulsion method (water/oil/water) was used for encapsulation inside the nanoparticle. The encapsulation efficiency was measured by using a spectrophotometer at 266 nm. The study reported drug encapsulation efficiency of up to 90%. Based on the characterization studies, FT-IR showed an exact peak at 580 cm−1 for distinct Fe-O bond stretching in Fe3O4, while XRD data showed an inverse spinel structure. SEM analysis corroborated the well-aggregated structure of the nanoparticles. In the in vitro drug release studies, SPIONPs released a maximum amount of 5-FU (33.1%), and the overall release was 84.1% in 48 h depending on the acidic pH (pH 5.4) [Another study reported the use of modified superparamagnetic iron oxide nanoparticles (SPIONPs) using block copolymers such as PCL-PEG-PCL. The study involved the preparation of nanoparticles by using the same principle; ammonium hydroxide was used as a base. In the case of co-polymer synthesis, the authors used the ring-opening polymerization technique, where Sn(Oct)(pH 5.4) .3O4 nanoparticles, hexaethyl cellulose (HEC), NCC, and polyvinylpyrrolidone could be used for surface modification. In the cell viability assay performed against hFOB cells, all surface-modified nanoparticles showed reduced toxicity compared to free Fe3O4 nanoparticles. Among them, the lowest toxicity was shown by particles coated with HEC, although cationic charges are more prone to be cytotoxic. The drug loading efficiency was 71% for HEC-coated nanoparticles and 89% for PVP-coated nanoparticles. Examination of cytotoxicity was performed with the MCF-7 cell line. Equal toxicity was observed for both DOX-loaded nanoparticles and pure DOX at higher concentrations in the range of 400–200 µg/mL. PVP-coated nanoparticles with doses <250 µg/mL showed no noteworthy toxicity towards normal cells (p > 0.05); however, HEC-coated nanoparticles showed higher toxicity towards cancer cells, making them a perfect candidate for drug delivery carriers [In DOX-encapsulated Fecarriers .3O4@SiO2 nanoparticles were used for which their surfaces were modified by (NIPAM-co-GMA) (PNG) chains via surface-initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization. Hydrazine was used to modify the polymer bushes. Encapsulation efficiency peaked at 78%. At high concentrations of DOX-and DOX-conjugated nanoparticles, high cytotoxicity was observed against the cancer cell line (HeLa cells). The study was performed with stimuli-responsive nanocarriers showing enhanced biocompatibility [Another DOX carrier was reported in 2019. Here, Fetibility .2 (@SiO2), mesoporous SiO2 (m@SiO2), and a mixture of both have been reported for targeting human lung cancer cells A549 and BEAS-2B. They used tetraethyl orthosilicate as a precursor and hexadecyltrimethylammonium bromide as a pore former for m@SiO2 only. While treating cancer cells with SPIONs, we have to be cautious about one side effect: Dissolution of SPIONs and its possible release of iron at the target site can encourage tumor growth. These coatings significantly altered the surface morphology of SPIONs, and during experimentation, it was evident that a single m@SiO2 coating constrained iron release from the nanoparticles by more than 10-fold when compared to that observed with unmodified SPIONs. Based on the AAS-ET measurements, it was evident that both nanoparticles were effectively assimilated by these two cells. Both nanoparticles strongly affected the proliferation of BEAS-2B cells; however, in both cases, no cytotoxicity was observed. Therefore, it was concluded that both nanoparticles were cytocompatible with lung epithelial cells [Surface-modified superparamagnetic iron oxide nanoparticles (SPIONs) with nonporous SiOal cells .Lipoamino acid-coated SPIONs have also been reported. Studies performed with human hepatocarcinoma cell line Hep-G2 showed that compared to the naked SPIONs, surface-modified cells showed less cytotoxicity and higher cell viability (more than 100%). Cell viability increased in a time-dependent manner. Lipoamino acid-coated nanoparticles showed growth-enhancing effects due to the supervised release of ionic iron into cells, rendering them highly biocompatible and a good targeted delivery system for cancer therapeutics .50 = 188.5 µg/mL), the nanocomposite shows much higher cytotoxicity against HT29 cells as well as lower IC50 value (IC50 = 45.63 µg/mL). Hence, this nanocarrier is both selective and more efficient than pure PTA [CS-coated iron oxide MNPs with phytic acid (PTA) were reported in 2017 by Dena Dorniani et al. to develop nanocarriers, which showed impressive anticancer activity against human colon cancer cells and no toxicity towards healthy fibroblast cells. However, the loading of PTA was significantly lower (12.9%), which was confirmed via spectroscopic studies. The PTA release profile suggested that the release of PTA was significantly lower than that of the physical mixture of PTA sodium salt of CS and MNP, corroborating the fact that the aforementioned nanocomposite can be used as a controlled-release drug delivery carrier. The release, which follows pseudo-first-order kinetics, reached 93% within 56 h when the pH was 4.8 and 86% within 127 h when the pH was 7.4. These effects were attributed to the instability of the compound in acidic