What is the association between exposure to the COVID-19 pandemic and preschool-aged children’s cognitive and emotional development?In this cross-sectional study including data from the Ontario Birth Study, pandemic-exposed children had significantly higher problem solving and fine motor skills at 24 months of age but lower personal-social skills compared with nonexposed children. At 54 months of age, pandemic-exposed children had significantly higher vocabulary, visual memory, and overall cognitive performance compared with nonexposed children.These findings suggest that health care practitioners and educators may encounter a mix of pandemic-related outcomes among young children as they plan recovery efforts following the pandemic. This cross-sectional study compares cognitive and emotional development scores of preschool-aged Canadian children exposed to the COVID-19 pandemic with scores of children assessed prior to the pandemic. The association between COVID-19 social disruption and young children’s development is largely unknown.To examine associations of pandemic exposure with neurocognitive and socioemotional development at 24 and 54 months of age.This cross-sectional study evaluated associations between pandemic exposure vs nonexposure and developmental outcomes with covariate adjustment using data from the Ontario Birth Study collected between February 2018 and June 2022. Eligible participants were children aged 24 and 54 months. Data were analyzed from June to November 2022.COVID-19 pandemic exposure defined as assessment after March 11, 2020.Neurodevelopmental assessment using the ASQ-3  and MCHAT-R  at 24 months of age, and neurocognitive and socioemotional assessment using the National Institutes of Health Toolbox at 54 months of age.P = .005) and higher problem-solving  compared with nonexposed children. In contrast, pandemic-exposed children had greater risk for personal-social difficulties using cutoff scores  and continuous scores  compared with nonexposed children. At 54 months of age, pandemic-exposed children had higher receptive vocabulary , visual memory , and overall cognitive performance  compared with nonexposed children, with no differences in socioemotional development.A total of 718 children at age 24 months  and 703 at age 54 months  were included. At 24 months of age, 460 participants  were assessed during the pandemic  and 258  were assessed prepandemic . At 54 months of age, 286 participants  were assessed from March 14, 2020, to June 6, 2022, and 417  were assessed from February 8, 2018, to March 10, 2020. At 24 months of age, pandemic-exposed children had reduced risk of problem-solving difficulties using cutoff scores (odds ratio [OR], 0.33; 95% CI, 0.18-0.62; This cross-sectional study found both positive and negative associations between pandemic exposure and preschool children’s cognitive and emotional well-being within a relatively socioeconomically advantaged sample. However, long-term consequences of the pandemic on developmental outcomes in children are not fully understood, particularly for preschool-aged children who may be highly sensitive to pandemic stress given the heightened plasticity of the brain during this period.6 Understanding how the pandemic may have affected preschool children’s development is important for practitioners who provide care to children and families, and to acquire evidence to increase preparedness for future disasters.The COVID-19 pandemic produced pervasive social disruption, widely believed to have affected the well-being of children and families.11 In contrast, few studies have examined the effects of the pandemic on children’s neurocognitive functioning. A 2022 meta-analysis12 found limited evidence for significant neurodevelopmental difficulties among infants and young children born or assessed during the pandemic compared with prepandemic children, with marginal evidence of communication problems among those assessed during the pandemic. The small number of studies in this area make it unclear whether, and to what degree, the pandemic may have adversely affected children’s neurocognitive development.Most studies in children and adolescents during the pandemic focused on socioemotional outcomes with longitudinal studies and meta-analyses suggesting that the prevalence of mental health problems increased during the pandemic compared with prepandemic levels.17 These include the fact that most studies: (1) have been conducted with small and highly selected samples; (2) rely on parental reports of outcomes, which are prone to reporting biases; and (3) lack a prepandemic comparison sample or use data from historical samples that differ on key sociodemographic characteristics from the pandemic-exposed group. The current study addresses these limitations by combining assessments of socioemotional and neurocognitive development during the pandemic using both parent-report and performance-based measures with comparisons to a prepandemic cohort from the same study using matched methods and measures. Specifically, we leverage data from the Ontario Birth Study (OBS), a prospective pregnancy cohort. The OBS began prior to the pandemic and continued recruitment and follow-up during the pandemic. In the current study, we examined cross-sectional associations between general pandemic exposure vs nonexposure with child neurodevelopment at 24 months of age and neurocognitive and socioemotional functioning at 54 months of age. We hypothesized that children assessed during the pandemic would demonstrate less optimal neurodevelopmental, neurocognitive, and socioemotional outcomes at both ages compared with children assessed prepandemic.Existing studies examining pandemic effects on children have several limitations.18 This study was approved by the research ethics board at Mount Sinai Hospital and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.This cross-sectional study used data from the OBS, a prospective pregnancy study with continuous recruitment since 2013. Women receiving prenatal care at Mount Sinai Hospital in Toronto, Ontario, were recruited before 17 weeks’ gestation. Participants were asked to complete questionnaires that included sociodemographic and health information and to consent to the collection of clinical information.In 2018, a companion protocol, OBS Kids, was initiated to follow participating mothers and their liveborn children to age 54 months. Telephone follow-up was conducted at 8 and 36 months, and in-person visits were conducted at 24 and 54 months of age, when development was assessed. As of June 29, 2022, there were 2501 mother-child dyads eligible for OBS Kids. For 1545 of these, the child had reached 48 months of age; 1258 were invited to complete the 54-month follow-up, with 753 total completions and 724 completed by June 29, 2022. Twenty-one twins were excluded , leaving 703 for analyses at age 54 months. For 1346 of the eligible mother-child dyads, the child had reached age 24 months; 1140 were invited to complete the 24-month follow-up, with 762 total completions and 738 completed by June 29, 2022. Twenty twins were excluded, leaving 718 for analyses at 24 months.19 Participants in the nonexposed group were assessed before this date, meaning they had no exposure to the pandemic at assessment. The groups were compared independently at ages 24 and 54 months with little overlap.The exposure was any early childhood exposure to the COVID-19 pandemic. Participants were considered part of the pandemic-exposed group if they completed assessments after March 11, 2020, the date the World Health Organization declared COVID-19 a global pandemic.20 For analyses, scores on the ASQ-3 were included both as continuous variables  and binary variables defined by scores either below or above a standard cutoff value.20 For the latter, scores in the monitoring or below cutoff range  were combined into the at-risk category; scores above this cutoff were included in the typically developing category .20The Ages and Stages Questionnaire, Third Edition (ASQ-3) was used to assess neurodevelopment at 24 months. The ASQ-3 is a psychometrically sound screening tool measuring communication, gross motor, fine motor, problem solving, and personal-social skills.20 provided an additional neurodevelopmental measure. Scores from 0 to 2 were considered low risk, while scores from 3 to 20 were considered higher risk, resulting in a binary variable  included in analyses. The ASQ-3 and MCHAT-R were completed by mothers as part of an in-person visit or over the telephone. Before the pandemic, 22% of questionnaires were completed by phone, compared with 91% during the pandemic.The Modified Checklist for Autism in Toddlers, Revised (MCHAT–R), a validated and adequately reliable screening tool for autism,21 This instrument has strong validity and reliability and has been widely used in this age group.23 Age-corrected standard scores with a mean (SD) score of 100 (15) were used in analyses. A Cognitive Composite score reflecting overall cognitive skills was also analyzed.24 Higher scores represented better performance for all tasks.Children completed the NIH Toolbox Early Childhood Cognitive Battery at age 54 months, administered on iPads during in-person visits to participants’ homes. The Flanker Inhibitory Control Test, Dimensional Change Card Sort (DCCS) Test, Picture Sequence Memory Test, and Picture Vocabulary Test were administered. These tasks assess inhibitory control and attention, cognitive flexibility, visual episodic memory, and language skills, respectively.26 Age- and sex-corrected T-scores  were used in analyses.Mothers also completed the NIH Toolbox Emotion Battery. Before the pandemic, 8% of questionnaires were completed by phone, while 72% were completed by phone during the pandemic. The Anxiety, Negative Psychosocial Functioning, and Psychological Well-being summary scores, computed using standard methods, were used.B, where a 1-unit increase in the variable is associated with a B unit increase in the outcome on the outcome’s original scale). We tested both unadjusted models and adjusted models that controlled for maternal age (years), child sex , gestational age, birth weight, maternal race , maternal birth country , maternal education , and household income . Covariates were selected based on associations with children’s cognitive and emotional development in prior