Prostate cancer can develop under hormone treatment and chemotherapy from a castration-sensitive towards a castration-resistant into a drug resistant-tumor. The main hormonal drug target is the androgen receptor (AR). Androgen deprivation therapy reduces body-own androgen production and AR antagonists inhibit androgen-mediated activation of AR. Here, molecular mechanisms are described that review knowledge about tumor cells escape therapy by developing bypass mechanisms of AR-signaling. This includes genomic and non-genomic signaling. Deciphering the involved molecules that mediate castration and drug resistance will provide the basis of potential novel drug targets that may be used in addition to AR inhibition as combinatory treatment.Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2–3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR‑dependent and contribute to PCa drug resistance will be discussed. Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer deaths in males in Western countries . PCa groCurrently, CRPC patients are additionally treated with AR-antagonists such as enzalutamide (Enz) and darolutamide (ODM-201) to fully block the AR-axis. The use of these AR-antagonists shows long terms benefits, including significantly lowering serum PSA level, decreases the risk of metastasis and prolonged overall survival in CRPC patients ,8. HowevMechanistically, AR antagonists can induce cellular senescence in PCa cells in vitro as well as ex vivo in patients PCa samples. This indicates that AR antagonists do not completely inhibit the AR rather promote the induction of an AR-dependent cellular senescence pathway ,12,13. AClassically, androgens, preferably dihydrotestosterone (DHT), bind to the AR, induce a conformational change that leads to dissociation from heat shock factors. This allows dimerization and nuclear translocation of AR to regulate the target genes. The activated AR acts as a transcription factor and suppresses or activates directly androgen-responsive target genes such as prostate-specific antigen (PSA) and many other genes involved in the differentiation and proliferation of prostatic cells . AR antaThe most common documented genomic aberration in CRPC, with around 60% of tumors, is AR gene amplification or mutation, leading to increased AR activity . AR overIt is widely accepted that mutations of AR in PCa under selection by anti-androgen treatment are one of the main reasons for DRPC ,23. MostAnother adaptive mechanism that bypasses ADT and leads to therapy resistance is the expression of AR splice variants. Approximately one-third of Enz or abiraterone treated patients express truncated receptors arising from AR splice variants (AR-Vs) . Enz treCRPC patients who express AR-V7 have both a shorter progression-free survival and overall survival. These patients fail mostly to respond to Enz or abiraterone treatment, and thereby the suggested treatment is those alternative drugs that target the N-terminal domain (NTD) , such asSo far, several EPI-derived compounds have been designed, analyzed on the molecular level and included in clinical trials. A new derivative of EPI is EPI-506 or ralaniten acetate that is used in a clinical trial for mCRPC patients as an oral soft gel capsule (NCT02606123). In this study, different concentrations (80–1800 mg) of EPI-506 were used, while only high doses >1280 mg) showed a meaningful decrease in PSA level for a short period ,34. This0 mg showIn CRPC a specific AR enhancer located 650 kb centromeric to the AR gene body was identified to be activated, led to gain of function probably due to the selective pressure exerted by anti-androgen treatment. This AR enhancer gene is either co-amplified with the AR gene in CRPC or even amplified at a higher rate. Further, it was detected that AR enhancer is enriched with H3K27 acetylation . AnotherThe AR transcriptional activity is regulated by a series of co-regulator complexes such as chromatin remodelers, co-activators and co-repressors that are co-recruited by the AR to chromatin by binding directly or in a protein complex to AR to regulate gene activity. A battery of different co-activators and co-repressor are known that interact with the AR . In geneCHD1 encodes an ATP-dependent chromatin remodeler. CHD1 regulates AR occupancy at a subset of AR binding sites of lineage-specific enhancers. CHD1 loss alters AR binding at lineage-specific enhancers and modulates distinct transcriptional programs to drive prostate tumorigenesis [CHD1 in vivo is the basis of a heterogeneous drug resistance mechanisms to Enz [The binding of AR to