media, which suggests a bias towards the acidic pH environment. With respect to pure compound  triethoxysilane (APTES), folic acid (FA), and carboxylated PEG have been demonstrated against FA receptor-negative A549 and FA receptor-overexpressed MCF-7 and HeLa cells, which have paved the way for the development of candidate nano drugs against breast and cervical cancer cell lines . Heat shem cells . Temperaem cells . Transfeem cells .2O4 and BaTiO3 with surface functionalization by glycerol-monooleate demonstrates a non-zero magnetic moment, which helps to move the carrier in the circulatory system owing to the external magnetic field. In vitro and in vivo studies demonstrate that upon treatment with an intravenous injection of the PTX-loaded drug carrier followed by the application of an external magnetic field for three weeks, nude mice with xenografted ovarian carcinomas were completely cured. This claim was supported by IR imaging histology studies performed via energy-dispersive spectroscopy and immunohistochemistry [By utilizing the magnetoelectric properties of nanoparticles, their use as nanocarriers is also a smart approach in modern biopharmaceuticals that exploit magnetic and electric field interactions during drug loading and delivery to a specific target site ,134. Thehemistry .In order to understand the interaction between nanomaterials and biological systems in terms of biocompatibility and minimal biological toxicity as well as to achieve desired therapeutic efficacy, researchers have been investigating a diverse range of nanomaterials, such as zero-dimensional , one-dimensional , and two-dimensional  nanomaterials along with polymer-based nanoparticles for diagnosis, imaging, and therapy ,137. AmoElectrospinning is a versatile technique that is easy to perform on a bulk scale with a diverse range of sizes from nanometer to micrometer scale with a variety of materials such as inorganic, hybrid (organic–inorganic), and natural and synthetic polymers . This meNanofiber-based delivery systems have demonstrated to be potent candidates among other delivery systems because of their superior loading capacity and high surface area for the desired functionalization. In the last few decades, FDA-approved PTX has become a vital and effective drug for cancer treatment. The delivery of PTX to accurate tumor sites with higher loading efficiency for cancer treatment remains the most challenging issue because of its poor solubility. In order to overcome this problem, Xu and co-workers developed nanofibers fabricated using PTX and succinic acid, which showed the highest loading efficiency of ~89% with a controlled release profile. Moreover, these nanofibers significantly inhibited the proliferation of human lung adenocarcinoma cells in both in vitro and in vivo evaluations . AnotherNorouzi et al. demonstrated salinomycin-loaded electrospun nanofibers for the first time during local glioblastoma therapy and tumor recurrence prevention. The nanofibers were composed of biodegradable poly lactic-co-glycolic acid polymers developed via electrospinning. These fibers were stable for approximately 30 days and showed a sustained release of approximately 80% of salinomycin in 4 days, and the remaining drug was released within two weeks of the initiation of nanofiber degradation. The sali-loaded nanofibers were capable of generating intracellular reactive oxygen species and upregulating the expression of Rbl1 and Rbl2 tumor suppressor genes as well as caspase 3, which can induce cancer cell apoptosis. These nanofibers demonstrated significant cytotoxicity against U251 glioblastoma cells compared to free Sali, which could be a potential candidate for brain tumor degradation .With continued innovation in medicinal chemistry, the development of nanomaterials for biomedical applications has shown promise for applications in biological systems, and nano DDSs have shown great potential in cancer research. Even though anticancer drugs such as DOX, PTX, and curcumin are used for treatments, their performances are limited when it comes to the targeted drug delivery to the tumor site. Stimuli-sensitive nanocarriers for controlled drug release have garnered interest in cancer therapy. Bispecific antibody-conjugated nanotherapeutics can be used to enhance targeting efficiency. Recently, many approaches have been developed along with the design of inorganic nanoparticle-mediated DDSs. Although a significant amount of research on smart nanocarriers has been performed over time, improvements are needed for surface fabrication as well as enhanced efficacy in order to push them further into clinical trials. Further research is required for the design of smart nanosystems with stability and specificity. Lipid nanocarriers for RNA delivery have also been developed. They can protect naked RNA and deliver RNA into cells . Smart iElectrospun nanofibers are attractive and promising candidates for cancer therapy owing to the manufacture of nanofibers from the laboratory at the industrial level. Owing to their remarkable properties, nanofibers have been used extensively in biomedical applications. Although production and applications are promising, further development and improvements are required for enhancing the efficacy of therapeutic systems.