studies. Information on participant race and ethnicity was self-reported and collected as part of the overall sociodemographic information collected for the OBS. Race and ethnicity was stratified as White and other or mixed race in analyses due to the small size of groups other than White. We focused on the adjusted analyses.Analyses were conducted using R version 4.2.1 . Associations between pandemic exposure vs nonexposure (reference group) and neurodevelopment were tested using either logistic or linear regression. In the logistic regression models at 24 months, the typically developing category was the reference group. At 24 and 54 months of age, linear regression was used to test the association between pandemic exposure vs nonexposure and children’s outcomes  using the MICE package in R. The frequency of missing data appeared to be randomly distributed . Sensitivity analyses were conducted in which children with known neurodevelopmental diagnoses  were excluded. To test whether the results were robust to the analytic method chosen, we conducted additional analyses to assess whether children’s outcomes varied based on duration of pandemic exposure or proportion of one’s life spent in the pandemic, as well as hierarchical linear regression models that controlled for exposure duration  and 460 were assessed during the pandemic  . At 54 mMost participating mothers self-identified as White  and approximately half reported a household income greater than $150 000 . Additionally, 304 mothers (42.3%) in the 24-month cohort and 264 mothers (37.6%) in the 54-month cohort attended graduate or professional school. There were no sociodemographic differences between pandemic-exposed and nonexposed groups. Distributions of outcome measures are shown in P = .005) but a significantly higher risk of personal-social difficulties  compared with the nonexposed group , but lower personal-social skills , compared with the nonexposed group. Fine motor skills were significantly higher in the pandemic-exposed group . Results were similar after removing children with known neurodevelopmental diagnoses  and picture sequence memory scores  compared with the nonexposed group, as well as higher cognitive composite scores   . There wP = .02) .B, 0.01; 95% CI, 0.003 to 0.02; β = 0.003; P = .01; proportion of life in pandemic: B, 7.15; 2.47 to 11.83; β = 0.15; P = .003). The age 54 months cohort had no associations with outcomes.We examined duration of pandemic exposure (in days) prior to assessment, as well as the proportion of one’s life spent during the pandemic   and personal-social skills , while those with 15 to 20 months or 20 months or more had better fine motor  and problem-solving skills . Higher problem solving was also observed for children with 10 to 15 months of exposure compared with those with less than 5 months’ exposure . At 54 months, children with 12 or more months’ exposure to the pandemic had higher picture sequence memory  and overall cognitive composite scores  compared with those with less than 6 months’ exposure.We then conducted analyses where pandemic exposure was categorized into binned groups (eTables 8-9 in P = .01) and personal-social skills , but better problem-solving skills , at 24 months (eTables 10-12 in P = .02) and cognitive composite scores , but not with pandemic exposure itself.Finally, hierarchical regression models that controlled for exposure duration revealed that pandemic exposure itself was associated with lower gross motor  may have resulted in less stress and more time spent with children at home. Combined with greater overall resources, these parents may have been able to provide cognitively stimulating learning environments that are well-known to foster cognitive development35 and buffer against the effects of adversity.37 Thus, the developmental advantages observed in the current study for pandemic-exposed vs nonexposed children may reflect the relatively privileged nature of our sample. Additional studies with greater representation across social, economic, and racial or ethnic categories are vital to understand the extent to which the current results generalize across diverse populations.Prior studies using the ASQ-3 to assess associations between pandemic exposure and children’s neurodevelopment have generated mixed results,38 Sensitivity analyses suggested that concerns with social development may have been somewhat brief, with the most significant concerns for children assessed 5 to 10 months after the pandemic began compared with those assessed within 5 months. In Ontario, this period was characterized by school closures that, while not directly relevant to the preschool-aged children in our sample, was linked to increased social distancing overall among families with children. This may have contributed to an overall perception of reduced personal-social skills that eventually eased by the end of the first year of the pandemic.Although higher functioning during the pandemic was observed for several areas of development at 24 and 54 months of age, children assessed during the pandemic had lower personal-social skills at 24 months, consistent with other studies during this period.In addition to limited socioeconomic variability, the results should be considered in light of additional limitations. First, the study was cross-sectional with 2 separate age cohorts (ages 24 and 54 months). Additionally, we only included children exposed to the pandemic in early childhood. In the future, we will be able to assess whether pandemic exposure prenatally confers risk to children’s development. Also, sources of resilience or social buffering were not explored and further work in this area is needed. Finally, we need to consider the potential for spurious results given the number of comparisons. We note that a number of comparisons were not independent, and we focused our interpretation on overall consistent patterns rather than individual nominally significant results.Findings from this cross-sectional study paint a nuanced picture regarding the well-being of preschool-aged children exposed to the COVID-19 pandemic. Our results underscore both the challenges and potential areas of resilience relevant to policymakers, systems of education, and mental health professionals as they develop remediation efforts to support families with young children.


Integration of vocational rehabilitation and mental healthcare has shown some effect on work participation at 1-year follow-up after sick leave with depression and anxiety. We aimed to study the effect on work and health outcomes at 2-year follow-up, why we performed a randomized trial was conducted to study the effectiveness of integrated intervention (INT) compared to service as usual (SAU) and best practice mental healthcare (MHC). We included 631 participants, and at 24-month follow-up, we detected no differences in effect between INT and SAU. Compared to MHC, INT showed faster return-to-work (RTW) rates (p = 0.044) and a higher number of weeks in work (p = 0.024). No symptom differences were observed between the groups at 24 months. In conclusion, compared to SAU, INT was associated with a slightly higher work rate reaching borderline statistical significance at 12-month follow-up and lower stress levels at 6-month follow-up. The disappearance of relative effect between 12 and 24 months may be explained by the fact that the intervention lasted less than 12 months or by delayed spontaneous remission in the SAU group after 12 months. Despite the lack of effect at long-term follow-up, INT still performed slightly better than SAU overall. Moderate implementation difficulties, may partly explain the absence of the hypothesized effect. Integrated intervention, as implemented in this trial, showed some positive effects on mid-term vocational status and short-term stress symptom levels. However, these effects were not sustained beyond the duration of the intervention.The online version contains supplementary material available at 10.1007/s10926-023-10094-7. In terms of weeks in work, SAU was equal to MHC and INT. Table Reccurring long-term sick leave (≥ 4 weeks) affected 99 (22.2%) of the 445 participants who returned to work. Of the 149 persons who returned to work in the SAU group, 26 (17.5%) experienced reccurring sick leave. In the MCH group, the corresponding number was 32 (23.5%) of 136 participants, and in the INT group 41 (25.6%) of 160 persons.At 24-month follow-up, we observed no statistically significant differences between any of the self-reported outcomes: symptoms of anxiety, depression or stress, level of functioning, self-efficacy, quality of life, and presenteeism. These results are presented in Supplement 5.Subgroup analyses for all outcomes  are shown in Supplement 6. Only selected and significant subgroup or interaction analyses for outcomes at 24 months are described here. When comparing INT with the other two groups, interaction was seen for the variable baseline diagnosis (anxiety vs. depression) on RTW rates and proportion in work. This was supported by subgroup analyses of persons with anxiety in which the MHC group showed considerably poorer vocational outcomes than the other groups. This tendency was not seen among participants with baseline depression; here, no significant differences between the three groups were observed.In the small subgroup of participants without employment at baseline , the INT group had worked 39.4 weeks (SD 7.6) at 24-month follow-up. In the other groups, the number was 28.6 weeks (SD 7.0) for SAU and 27.3 weeks (SD 6.6) for MHC. Yet, these differences were not statistically significant .Sensitivity analyses of all questionnaire outcomes are shown in Supplement 7. Best/worst-case scenarios showed substantial deviations from the main results. This was expected because of the low response rates and large differences in response rates between trial arms (between 56.7% and 66.5%).This trial was conducted to test if INT would improve the RTW process of persons on sick leave with anxiety or depression. The long-term results of this trial do not generally support our hypotheses, as SAU and INT differed neither on vocational nor on self-assessed outcomes. Compared to MHC, though, INT showed some vocational benefits in terms of weeks in work and time to RTW.Establishing true integration of the intervention components in INT proved to be a