androgen response elements (ARE) itself can be regulated by diverse factors. The prostate-specific tumor suppressor gene igenesis . It has s to Enz .Another AR co-regulator and chromatin pioneering factor is homeobox B13, HOXB13, which interacts with AR to bind to AR target loci. HOXB13 is a homeodomain transcription factor that is involved in the development of normal prostate, as well as the formation and maintenance of prostate cancer . InteresAlongside with HOXB13 other pioneering factors such as FOXA1 and GATA2 act as chromatin factors at enhancer sites to regulate on one hand the expression of AR and on the other hand the activity of AR and AR-V7 at chromatin in mCRPC. FOXA1 induces open chromatin conformation to allow the binding of other transcription factors . This piAlso, GATA2 promotes AR activity and enhances progression of androgen dependent PCa to CRPC status. High GATA2 expression correlated with more aggressiveness of PCa . Higher Another epigenetics regulator of AR is enhancer of zeste homolog 2 (EZH2), which is a member of the polycomb group protein. . Of noteAnother AR-coactivator is CREB5, being amplified and overexpressed in CRPC, and associates with resistant PCa. In a recent clinical study, studying more than 1000 PCa patients under Enz treatment has shown that the expression of the oncoprotein CREB5 was abnormally high in ADT resistant tumors, which is due to an increased copy number of CREB5. High expression of CREB5 enhances the proliferation of PCa cells under ADT condition and mediates also resistance to Enz treatment. Therefore, drugs targeting CREB5 might be useful in DRPC therapy . Also, AR co-repressors may mediate castration resistance. The AR co repressor LCoR is recruited to AR in the presence of androgen. This recruitment of LCoR to androgen-bound AR inhibits AR action associated with inhibition of tumor progression in xenograft tumors of CRPC cells . The oveBesides the genomic action of AR to regulate gene expression by recruitment to chromatin, the non-genomic action of AR includes the regulation of several signaling pathways in the cytoplasm, including membrane-bound protein receptors .It is known that not all androgen-activated AR translocates into the nucleus. Androgen-activated AR interacts in the cytosol with other factors at non-genomic level. This interaction leads on one hand to modulation of signal transduction pathways and on the other hand, to phosphorylation of AR. Factors that interact with AR include the non-receptor tyrosine kinase Src, AKT and PKA. In addition, AR interacts with PTEN-PI3K, and the mTOR-autophagy pathways. These pathways cross-regulate each other. They may therefore contribute to drug resistance and promotion of PCa progression ,64. VariPreclinical studies showed that nerve growth factor (NGF) signaling enhances proliferation and metastasis in PCa. NGF binds to tropomyosin receptor kinase A (TrkA), which in turn activates the Ras/MAPK and AKT pathways . In LNCaA further important aspect which promotes PCa progression and contributes to drug resistance is the PCa microenvironment. The tumor microenvironment consists of stromal and inflammatory cells in addition to cancer-associated fibroblasts (CAFs). CAFs lead to the reorganization of structure and composition of the connective tissue, as well as enhanced tumor growth, invasiveness, and drug resistance of PCa. Hence, CAFs promote PCa progression. In the presence of androgen, the AR co-localizes with the scaffold protein filamin A (FilA) in fibroblasts. The AR/FilA complex results in CAFs moving towards PCa cells in 2D and 3D culture by increasing migration and invasiveness. An AR-derived staple peptide, Rh-2025u, was developed to disrupt the AR/FilA complex. The disruption inhibited migration and invasion. This peptide also impaired the AR induced metalloprotease cascade and thereby inhibiting remodeling of extracellular matrix, implying to be an interesting new therapeutic drug useful in combination with AR inhibition .In addition to the expression of AR splice variants that lack the AR LBD, other mechanisms of alternative activation of AR signaling have been described. In line with the interference of PI3K/AKT signaling with AR, PTEN gene mutations are common in PCa cancerogenesis, with loss of PTEN being identified in many metastatic PCa. PTEN is a tumor suppressor that inhibits the PI3K/AKT pathway. This augments the upregulation of the PI3K-AKT pathway in PCa and especially in mCRPC. First studies focused on blocking PI3K/AKT pathways as a possible therapeutic approach to treat PCa, since PI3K, through basal