Based on recommendations from the Royal College of Psychiatrists, this project aimed to evaluate the impact of the first peak of the COVID-19 pandemic on referral patterns to the Queen Elizabeth Hospital Birmingham (QEHB) Liaison Psychiatry (LP) service. Additionally, we aimed to explore staff experiences in LP services across Birmingham and Solihull Mental Health Trust (BSMHFT) in order to generate Trust recommendations promoting optimal healthcare provision amidst the on-going pandemic.A mixed method service evaluation was conducted using quantitative and qualitative analysis. Quantitative methods involved reviewing referrals made to the QEHB LP service from March to June 2020, compared with the equivalent time period in 2019. Data were retrospectively extracted from the electronic clinical databases RIO and PICS, and subsequently analysed using Microsoft Office. The number of, and reasons for referrals to LP were identified, whilst focus groups were conducted to explore the subjective experiences of staff working across BSMHFT LP services.Between 1st March and 30th June 2020, 984 referrals were made to the QEHB LP service, compared to 1020 referrals in 2019, representing a 3.5% reduction. From 2019 to 2020, referrals due to psychotic symptoms and deliberate self-harm rose by 12.8% and 14.1% respectively, whilst referrals for drug and alcohol-related causes reduced by 28.3%. A significant increase (150%) in referrals for medication or management advice was seen. Focus groups indicated that staff perceived an initial reduction in number of referrals, but an increase in the acuity of patient presentations.Staff reported anxiety around contracting and transmitting SARS-Cov-2, exacerbated by uncertainty around patients’ COVID-19 status. In QEHB, sixty-five of the 984 referrals (7%) had a positive SARS-Cov-2 PCR swab, with the remaining 919 referrals being either negative (68%) or unknown (25%). Ninety-six percent of consultations were conducted face-to-face in QEHB. There were conflicting views amongst staff regarding whether more consultations could have been conducted remotely. Furthermore, varying perceptions of support and communication from both the physical and mental health trust were reported.Quantitative data indicates that COVID-19 impacted LP healthcare provision in BSMHFT. Whilst referral numbers remained similar between the equivalent period in 2019 and 2020, a change in the nature of referrals to LP at QEHB was seen. This was corroborated by qualitative data which highlighted a perceived change in acuity of referrals. These findings have been disseminated across the Trust and subsequent recommendations are being implemented during the on-going pandemic.