difficult, time-consuming venture that was complicated by distrust and diverging goals and norms between the involved organizations , 27. ThuThe disappearance of effect on proportion in work, specifically between 12- and 24-month follow-up, could be due to several factors. First, the interventions in INT spanned several months, and for many participants it lasted more than 6 months after randomization. Despite the fact that a substantial proportion of the participants had still not returned to work 12 months after randomization, practically nobody received any interventions beyond that point. This could explain why no effect was seen thereafter. If so, a long-term effect might be achievable if the intervention is continued for participants who have still not returned to work after 12 months. Second, the disappearance of effect on this outcome may be caused by spontaneous remission to a ceiling level in the SAU group between 12- and 24-month follow-up, while this ceiling was reached just before 12-month follow-up in the INT group as a result of the intervention. If that explains most of the difference in effect, this group (at baseline) should still be considered at high risk of long-term negative vocational outcomes that call for the development of effective interventions. Third, it may matter that some of the practitioners delivering the interventions were only trained for a rather short period of time and hence lacked experience, unlike in other studies of effective RTW interventions (see for example ). Yet, tOne other trial has tested an integrated mental healthcare and vocational intervention: the Norwegian At Work and Coping (AWaC) intervention for persons either at risk of or on actual sick leave or on long term health-related benefits. Here, 7.8% more persons had increased work hours or stable work after the integrated intervention compared to SAU after 18 months (p = 0.018) . Our stuThis trial has a sufficiently large sample size and thus relevant power on primary and secondary outcomes. However, the study has some serious limitations that prevent strong conclusions. Like in similar RTW trials, workplace-directed service components were only implemented to a fair degree . WorkplaMulti-disciplinary and integrated interventions using elements such as roundtable meetings and co-location are difficult to implement and demand great effort from the involved organizations . The impThis trial compared INT to SAU and MHC. Against our hypothesis, long-term results showed that, INT did not cause improved vocational status, symptom levels, quality of life or self-efficacy compared to SAU at 24-month follow-up. However, compared to SAU, INT showed slightly greater stress symptom reduction at 6-month follow-up and a slightly higher proportion in work at 12-month follow-up. Compared to MHC, INT showed better vocational outcomes at both 12- and 24-month follow up but no effect in terms of self-reported health. INT was only implemented to a fair degree throughout the trial, and further research should be conducted to affirm the effect and feasibility of integrating healthcare with vocational rehabilitation in similar welfare settings.Below is the link to the electronic supplementary material.Supplementary Material 1


Background: The impact of inhaled corticosteroid (ICS) in the interaction between asthma, COVID-19 and COVID-19 associated outcomes remain largely unknown. The objective of this study is to investigate the risk of COVID-19 and its related outcomes in patients with asthma using and not using inhaled corticosteroid (ICS).Methods: We used the TriNetX Network, a global federated network that comprises 55 healthcare organizations (HCO) in the United States, to conduct a retrospective cohort study. Patients with a diagnosis of asthma with and without ICS between January 2020 and December 2022 were included. Propensity score matching was used to match the case cohorts. Risks of COVID-19 incidence and medical utilizations were evaluated.Results: Out of 64,587 asthmatic patients with ICS and without ICS, asthmatic patients with ICS had a higher incidence of COVID-19 . On the contrary, asthmatic patients with ICS revealed a significantly lower risk of hospitalization , emergency department visits , and mortality . In addition, subgroup or sensitivity analyses were also conducted to examine the result of different vaccination status, disease severity, or COVID-19 virus variants.Conclusion: For asthmatic patients using ICS, risk of COVID-19 was significantly higher than non-users. The observed association could provide potential guidance for primary care physicians regarding the risk of COVID-19 in asthmatic patients. UncontrCOVID-19 is a pandemic with more than 580 million confirmed cases and more than 6.4 million deaths worldwide as of August 2022 . AirbornPatients often die of respiratory failure. As COVID-19 patients are infected through the respiratory tract, it was speculated that patients with asthma had a potentially heightened risk of acquiring SARS-CoV-2 infection as well as worse COVID-19 outcomes .The severity of COVID-19 is often linked to changes in the status of white blood cell, particularly the presence of lymphocytopenia, with indications that cytokine storm conditions are associated with disease severity. In patients with severe COVID-19 symptoms, the serum TNF alpha and IL-6 were reported to be massively elevated . InhaledHowever, according to a study by Aveyard et al., asthma does not appear to be associated with an increased risk of severe COVID-19. In contrast, chronic obstructive lung disease and interstitial lung disease are linked to a 50% higher risk of severe COVID-19. It's important to note that while these increased risks exist, they are relatively small when compared to factors like gender and diabetes. These findings should be considered within the broader context of overall mortality risk, potentially helping to alleviate anxiety among individuals with respiratory conditions. Additionally, the relationship between the use of inhaled steroids and the risk of severe COVID-19 remains uncertain . NonetheConflicting results regarding whether a diagnosis of asthma increases the risk of severe COVID-19 and whether the use of ICS has an impact on the prognosis is unclear. The purpose of this study was to evaluate medical data on asthmatic patients with and without ICS use to determine any associations with the prognosis for COVID-19. To our knowledge, this is the first study to use TriNetX data to examine the association between COVID-19 and asthmatic patients with ICS and without ICS. We aimed to study the risks of incident COVID-19 risk and medical utilization in asthma patients with and without ICS.https://trinetx.com/. The variables which can be captured from TriNetX include demographics, diagnoses , procedures , medication (coded in Veterans Affairs (VA) National Formulary or Anatomical Therapeutic Chemical (ATC) Classification System), laboratory measures , genomics , and healthcare utilization.This was a retrospective cohort study. The data used in the present study was aggregated from TriNetX, the world’s largest, living ecosystem of real-world data and evidence for the life sciences and healthcare. It contains de-identified electronic health records of more than 250 million persons from more than 120 global healthcare organizations (HCOs) from countries in North and South America, EMEA, and Asia-Pacific, including Japa, providing up-to-the month real-time data. TriNetX employs a standardized framework to ensure data quality, which encompasses three primary categories of quality metrics: conformance, completeness, and plausibility . It has Data and analysis were done in June, 2023. We used the US Collaborative Network, the subnet of TriNetX platform to perform the related analysis. This network includes 56 HCOs. Due to our study objective, the duration of the study was limited to the period between 1 January 2020 and 31 December 2022.Study subjects included newly diagnosed adult asthma (ICD-10-CM code J45) patients (≥19 years old) enrolled in the TriNetX US database between 1 January 2020 and 31 December 2022. The study subjects were then divided into two cohorts according to whether the patients had been prescribed inhaled anti-inflammatory medicine (VA code RE101), which included mometasone (ATC code R01AD09), flunisolide (R01AD08), beclomethasone (R03BA01), budesonide (R03BA02), fluticasone (R03BA05), and ciclesonide (R03BA08). The index date for the ICS cohort was set as the date when the inhaled anti-inflammatory medicine was first prescribed, whereas the index date for the control cohort was established according to the date of the initial asthma diagnosis. Selection process were presented in The following covariate factors (within 1 year prior to the index date) were incorporated into the present study to reduce confounding effects.Age at index was used; sex was coded as female or male; race was encoded as White, Black or African American, Asian, and American Indian or Native Hawaiian; and social economic status was encoded as a proxy code .Nicotine dependence (ICD 10 code F17) and tobacco use (ICD 10 code Z72.0) were encoded as proxy codes for smoking. Alcohol-related disorders (ICD 10 code F10) were used as a proxy for alcohol drinking status.All comorbidities were coded as presence or absence, i.e., dichotomous variables, and were coded as ICD-10 codes. The comorbidities used in the present study included gastro-esophageal reflux disease without esophagitis (ICD 10 code K21.9), liver disease (K70-K77), essential hypertension (I10), diabetes mellitus (E08-E13), disorders of lipoprotein metabolism (E78), systemic lupus erythematosus (M32), Sjogren syndrome (M35.0), chronic kidney disease (N18), gastritis and duodenitis (K29), depression (F32), ischemic heart disease (I20-I25), and overweight and obesity (E66).COVID-19 vaccination status was considered an important factor that may be related to outcomes, and thus the present study incorporated COVID-19 vaccine data into the analysis. Medications were divided into user or non-user based on the prescription information, and included adrenergics, inhalants (ATC code R03A), adrenergics for systemic use (ATC code R03C), other systemic drugs for obstructive airway diseases (ATC code R03D), vasoprotective corticosteroids (ATC code C05AA), and corticosteroids for systemic