Systemic corticosteroids and immunosuppressant agents are the mainstay of therapy for non-infectious uveitis (NIU). However, the risks associated with systemic administration and the need of delivering an effective and safe anti-inflammatory treatment targeted to the site of inflammation have prompt the use of local therapy in the management of NIU. This review will analyse the different local treatment options available, including corticosteroids, anti-vascular endothelial growth factor (VEGF), methotrexate and the recent biologics. Non-infectious uveitis (NIU) encompasses a wide range of ocular inflammatory disorders, accounting for up to 20% of cases of severe vision impairment in adult population , 2. TherSystemic corticosteroids, eventually associated with second-line immunosuppressive agents, are the mainstay of treatment for non-infectious posterior uveitis (NIPU) , 5. HoweCorticosteroids commonly administered via local route include triamcinolone acetonide (TA), dexamethasone (DEX) and fluocinolone acetonide (FA).TA has long been the most commonly used corticosteroid for treatment of unilateral, refractory macular oedema secondary to NIU –9. It caCompared to periocular and intravitreal TA, intravitreal corticosteroid implants offer the advantage of a gradual and sustained release of the drug to the posterior segment, resulting in reduced rates of relapses and re-injections.DEX insert 0.7 mg  is an intravitreal, biodegradable implant, approved for the treatment of macular oedema secondary to NIPU , 11. TheSafety and efficacy of 0.7-mg and 0.35-mg DEX implants for treatment of intermediate and posterior NIU have been compared in a 26-week sham-controlled trial . Eyes trThe PeriOcular versus INTravitreal (POINT) trial compared the effectiveness of 40-mg periocular triamcinolone acetonide (PTA), 4-mg intravitreal triamcinolone acetonide (IVTA) and 0.7-mg intravitreal dexamethasone implant (IDI) for treatment of non-infectious uveitic macular oedema over a 6-month follow-up . CRT andTo summarize, the results suggest that intravitreal treatment is superior to periocular approach in the management of macular oedema and improvement of visual acuity, and that the efficacy between intravitreal treatments, namely TA and DEX implant, is comparable . In thisAlthough macular oedema is the most frequent indication to intravitreal corticosteroid implants in the management of NIPU, it is not the only one. A multicenter retrospective cohort study on intravitreal corticosteroid implants in NIPU showed that vitritis is the second most common indication, confirming the use of local corticosteroids devices with the aim of achieving control of both macular oedema and vitreous inflammation . SimilarFA implants are available at different doses: 0.59 mg , 0.18 mg  and 0.19 mg . Despite the short systemic half-life of FA, the non-biodegradable FA implant (FAi) releases the steroid at a stable rate for up to 3 years, a much longer period of action than DEX and TA , 20.Intravitreal 0.59-mg FA implant (Retisert®) was the first FDA-approved implant for treatment of NIPU. The implant was intravitreally placed through a pars plana sclerotomy and then fixed to the sclera. It releases FA over a period of 3 years at a rate of 0.6 μg/day during the first month and 0.3–0.4 μg/day for about 30 months.The Multicenter Uveitis Steroid Treatment (MUST) trial compared efficacy and safety of systemic corticosteroids (plus immunosuppressants when indicated) and 0.59-mg FAi in 479 eyes with NIPU over a 24-month follow-up period . The resThe MUST Follow-up Study followed 248 eyes enrolled in the MUST Trial for up to 7 years with a focus on long-term outcome of macular oedema . OverallSimilarly, a randomized clinical trial compared the effectiveness of 0.59-mg FAi and systemic therapy (corticosteroids ± immunosuppressive agents) in 140 patients with NIPU analysing time of first uveitis recurrence at 24 months . SubjectSince 0.59-mg FA implant requires surgical implantation with associated risks of post-surgical hypotony, resistant IOP elevation requiring device explant, scleral thinning, endolphthalmitis and separation of the implant from the strut, new corticosteroids intravitreal implants have been introduced, utilising a simpler delivery method and overcoming some of these limitations.Both 0.19-mg (Iluvien®) and 0.18-mg (Yutiq®) FA implants are intravitreally injected through the pars plana with a preloaded applicator with a 25-gauge needle in an office-based setting. Both are designed to release FA over a 3-year period at a rate of 0.2 μg/day, progressively decreasing to 0.1 μg/day.The three-year results of the prospective, randomized, sham injection-controlled clinical trial analysing the recurrence rate of uveitis in adults with a diagnosis of NIPU treated with intravitreal 0.18-mg Fai compared to the standard of care have been recently published , 24. TheGiven the lack of comparative trials between low-dose FA and DEX implants and long-term studies on repeated injections of DEX implants, it is difficult to draw conclusions about which implant is better in terms of efficacy and safety in the treatment of NIU , 24. It Intravitreal anti-VEGF agents are diffusely used to treat choroidal/retinal neovascularization and cystoid macular oedema (CMO) secondary to degenerative, vascular and inflammatory diseases. VEGF takes part in the inflammatory response by increasing vascular permeability and contributing to the blood-retinal barrier disruption that lead to CMO, the most common cause of visual impairment in uveitis . Mean leA number of studies on anti-VEGF use in the treatment of uveitic macular oedema has been published, although the retrospective