use, plain (ATC code H02A).2) and immunoglobulin E .Laboratory results were also included in the analysis to explore the baseline characteristics between the two cohorts, and included body mass index  or confirmed by laboratory RNA testing .2. Medical utilization, which included hospitalization , emergency room visit (CPT code 1013711), critical/intensive care (CPT code 1013729), and mechanical ventilation .3. All-cause mortality, defined by vital status record (deceased) encoding in TriNetX. The mortality information in the TriNetX database was gathered from Social Security Administration and published obituary records.The outcomes of interest in the present study wereBoth cohorts were followed up between 1 day after the index date to 365 days.vaccinated with COVID-19 related vaccines before index date, never vaccinated with a related vaccine, detailed in severe: inpatient or used emergency department services, critical care services within 1 month on or after the index date, non-severe: never hospitalization, emergency room visit, or critical care services within 1 month on or after the index date) were performed to explore the differences among those groups. Sensitivity analyses were performed to illustrate the consistency of results among different virus  time wave.We used the built-in capability of TriNetX to generate propensity scores and performed 1: 1 matching using greedy nearest neighbor matching with a caliper of 0.1 pooled standard deviations of the two groups. In addition, to examine the effect of adjusting for different factors on the results, this study aggregated the results of four models, namely, 1) model 1: before matching, 2) model 2: matching with age at index, sex, race, 3) model 3: matching with age at index, sex, race, social economic status (SES), lifestyles, vaccination and body mass index (BMI), and 4) model 4: matching with age at index, sex, race, SES, lifestyles, comorbidities, vaccination, medication usage, and body mass index (BMI). Comparisons between two groups before and after matching were explored with a standardized mean difference. If the standardized mean difference was lower than 0.1, it was considered a good match. Kaplan-Meier analysis was used to estimate the probability of the outcome of interest including mortalities, medical utilization, including hospitalization and emergency room visit, critical/intensive care, and mechanical ventilation. The hazard ratio (HR) and its associated confidence intervals (CI), together with the test for proportionality were calculated using R’s Survival package v3.2–3. The proportional hazard assumption was tested using the generalized Schoenfeld approach. The TriNetX platform also runs a suite of tests, comparing the outcome from independent, industry-standard methods, to verify that all counts, rates, and statistics are calculated correctly as outlined in https://support.trinetx.com/hc/en-us/articles/360053133594-How-does-TriNetX-test-for-proportionality-on-a-hazard-ratio-. Log-Rank test results indicated whether the survival curves were different between groups, and were done within TriNetX. Subgroup analyses based on COVID-19 vaccination status (The basic characteristics of the subjects before and after matching are shown in p < 0.001). Due to the results violate the proportional hazard assumption, we further present the results from different study period to explore the results over time , and emergency department visits , .The ICS cohort exhibited a significant lower mortality risk than control cohort  .We further examined the risk of outcomes in subgroups stratified by COVID-19 vaccination . Among tWe further divided study subjects into severe and non-severe based on whether they were hospitalized or visit emergency department or used critical care services within 1 month on or after the index date. Among the severe subjects, the ICS cohort had a higher risk of COVID-19 incidence , hospitalization , critical/intensive care , and mechanical ventilation usage  than the control cohort. Among thenon-severe subjects who had been prescribed an inhaled anti-inflammatory medication exhibited a significantly higher risk of incidence of COVID-19 , and medical utilization . The non-severe ICS cohort also reveal lower risk of hospitalization  than non-severe control cohort. .In order to demonstrate the consistency of results, we implemented the identical study design across various time waves of the COVID-19 virus . Irrespective of viral prevalence, ICS cohort demonstrated elevated rates of COVID-19 in comparison to the control cohort. However, the statistical disparities were solely evident during the Delta variant pandemic . Irrespective of viral prevalence, ICS cohort exhibited a significantly lower risk of hospitalization and emergency department visit .This large retrospective cohort study utilized TriNetX, a real-world database, to investigate the association of ICS and the risk of COVID-19 incidence. In this analysis, we found that patients with newly diagnosed asthma who were prescribed with an inhaled corticosteroid had a higher risk of COVID-19 incidence than patients not on ICS. ICS usage lowered risks for medical utilization, including hospitalization, emergency department visits, and also the risk for mortality.ICS is the backbone therapeutic option in the treatment of asthma. It not only controls the asthmatic condition, but it has also been suggested as a reliever in combination with formoterol in the current GINA guideline . Since tIt is recommended that asthma patients should be up-to-date with COVID vaccinations according to the major respiratory societies . In the Severity of asthma was difficult to measure and most studies performed assessments based on the patient’s medication use, according to the guidelines of the Global Initiatives for Asthma (GINA) . It was Hospitalization due to acute exacerbations is an important prognostic factor and exacerbation triggers are often unpredictable, such as viruses, pollens, pollution, and poor adherence . StudiesThe mechanism linking ICS use and COVID-19 infection is not clear. It has been shown that a lower expression of ACE2 and TMPRSS2 in patients under ICS use could have a protective effect in preventing COVID-19 infection . IzquierBased on the findings of this article, it appears that we should place even greater emphasis on whether patients are attentive to practicing social distancing while using ICS. The use of ICS may indeed present an ideal opportunity for our mucous membranes to interact with the external environment. In the future, research should continue to investigate whether patients’ failure to maintain adequate social distancing during ICS use may be linked to COVID infection. If this hypothesis proves to be accurate, it becomes essential to educate patients about the significance of observing social distancing measures while using ICS.This study had several strengths. We included newly diagnosed patients in our comparisons, rather than using existing asthma patients, which possibly excluded those with previous acute exacerbation histories, thereby potentially confounding the medical utilization results. We included laboratory data, including IgE level and BMI data, to help confirm the diagnosis and severity. The data contain both insured and uninsured patients with a large patient number, providing an accurate account of the burden of specific diagnoses on healthcare systems from the EMR.However, there were some limitations in this study. First, we may have underestimated the risk of COVID infection if patients did not seek medical help when symptoms developed under ICS use. Regional variation existed in reporting COVID symptoms during the pandemic . Second,We observed a positive association between the use of ICS and incident COVID within a subsequent year of the initial diagnosis of asthma, based on a comparison with propensity score-matched patients not exposed to ICS. Patients on ICS should follow their treating physician’s advice to prevent COVID-19 infection.


Background: COVID-19 continues to present challenges in the care of older adults with frailty and/or comorbidities and very old patients, who can be hospitalized with severe COVID-19 despite full vaccination. Frailty is a heterogeneous syndrome characterized by an increased aging-related vulnerability due to a reduced physiological reserve and function of systemic organs, and is associated with an impairment of activities of daily living. Frail older adults remain at elevated risk of mortality from COVID-19 compared to older adults without frailty, and some pre-existing risk factors such as malnutrition, prolonged bed rest, and the association with comorbidities can aggravate the SARS-CoV-2 infection. Furthermore, the severity of COVID-19 can impact on long-term functioning of older patients surviving from the infection. Persistent symptoms are another emerging problem of the post-vaccination phase of pandemic, as most patients suffer from chronic symptoms which can become debilitating and affect the daily routine. Aim of this review: In this complex relationship, the evaluation of COVID-19 in vulnerable categories is still a matter of high interest and personalized care plans based on a comprehensive geriatric assessment, tailored interventions; specific therapeutic algorithms among older adults are thus recommended in order to improve the outcomes. The COVID-19 pandemic, caused by the rapid diffusion of the novel coronavirus SARS-CoV-2, has rapidly spread in the world since December 2019. About seven million people died during the COVID-19 pandemic [Frailty is a heterogeneous syndrome and there is no consensus about its correct definition. Several risk factors of frailty have been identified, such as malnutrition, inactivity and polypharmacy and patients with frailty syndrome are at risk for poor clinical outcomes such as hospital admission, reduced mobility, high risk of falls, mortality and cumulative decline in multiple physiological systems ,4.WHO defines frailty as a condition characterized by an increased aged-related vulnerability due to a reduced physiological reserve and function of systemic organs, and is associated with an impairment of activities of daily living (ADL) .Frailty is very common in adults older than 70 years, and the incidence of frailty increases progressively with age. It has indeed been estimated that about 15% and 25% of subjects older than 65 and 85 years are affected by frailty, respectively.Frailty is a dynamic and potentially reversible process which affects more often older women than men, who are however more susceptible to deterioration .p = 0.03 and of 7.47, 95% CI 1.73–32.34, p = 0.007 for pre-frail and frail patients, respectively) [In the context of COVID-19, frail older adults were approximately 51% of hospitalized patients with elevated risk of mortality compared to older adults without frailty. Since the beginning of the SARS-CoV-2 pandemic, older adults have been the most affected group by severe COVID-19. In March 2020, the Centre for Disease Control and Prevention (CDC) has reported that adults aged > 65 years accounted for 80% deaths from COVID-19 . It has ctively) .p = 0.028), a history of depressive disorder , stroke  and complications  at a multivariate analysis [The severity of COVID-19 seems to impact also on long-term functioning of older patients surviving from the infection. Persistent symptoms are another emerging problem of the post-vaccination phase of the pandemic, as most patients suffer from chronic symptoms which can become debilitating and affecting the daily routine. The presence of persistent symptoms after an acute infection from SARS-CoV-2 has been defined ‘long COVID’ ,24. Alsoanalysis . These danalysis ,26.Some hypotheses have tried to explain the differences in terms of risk of morbidity and mortality of older adults with COVID-19, but few studies have investigated the mechanisms underlying the difference of risk between older and younger people. Potential mechanisms of explanation are immunosenescence, microbial dysbiosis and inflamm-ageing .SARS-CoV-2 is transmitted through respiratory droplets from person to person. The virus enters in host cells by binding angiotensin-converting enzyme 2 (ACE-2) receptors and can spread to the lungs by infecting pneumocytes, also called alveolar type 2 epithelial cells. They are not the only cells infected because another molecule, the lymphocyte function-associated antigen 1 (LFA-1), mediates the entry of SARS-CoV-2 into T lymphocytes .via Toll-like receptors (TLRs), recognize pathogen-associated molecular patterns (PAMPs). This mechanism is impaired in older adults and contributes to the significant increase of injury in COVID-19 patients.Some people, especially older adults, are at high risk of acute respiratory distress syndrome (ARDS), because they have a significant reduction of ACE2 activity related to aging which leads to the increase of severity of lung injuries . FurtherImmunosenescence is an impairment of the immune system associated with ageing. In older adults the immune system has a decreased capacity to cope with infections, which hampers the pathogen clearance.The other immune mechanism which occurs with aging is inflamm-ageing, a chronic increase of systemic inflammation. The immune system is always hyperactive, but in an ineffective way .Inflamm-aging leads to an increased production of proinflammatory cytokines (e.g. interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)). SARS-CoV-2 enters into human cells and causes an activation of the cells of innate and adaptive immunity. Macrophages and dendritic cells that belong to the first group, through the Toll-like receptor (TLR) 3, 7 and 8, recognize the viral RNA. This binding results in the activation of the inflammasome and the production of cytokines such as IL-1β, IL-6 and TNF-α. The production of these molecules is necessary for the human body to protect itself from the viral invasion not only at the respiratory level but also in other organs affected with SARS-CoV-2 such as the heart, blood vessels, kidneys and brain ,33.During severe COVID-19 a hyperactivation of the immune system has been observed, together with an excessive production of cytokines, which causes negative effects on the body such as multi-organ failure and ARDS .Older adults tend to develop severe forms of COVID-19 and have stronger hyper inflammation  and hymmune response as compared to young people. In these subjects, there is a more suitable environment for the activation of the inflammosome than in younger adults, through the TLR receptors and through the viroporins, which are ion channels built by the virus in host cells and that release K + into the extracellular fluid, changing the ionic balance and activating the inflammosome. In the older adults some conditions such as aging, renal disease, reactive oxygen species (ROS) unbalance and hyperproduction, facilitate this electrolyte imbalance and the cytokines hyperproduction .A reduced immune response is instead a peculiar characteristic of very old patients; they commonly present less ground glass opacities than younger counterparts on CT findings .Intestinal microbiota alterations related to aging can be associated with chronic systemic inflammation, oxidative stress, insulin resistance and may negatively impact on muscle protein synthesis and function .It has been hypothesized that gut dysbiosis is also associated with altered inflammation in older adults with COVID-19 and contributes to the alteration of the immune system and the severity of the disease. Recent evidence has revealed that microbiota changes are linked to superinfections in COVID-19 patients, especially in older adults. Several studies suggest that SARS-CoV-2 infection could cause a decline in gut microbiota diversity leading to an increase of opportunistic bacteria such as Actinomyces Streptococcus, Rothia, Enterococcus and a decrease of some species such as Faecalibacterium, Eubacterium, Coprococcus and Ruminococcus . This dyThere is evidence also from autopsy studies that gut dysbiosis related to corticosteroid therapy, persistent mechanical ventilation, prolonged hospital stays and lymphocyte depletion is associated with fatal COVID-19 related to opportunistic infections ,49. FiguVaccination campaigns against SARS-CoV-2 have significantly reduced globally the number of deaths and the risk of severe disease, but there is still a great field of uncertainty in the older age, especially in frailty subjects. Only a limited percentage of frail older patients has been included in the vaccine arms of clinical trials , specifiThe real-word evidence documents that some older adults are still hospitalized for severe COVID-19 and have a significant risk of death despite full vaccination .Tang et al. have evaluated the SARS-CoV-2 vaccine effectiveness during the Delta wave according to frailty status in a total of 58,604 U.S. veterans . Among these, 27.8% patients were in prefrail, and 24.9% in frail conditions. The authors found a reduced mRNA vaccine effectiveness against the Delta variant in frail and pre frail patients (respectively 62.8% (95%CI: 59.8–65.7), and 73.9% (95%CI: 72.0–75.7)). The effectiveness was highest in robust patients, reaching 77.0% (95%CI: 75.7–78.3) .The mechanisms underlying the lack of a complete vaccine effectiveness in some group of patients are still unknown. Immunosenescence and inflamm-aging can be linked to an altered immune response against the vaccination. Adaptative immune system decreases with age and data indicate that antibody responses decline after a booster dose in adults older than 60 years ,56.Another issue to consider when administering vaccines to older adults is the susceptibility to adverse events (AEs). A previous study enrolling 134 frail patients older than 65 years  and residents in Spanish long‐term care facilities (LTCFs), excluded a significant increase of adverse reactions in this group. Factors such as older age, frailty, cognitive impairment and comorbidities were not associated with significant changes in antibody titers, and the authors concluded that the BNT162b2 mRNA COVID‐19 vaccine was effective and safe in older adults with frailty. However, these data were taken with caution given the limited sample size of the study .More recently, a large phase 2, randomized clinical trial has documented a significant higher rate of AEs in at-risk patients with at least one Charlson Comorbidity Index condition . FurtherA Comprehensive Geriatric Assessment (CGA) is a multidimensional (multidomain) approach aimed at evaluating specifically the different patient’s domains such as functional ability, physical, cognitive and mental health, and also other domains such as financial status, social support and environmental factors .There isSome methods are especially useful to identify frailty among patients with COVID-19, the most important are the Clinical Frailty Scale (CFS), which gives a score to patients on the basis of their daily functions and is a useful tool to identify subjects at risk of mortality for COVID-19, the Frail Scale (FRAIL), which is a simple and low-cost method including five criteria that categorize a patient in robust, pre-frail and frail, and the Edmonton Frailty Scale (EFS), which reveals the risk of frailty by investigating nutrition, mood and drugs .The most common instrument to measure frailty in COVID-19 patients and to predict their prognosis is CFS . SeveralIn another single-center prospective observational cohort study which enrolled 729 patients aged ≥80 years, 251 were frail according to the CFS. The evaluation of frailty in the Emergency Department (ED) was useful to predict the risk of in-hospital death in older COVID-19 adults In a retrospective cohort study of 103,561 COVID-19 patients  hospitalized in England, the authors examined the relationship between frailty and COVID-19 mortality using the Hospital Frailty Risk Score (HFRS), a method which records ICD-10 codes for dividing patients into three frailty risk categories (low (< 5), intermediate (5–15), and high (> 15)). Intermediate and high frailty risk categories had reduced survival days compared to those without frailty (accelerated failure time estimates for intermediate and high risk categories of 0.63 (95% CI 0.58–0.68) and 0.67 (95% CI 0.62–0.72), respectively) [p < 0.001). Also delirium was a predictor of death (p = 0.007) and a higher prevalence was observed of heart failure and peripheral artery disease  [The risk of death driven by frailty seems to be enhanced by the presence of comorbidities . The retctively) .In the GeroCOVID study, disease severity was not associated with loss of autonomy in survived COVID-19 older patients; on the contrary, the pre-morbid