design, small sample size, different protocols used and lack of direct comparison among anti-VGEF agents make it difficult to interpret often conflicting results. In a retrospective case series of 13 patients with recalcitrant uveitic macular oedema, a single intravitreal injection of 2.5-mg bevacizumab  resulted in a significant reduction of CRT. However, there was no improvement of BCVA at 3 months . By contOther studies compared intravitreal anti-VEGF agents with intravitreal TA. A single injection of 4-mg intravitreal TA (IVTA) and 2.5-mg bevacizumab were retrospectively compared in recalcitrant uveitic macular oedema over a 6-month follow-up period. CRT significantly improved in both groups, while a significant BVCA improvement was observed only in IVTA-treated patients . OppositAltogether the result support the use of intravitreal anti-VEGF agents as alternative or supplementary treatment for recalcitrant uveitic macular oedema. Compared to intravitreal corticosteroids, anti-VEGF agents are associated with a significantly lower risk of cataract development and IOP elevation, although characterized by limited anti-inflammatory effect and short intravitreal half-life requiring monthly injections , 32.Methotrexate (MTX) is a steroid-sparing agent, commonly administered via systemic route in inflammatory diseases with or without ocular involvement. MTX is an antimetabolite that interferes with the metabolism of folic acid and thus with DNA synthesis, inhibiting the dihydrofolate reductase. Intravitreal MTX was first used in the treatment of primary intraocular lymphoma. Given its anti-inflammatory effect, the drug has been used and proven effective as an alternative option in patients with NIPU and/or macular oedema difficult to treat with conventional therapy , 38. In Efficacy of a single intravitreal injection of 400 μg-MTX in 0.1 ml has been evaluated in a case series of 15 patients with unilateral exacerbations of NIPU and /or macular oedema over a 6-month follow-up period . MTX injSirolimus, also known as rapamycin, is a macrolide with antifungal, anti-inflammatory and immunosuppressive effects on T-lymphocytes . Oral siThe Sirolimus Study Assessing Double-masKed Uveitis TReAtment (SAKURA) included a total of 592 patients (347 patients in SAKURA 1 and 245 patients in SAKURA 2) randomly assigned to receive three injections of 44 μg (low-dose active control), 440 μg or 880 μg intravitreal sirolimus at by-monthly intervals –48. In bDespite the limited data available, patients receiving intravitreal sirolimus are unlikely to develop cataract or glaucoma, even though comparative studies between sirolimus and corticosteroids have been not performed. Although characterized by anti-inflammatory activity which makes the sirolimus suitable as alternative treatment for recalcitrant NIU with or without macular oedema, its short half-life requiring multiple re-injections is one of its main disadvantages. To date, the safety of a biodegradable intravitreal sirolimus implant has been tested in rabbits with promising results .Monoclonal antibodies against TNFα, a key pro-inflammatory cytokine, are diffusely used for the treatment of eye-involving systemic inflammatory diseases , 51. UntIntravitreal treatments, in particular corticosteroids, have gained a prominent role in the treatment of NIU. The use of slow-release devices has overcome the limitations of repeated injections and still represent an important option in the management of NIPU. Current available options for intraocular therapy result in control of inflammation for periods ranging from 3 to 36 months. Even though the price of the devices is high when considering individual use, the long effect and the benefit of avoiding systemic therapy with all possible side effects and the need for regularly monitoring of the patients, which includes several hospital visits, blood tests and use of preventative therapy for known side-effects such as osteoporosis, makes this option an attractive alternative in terms of health economics. Cataract surgery is a common complication when using local steroids, but it also represents a common problem in uveitis patients in general.The use of local therapy has been predominantly used for patients with unilateral or asymmetric disease and for those without an active systemic disease. These are obvious indications, as long as there are no contraindications such as steroid induced ocular hypertension/glaucoma. Bilateral cases may also benefit from this strategy both as a primary therapy in cases of contraindication or intolerance to systemic therapy and as an adjunct to help reduce the burden of systemic therapy. This is something that became quite obvious in the management of Birdshot retinochoroiditis where the use of a dual approach has allowed good control of the retinal vasculitis and choroiditis with the use of reduced systemic therapy (unpublished data). Ozurdex is the choice for local therapy in cases of active disease, including macular oedema, and Iluvien becomes the option for those who need long-term control using local approach. A good response to Ozurdex is reassuring but does not guarantee an equal response to Iluvien.Despite their anti-inflammatory efficacy, the well-known ocular side effects, the occurrence of recalcitrant inflammation and the presence of contraindications to corticosteroids have prompted the search for alternative, nonsteroidal therapies. An increasing number of intravitreal drugs is being studied for NIU treatment, including anti-VEGF, immunomodulating and biological agents, with encouraging results. Randomized clinical trials are needed to reliably establish their efficacy, safety and indications.