ADL and frailty had a primary role in the loss of ADLs .Since the pandemic outbreak, researchers have tried to identify strategies able to reduce the risk of clinical deterioration from COVID-19, hospitalization and mortality. Before the development of an effective campaign of vaccination, some drugs already available on the market were urgently evaluated and employed in order to try to improve the outcome of COVID-19 patients, especially older adults .The use of hydroxychloroquine, an antimalarial drug, was suspended as it did not show an improvement in survival, and was associated with important AEs such as prolonged QT interval and the risk of secondary arrhythmias .Other pharmacological classes were considered, including antivirals, anticoagulants and anti-inflammatory drugs.p = 0.03). especially in mechanically ventilated patients , therefore a time > 7 days from symptom onset should suggest a cortisone treatment [p = 0.63) [The use of dexamethasone remains the mainstay of treatment in hospitalized patients having a severe COVID-19 pneumonia. Very old patients, despite full vaccination and/or not having taken antiviral drugs in an early phase of the disease (see below), can still have a severe lung disease with respiratory failure, needing oxygen and/or ventilation and may benefit of cortisone therapy in a late (hyper inflammation) stage of the disease. The RECOVERY trial has demonstrated efficacy in reducing the mortality at 28-day of dexamethasone therapy in those who need either invasive mechanical ventilation or oxygen. Among 2104 patients of the RECOVERY trial who were assigned to dexamethasone, 469 and 494 were aged between 70 and 79 years and ≥ 80 years respectively (22 and 23%). Age-stratified data were not available, therefore any additional benefit in older adults was not reported [reatment . An earl = 0.63) . Moreove = 0.63) .The first antiviral drug which was approved for COVID-19 in patients at high risk of progression to severe disease was remdesivir, a viral RNA polymerase inhibitor and adenosine nucleotide analogue . Two difThe effectiveness and safety of this drug in older adults are still largely unknown, even though some studies have shown efficacy in reducing the risk of severe COVID-19 disease in this population. The SEMI-COVID-19 Registry, a large retrospective analysis of 4331 SARS-CoV-2 vaccine-free patients (1312 aged ≥ 80 years), who were hospitalized for COVID-19 between July and December 2020 in Spain, has shown that 140 very old patients who were treated with remdesivir had a lower mortality risk than those were not treated (OR (95% CI): 0.45 (0.29–0.69)) .Against beneficial effects, remdesivir can cause severe hepatic and/or renal dysfunction, and the drug should be used with caution especially in the first days of treatment, with monitoring of liver and kidney function. Interestingly, there is low data about the safety profile of remdesivir in very old patients. A study enrolling 80 patients of whom only 32.5% were aged ≥ 80 years has shown that liver dysfunction induced by remdesivir occurred in 36.3% of all-age groups, and that there were no significant differences in terms of AEs between younger and older patients .In nonhospitalized patients, other two drugs have been approved in COVID-19 patients at risk of progression to severe disease: Paxlovid (Nirmatrelvir/Ritonavir) and Molnupiravir (Lagevrio). Both drugs have been indicated in patients who do not require supplemental oxygen therapy and should be administered within 5 days of the onset of symptoms. Despite the first positive results of the MOVe-OUT study , howeverPaxlovid (Nirmatrelvir/Ritonavir) has resulted instead in a risk reduction of 89% versus placebo of progression to severe Covid-19, without significant safety concerns .The recommended dose is 300 mg of Nirmatrelvir (2 × 150 mg tablets) with 100 mg of ritonavir (1 × 100 mg tablet) taken together orally every 12 h for a total of 5 days.Nirmatrelvir inhibits the 3CL main protease (Mpro) from SARS-CoV-2 and reduces the ability of SARS-CoV-2 to replicate in human cells, while ritonavir is a strong inhibitor of cytochrome P450 (CYP) 3A4 and acts as a strong pharmacokinetic boosting agent, having already been used to enhance HIV protease inhibitors .The drug was effective to reduce hospitalization rates and risk of death associated with COVID-19 in patients aged ≥ 65 years during the omicron surge , but gave no benefits in younger adults . The useAnother early therapeutic option which can be used early to reduce severe forms of COVID-19 in hospitalized patients is represented by monoclonal antibodies (MonoAbs), which should be given within 7 days of the onset of symptoms. The administration after 7 days can be recommended only in patients with negative serology for SARS-CoV-2 and prolonged molecular swab positivity, and in subjects with immunodeficiency . Some thThe use of MonoAbs represents a valid therapeutic option in older adults . With pap < 0.001). The effect was highest at six months of follow-up . Median participant age was 53.5 ± 15.0 years, and adults aged ≥ 60 years had a higher RR reduction than those aged < 60  [The PROVENT trial, a large, randomized phase 3 study evaluating one dose of Tixagevimab-Cilgavimab (Evusheld) vs placebo in 5197 participants with an increased risk of an inadequate SARS-CoV-2 vaccination response and/or an increased risk of exposure, has found a significant risk reduction of symptomatic COVID-19 cases in drug vs placebo-treated patients  .p = 0.0096, absolute risk reduction of 4·5%  [Furthermore, the recent Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE) study has found a significant reduction of progression to severe disease or death in drug-treated (4% out of 407 participants) versus placebo-treated (9% out of 415 participants), both unvaccinated and SARS-CoV-2 positive patients  .EMA therefore recommends the use of EVUSHELD both for pre-exposure prophylaxis of COVID-19 in subjects with a high risk of inadequate response to active immunization  and for the treatment of COVID-19 adults and adolescents aged ≥ 12 years with a weight of at least 40 kg who are at risk of severe COVID-19 but do not require oxygen therapy .Paucisymptomatic or asymptomatic older adults with COVID-19 at home should be carefully evaluated. Good hydration, avoiding malnutrition and trying to keep stable the underlying disorders are useful measures to reduce the risk of hospitalization due to worsening of the clinical picture , and to A thorough clinical evaluation and a caregiver phone call can promptly identify a worsening of the clinical condition . PeripheThe SARS-CoV-2 vaccination has radically reduced the clinical impact of the current pandemic and has improved the prognosis in patients who are still affected with the disease. However, the issue remains still open in older patients with frailty and/or comorbidities and very old patients, whocan be still hospitalized with severe COVID-19 despite full vaccination. Current treatment strategies include the early use of monoclonal antibodies, which are effective and safe in patients, especially nonvaccinated, and older adults. The inclusion of older patients in specific trials aimed at evaluating the impact of COVID-19 in vulnerable categories is recommended, and clinicians should be encouraged to establish personalized care plans based on a comprehensive geriatric assessment, tailored interventions and specific therapeutic algorithms among older adults.


Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy . At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies . However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive of AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with restoration of sensitivity to subsequent AR inhibitor therapies. The authors present a review of their clinical studies of bipolar androgen therapy for patients with castration-resistant prostate cancer, in which supraphysiologic androgen is administered intermittently to result in cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. Bipolar androgen therapy (BAT) is a new treatment concept for men whose prostate cancer is resistant to standard hormone-blocking therapy. Here the authors review results of clinical studies that were performed to test BAT in asymptomatic men with castration-resistant prostate cancer. The key findings are that BAT is safe in asymptomatic men with metastatic castrate-resistant prostate cancer, does not cause prostate cancer progression, shows clinical response with decreased PSA and tumor regression in 30%–40% of patients, and can reverse resistance and prolong response to subsequent antiandrogen therapy. These results support further testing of BAT as a new kind of prostate cancer therapy.2 The current treatment paradigm for metastatic PCa is to treat men with ADT in combination with AR signaling inhibitors (ARSI) or chemotherapy until disease progression. From the very outset of ADT use, it was recognized that all men eventually develop resistance to primary ADT, a disease stage known as castration resistant PCa (CRPC). This resistance was presumed to be due to sustained AR signaling via non-prostate sources of androgens.2 Once the patient develops CRPC, additional AR inhibiting therapies are administered with decreasing effectiveness as more lines of therapy are given.4 In addition to therapeutic resistance, chronic exposure to ADT leads to excess morbidity and, in a subset of men, may lead to transdifferentiation to a more aggressive and lethal neuroendocrine phenotype.5In 1941, Dr Charles Huggins reported on the remarkable palliative benefit of surgical and medical castration in men with symptomatic, metastatic prostate cancer (PCa). Since that discovery, inhibition of androgen receptor (AR) function through androgen deprivation (ADT) and direct AR inhibition has remained the mainstay of treatment.6 These include the CYP17 androgen-synthesis inhibitor abiraterone and antiandrogens enzalutamide, apalutamide, and darolutamide. Both abiraterone and enzalutamide received initial FDA-approval based on modest survival benefit vs. placebo in men with mCRPC post-chemotherapy and subsequently in men treated pre-chemotherapy based on the results of the COU-AA-302 (abiraterone) and PREVAIL  studies, 7-10 The effectiveness of first-line combination androgen blockade was revisited with multiple trials such as LATITUDE (abiraterone), STAMPEDE (abiraterone), ARCHES , and TITAN  each demonstrating a significant survival advantage for combination therapy compared to ADT alone in men with high risk and metastatic PCa.11-14 Recent results from the ARASENS trial also demonstrated a survival advantage for “triplet” therapy consisting of ADT + docetaxel + darolutamide vs. the “doublet” of ADT + docetaxel.15 While these trials have shown significant improvement in survival vs. the control arm, once patients develop radiographic progression, survival is relatively short with median duration of survival in the range of 18-24 months.12A number of ARSIs have been developed as first-line therapy in combination with or after ADT aimed at further blocking androgen signaling through AR.16-19 Broadly, ~95% of patients respond to initial androgen ablative therapy, with ~65% response to first-line ARSI and ~25% response to second and further lines of ARSI therapy. Evaluation of patient biopsies and autopsy studies demonstrates that CPRC cells resistant to ARSI continue to engage in AR signaling and adapt to chronic exposure to low testosterone through a progressive, auto-regulatory increase in AR expression to sufficient levels to restore AR axis activity even in the absence of ligand.20-22 At each stage, resistance first manifests as a sustained rise in the androgen-responsive gene PSA, consistent with the reactivation of a functioning AR axis.Additionally, emerging data documents a significant reduction in response rate and response duration with sequential use of abiraterone or enzalutamide as “second- or third-line” ARSI therapy. Results from a series of small studies evaluating the use of enzalutamide after progression on abiraterone show a marked decrease in PSA PFS, time to progression, and objective response.23-27 Data from a variety of studies has demonstrated that AR expression persists even in men with CRPC who have died from PCa despite having received chronic ADT and multiple types of ARSI.25 Chen et al. demonstrated that PCa cell lines adapt to serial passage in castrated mice through an auto-regulatory increase in AR expression that is sufficient to induce resistance to both ADT and the anti-androgen bicalutamide.28 Isaacs et al. documented that AR levels increased 30-90 fold in CRPC cell lines and clinical samples compared to normal prostate cells.29 While this marked upregulation of AR can drive resistance to ADT, it also creates a therapeutic vulnerability to treatment with supraphysiologic androgen (SPA).28-30 SPA can lead to growth arrest or cell death in CRPC cell models. This paradoxical effect initially was extensively demonstrated by the work of Dr Shutsung Liao, whose laboratory showed that PCA cells adapted to grow in low androgen conditions had high AR levels and were growth-inhibited by SPA in vivo.31 Over time, these xenografts became resistant to SPA through downregulation of the AR, making them once again sensitive to ADT.A major factor driving resistance to ADT is the ability of PCa cells to adapt to chronic low androgen conditions by upregulating AR activity through overexpression, gene amplification, and expression of transcriptionally active AR variants that lack the ligand-binding domain, 29 AR over-stabilization by SPA inhibits DNA re-licensing resulting in death in the subsequent cell cycle.22 Haffner et al. showed that SPA generates transient double strand DNA breaks (DSBs) in CRPC cells through the recruitment of AR and topoisomerase II beta (TOP2B) to androgen response elements (AREs).32 SPA downregulates oncogenes and upregulates tumor suppressor expression, inhibits expression of the ligand-independent AR variant, AR-V7and produces profound metabolic and gene expression changes in CRPC cells that can lead to activation of autophagy and ferroptosis.33-35Several complementary mechanisms for this paradoxical effect of SPA have been described. Isaacs et al. demonstrated that AR is a DNA licensing factor that plays a critical role in DNA replication and must be degraded as the cell goes through cycle.n = 14), (2) RESTORE—testing efficacy and safety of BAT in men with CRPC progressing on ADT, abiraterone or enzalutamide (n = 88), (3) TRANSFORMER—a randomized study comparing BAT to enzalutamide in men progressing on abiraterone (n = 195), and (4) COMBAT—evaluating sequential BAT and nivolumab (n = 44).36-40Based on this extensive preclinical data, we instituted a clinical program to demonstrate the safety and efficacy of SPA, a treatment we have termed Bipolar Androgen Therapy (BAT), in men with metastatic CRPC. To date we have completed 4 studies: (1) a proof-of-concept pilot  levels is critical for achieving the desired pharmacologic effect on the target CRPC cells.The primary modalities used to assess therapeutic response in PCa are the serum PSA level, the CT scan, the bone scan, and clinical symptoms. PSA is an androgen-regulated gene whose expression is highly stimulated by testosterone and markedly inhibited by AR inhibitors, even in growth-arrested but viable PCa cells. Thus, reliance on PSA response alone may underestimate the effectiveness of BAT and, inversely, may overestimate the response to ARSIs. Three patterns of PSA response may be seen with BAT, 42 This flare response is the basis of the ongoing BAT-RAD clinical trial (NCT04704505) designed to assess whether BAT can enhance the efficacy of Radium223 (Xofigo) in men with bone-predominant metastatic CRPC. BAT effects on PSMA-based PET imaging must also be considered, as PSMA-expression can be negatively regulated by androgens.44In addition, BAT can also induce an initial “flare response” on the bone scan, 34 The rational for etoposide was based on findings that BAT could induce DSBs that could be stabilized by the TOP2B inhibitor etoposide.31 After 3 cycles, those with a declining PSA continued on BAT alone. BAT was well-tolerated and resulted in high rates of PSA50 (7/14) and objective responses (OR) , Based on extensive preclinical data supporting BAT, a pilot study was performed in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate  and etoposide .n = 30/cohort) progressing on either enzalutamide (Cohort-A) or abiraterone (Cohort-B) or ADT alone (Cohort-C).38 The primary endpoint of the first part of the study was to assess PSA response to BAT. The second part was to determine in BAT could re-sensitize to repeat exposure to the ARSI that patients were progressing on prior to receiving BAT. Thus, patients progressing on enzalutamide were re-exposed to enzalutamide after BAT and similarly to abiraterone. PSA50 response to BAT was 30% in post-enzalutamide, 18% post-abiraterone, and 14% post-ADT alone, 36-38 PSA50 response in Cohorts-A and B was not significantly different in patients who had received 1 vs. 2 prior ARSI . Adverse events (AEs) to BAT were primarily grades 1-2, with the most common being generalized musculoskeletal pain and sexual side effects that included breast tenderness, hot flashes, and gynecomastia. Serious AEs occurred in individual patients and were not attributed to BAT, with the exception of grade-3 hypertension in 3 patients.The RESTORE study (NCT02090114) was an NIH-sponsored phase II study designed to assess BAT in men  or BAT (n = 94) at 400 mg IM every 28 days. The primary endpoint was clinical/radiographic progression free survival (crPFS). At the time of progression, patients were given the option to cross over to the alternate therapy. The trial did not meet the primary endpoint of improvement in crPFS relative to enzalutamide, with crPFS of 5.7 months in both arms (P = .2267), P = .067). The best PSA50 response was 28.4% for BAT and 25.5% for enzalutamide (P = .697), The TRANSFORMER study (NCT02286921) was a DOD-sponsored randomized phase II study designed to compare the efficacy of BAT vs. enzalutamide in asymptomatic men with CRPC progressing on abiraterone, 45 This trial enrolled 44 patients with soft tissue lesions and required tumor biopsies at baseline and post-3 cycles of BAT, prior to initiation of Nivolumab. Prior treatment with multiple lines of ARSI and up to one prior taxane was allowed. The PSA50 response to BAT in these heavily pretreated patients was 40% and the OR was 24%, 46 After 3 cycles of BAT, total AR mRNA and protein levels declined, and AR protein was observed primarily in the nucleus, Based on preclinical data showing that SPA could activate interferon response pathways, and clinical data showing extreme response to anti-PD1 therapy in 3 men previously treated with BAT, we conducted a trial testing the efficacy of BAT followed by BAT plus Nivolumab (COMBAT study), (NCT03554317).33 Thus, patients progressing on enzalutamide were re-exposed to enzalutamide after BAT, and similarly to abiraterone. The PSA50 response to enzalutamide re-exposure was 71%, but only 21% for re-abiraterone exposure, 38 After BAT, these patients were treated with first-line abiraterone or enzalutamide. In this group of 24 patients, nine with M0 and 15 with M1 CRPC, the PSA50 was 94% with a PSA90 response of 83%, 38 Remarkably, PSA-PFS in this group was 28.7 months, although this was a mix of M0 and M1 CRPC patients.Prolonged exposure to SPA leads to a rapid adaptive downregulation of AR, which should have the potential to restore sensitivity to AR blockade. We first observed this potential re-sensitization in the initial pilot study of BAT where the PSA50 response to ARSI re-exposure was 90%, 19 Overall survival for patients receiving BAT and then enzalutamide was 37.1 months, compared to only 28.6 months for those receiving enzalutamide alone .In the TRANSFORMER study, at the time of progression 47 (49%) patients on enzalutamide crossed-over to BAT and 36 (33.7%) crossed from BAT to enzalutamide. Remarkably, the PSA50 response for patients who received enzalutamide after BAT was 77.8% compared to 25.5% for patients who received enzalutamide immediately after abiraterone. OR in the enzalutamide post-BAT patients was 28.6% compared to only 4.2% for enzalutamide given immediately post-abiraterone. Time to PSA progression was also markedly improved increasing almost 3-fold from 3.8 m post-abiraterone to 10.9 months post-BAT. Finally, post-hoc analysis of PSA progression to the first and second stages of the study (PSA-PFS2) for all patients revealed a median of 19.6 months for the sequence of enzalutamide crossing over to BAT but 28.2 months for a sequence of BAT crossing over to enzalutamide. In comparison, the PFS for patients receiving enzalutamide after abiraterone in this trial was 5.7 months, which is similar to PFS observed in other studies evaluating enzalutamide after abiraterone.16-19Taken together, these combined results support the conclusion that BAT can re-sensitize PCa cells to subsequent antiandrogen therapy with results that are superior to those observed in the multiple small studies assessing the efficacy of enzalutamide post-abiraterone, 30 SPA-induced DSBs were accentuated in BRCA2-deficient PCas, and combining SPA with PARP or DNA-PKcs inhibition further repressed growth. This observation formed the basis of a clinical trial testing BAT + olaparib (NCT03516812) in men with CRPC.47 Next-generation sequencing performed on biopsies from PCa patients receiving BAT revealed that patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to BAT. Sena et al. recently demonstrated that growth inhibition of PCa models by SPA required high AR activity and was driven in part by downregulation of MYC.46 Using matched sequential patient biopsies, AR activity scores were generated based on expression of 10 canonical AR-target genes. High AR activity in pretreatment biopsies predicted downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which was shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance could be overcome by alternating SPA with the enzalutamide, which induced adaptive upregulation of AR and re-sensitized PCa to SPA. This work identified high AR activity as a predictive biomarker of response to BAT and supported a treatment paradigm for PCa involving repeat cycling between AR inhibition and activation.48 This concept is being tested in the ongoing STEP-UP trial (NCT04363164), which involves repetitive sequencing between BAT and enzalutamide using two different sequencing schedules.BAT produces PSA and objective responses in ~30% of patients with CRPC. Predictors and mechanisms of response and resistance are currently under study. Previously, Chatterjee et al., demonstrated that SPA could repress genes involved in DNA repair and delay the restoration of damaged DNA that was augmented by PARP1 inhibition.36-40 We also excluded patients with urinary obstruction requiring catheterization due to enlarged prostate secondary to PCa or benign prostatic hypertrophy (BPH).At the outset, the major concern for use of BAT in men with mCRPC was the potential to stimulate PCa cell proliferation leading to rapid progression and inducing worsening symptoms particularly worsening bone pain. Earlier studies assessing testosterone in men with symptomatic PCa demonstrated the potential for significant worsening of pain that could occur often within hours to days of treatment with testosterone. On this basis, across all BAT studies we have limited eligibility to patients who are asymptomatic with no bone pain due to PCa and no worrisome lesions  that could cause severe symptoms in the event of tumor progression.37 Serious adverse events occurred in individual patients and were not attributed to BAT with the exception of grade 3 hypertension that occurred in 3 patients.With those caveats, to date we have observed that BAT is remarkably safe in men with asymptomatic mCRPC. In the RESTORE study, adverse events to BAT were primarily grades 1-2 with the most common being generalized musculoskeletal pain and sexual side effects that included breast tenderness, hot flashes, and gynecomastia.39 Only one grade 5 AE (death not otherwise specified) was observed in a patient on enzalutamide. Grade ≥3 AEs were primarily due to worsening generalized, back or extremity pain  in the BAT group and pain , fatigue , and hypertension  in the enzalutamide group. The incidence of AEs was generally similar in the 2 groups. Notable exceptions included fatigue with 48.5% of patients on enzalutamide experiencing grades 1-2 and 7.2% grade 3-4 fatigue, compared with 31.5% of BAT patients experiencing only grade 1-2 fatigue. Enzalutamide was associated with a higher percentage of grades 1-2 constitutional symptoms such as anorexia, depression, anxiety, insomnia, headache, and generalized muscle weakness as well as GI complaints . BAT was associated with grades 1-2 increased endocrine side-effects  and musculoskeletal complaints . Most patients on BAT experienced a significant increase in hemoglobin levels that returned to baseline once BAT was discontinued.In the TRANSFORMER study comparing BAT to enzalutamide, the majority of AEs were grade 1-2; serious AEs were comparable in the 2 arms and occurred in 19.1% of patients on BAT and 20.6% on enzalutamide.36 Significant improvement was observed on SF-36 Instrument subscales of Physical Function, Emotional Well-Being, and Energy-Fatigue, on the FACIT Fatigue Scale and on the International Index of Erectile Function (IIEF) survey for patients receiving BAT compared to baseline. No significant difference was seen in the PANAS-SF screens for positive or negative response. The TRANSFORMER study evaluated QoL for patients on BAT vs. Enzalutamide. Patients on BAT showed significant improvement compared to enzalutamide on the same SF-36 Instrument subscales, on the FACIT Fatigue Scale, and on the IIEF survey.39 In a recent study designed to assess the effect of BAT on body composition, image analysis of computed tomography imaging at baseline and after 3 cycles of BAT was performed on 60 patients from the RESTORE and TRANSFORMER trials.49 Cross-sectional areas of psoas muscle, visceral, and subcutaneous fat were measured at the L3 vertebral level. Overall, patients lost a mean of 7.8% of subcutaneous fat, 9.8% of visceral fat, and gained 12.2% muscle mass. However, change in body composition did not correlate with improvements in the FACIT-Fatigue or SF-36 subscales.49In the initial pilot study, many patients reported improvement in overall quality of life (QoL) and sexual function. To formally evaluate this effect, in the RESTORE study patients completed QoL questionnaires using validated instruments.36-40 While ADT for advanced PCa often produces debilitating sexual and metabolic side effects, another highly significant feature of this approach is that BAT can make men feel remarkably better by decreasing fatigue, increasing physical activity, and restoring libido and sexual function. BAT can also increase skeletal muscle tone and decrease visceral and subcutaneous fat.48 Thus, the incorporation of inexpensive, high-dose testosterone via BAT into the treatment paradigm for men with CRPC has the potential to improve quality of life (QoL) and minimize morbidity from the metabolic sequelae produced by androgen ablative therapies. Patients who are interested in more information on BAT can be referred to a recent review written for a lay audience.48Our cumulative clinical experience over the past 10 years treating >250 CRPC patients establishes the meaningful clinical activity and safety of BAT and supports additional studies to determine its optimal clinical integration. Key findings from these clinical studies are that BAT (a) can be safely administered to asymptomatic patients with mCRPC; (b) does not produce symptomatic disease progression; (c) produces sustained PSA and objective responses in 30%-40% of patients; and (d) can re-sensitize and prolong response to subsequent antiandrogen therapy.Ongoing clinical trials are designed to assess the optimal way to sequence and combine BAT in PCa. Patients are encouraged to seek out and participate in such clinical trials when possible. For those without access to trials, there are 2 clinical settings in which BAT could be recommended based on the available clinical data. First, for asymptomatic patients who have initially progressed on ADT, BAT could be administered prior to starting an ARSI due to its marked ability to enhance subsequent response to these agents. Second, in men with CRPC progressing on abiraterone, BAT can be considered as part of sequential therapy with an antiandrogen based on results from the TRANSFORMER study. Importantly, BAT should always be given in conjunction with ongoing ADT. BAT is not to be used in patients with castration-sensitive disease outside of a clinical trial. BAT is also not currently recommended for use in patients with PCa bone pain as these patients are at risk for significant worsening of pain following testosterone injection. In those few patients who experienced pain flares in BAT clinical studies, we have observed that the flare usually occurs within 12-48 h post-testosterone injection. Pain can be treated with anti-inflammatory medications but may be severe enough to require narcotics. It typically resolves after ~1-week post-BAT, when the testosterone level begins to fall. For those patients who do develop a pain flare on the first dose of BAT that resolves by the end of a 28-day cycle, consideration can be given to continue BAT for a second cycle. We have observed pain improvement or resolution that did not return with subsequent cycles of BAT. For those patients who continue to have pain at the end of the first 28-day cycle, BAT should be discontinued.40 olaparib (NCT03516812), 223Radium (NCT04704505), and carboplatin (NCT03522064). Finally, although BAT has activity as a single agent, more importantly the sequence of BAT→ARSI  should be considered as a therapeutic continuum. On this basis, the eficacy of repeat cycling between BAT and enzalutamide is being tested in the Sequential Testosterone and Enzalutamide Prevents Unfavorable Progress (STEP-UP) trial, Fig. 4. Further studies are required to assess the disease stage and optimal timing for sequencing between BAT and ARSI based on an understanding of PCa cells adaptive response to changing AR activity in the tumor microenvironment.Although our initial results have been encouraging, with some men responding to BAT for several years, the median duration of progression-free survival across these studies is approximately 6-9 months. Thus, rational combinatorial approaches are needed that can further enhance and prolong the efficacy of BAT. Combinations based on the current understanding of the profound effects of androgen on PCa cell gene expression, metabolism, and immune microenvironment are being explored in preclinical and clinical studies. These include BAT in combination with Nivolumab (NCT03554317),