activation of AKT, has been strongly related to PCa growth and progression. Pharmacological inhibition of PI3K increased AR protein levels and thereby activating HER3-mediated AR-related gene expression . This reMultiple studies, therefore, investigated the possible benefits of combined treatment compared to single-agent therapy. Treating xenograft mouse models of androgen insensitive LNCaP with AZD5363, an AKT inhibitor leads to transient inhibition of tumor growth and PSA stabilization but followed eventually by resistance to AZD5363. However, combined treatment of a CRPC mouse model with the AKT inhibitor, AZD5363, and the AR antagonist Bic prolonged disease stabilization without signs of drug resistance . AnotherSrc kinase also emerges as a major player in the resistance of PCa. Src belongs to the family of non-tyrosine kinase family (SFK). Src expression is often correlated with malignant tumors and has been targeted in many therapies in PCa . On one Mechanistically, it is suggested that the Src kinase-mediated phosphorylation of AR at Tyr267 in the NTD, harboring a potent AR transactivation domain, as well as Tyr551 and Tyr552 in the hinge region, harboring the AR NLS, promotes both the nuclear translocation and transactivation by AR. Inhibition of Src kinase with PP2 was able to reduce AR translocation . Pre-cliNoteworthy, an interesting link between Src and mutation in the tumor suppressor genes BRCA1 and BRCA2 was shown. It was reported that in mCRPC with loss of BRCA1/2 heterozygosity Src signaling is enriched, therefore being more sensitive to Src inhibitors relative to mCRPC with wildtype BRCA2. Furthermore, Src knockdown in BRCA-null PCa cells enhanced PARPi sensitivity and indicated that Src activation might be a mechanism for PARPi resistance. This is supported by the findings using a combined treatment of a Src inhibitor with a PARPi inhibitor revealing a synergistic effect to inhibit proliferation of BRAC2-null mCRPC. Thus, inhibition of both Src and PARP is a promising new approach to treating mCRPC .ADT and AR-antagonist treatment may also fail due to intratumoral androgen production and therefore can lead to castration resistance. It was shown that intratumoral testosterone and DHT levels in mCRPC patients were significantly higher than in the control group . Drug reThe AKT-mTOR pathway regulates autophagy, which is suggested to be also a crucial pro-survival mechanism for CRPC ,94. UndeIt was shown that CRPC cells can survive PI3K inhibition. The suggested underlying mechanism is that AR increases the expression of Integrin α6β1 and indirectly Bnip3. Active AR-Integrin signaling suppresses apoptosis and induces Bnip3-mediated autophagy and mitophagy. Notably, inhibition of integrin α6β1 re-sensitized PTEN-negative CRPC to PI3K inhibitors. Hence, this might explain the lack of successful clinical trials of PI3K inhibitors for AR-dependent CRPC and unfold on the other hand a new approach to therapy .A mechanism of therapy resistance by AR antagonists may be explained by the findings that Enz and Bic induce autophagy leading to a pro-survival response in PCa cells ,97. ApalTherapy resistance of PCa is not only caused by AR-dependent mechanisms but also by AR-independent mechanisms, still activating a part of AR signaling. A short overview of possible pathways, which results in primary and acquired resistance, is described briefly in the following. The glucocorticoid receptor  is also a nuclear steroid receptor and closely related to the AR. GR becomes increasingly expressed in primary PCa tissue after long-term treatment with Enz . TherebyMechanistically, GR may bind an overlapping set of AR target genes ,103,104 GR expression and activity is also associated PCa cells with resistance to radiation. After radiotherapy, resistant cells have constitutive activated GR and decreased expression of AR. In radioresistant PCa, results suggest that radiation-induced GR through increased cAMP levels. Survival is promoted by GR in androgen-dependent PCa, but not in CRPC . InsteadMYCN, which is required for PCa tumor maintenance [MYCN amplification or N-Myc overexpression [MYCN amplification, is associated with shorter survival [Combined ADT with AR-antagonists may also cause resistance and lead to the development of neuroendocrine PCa (NEPC), presumably due to selective pressure from ADT and AR antagonist treatment . NEPC isntenance . The conpression . It has pression . RNA-seqsurvival .N-Myc overexpression in C4-2 cell line confers resistance to Enz by increasing ATM kinase activity, which promotes migration and invasion of PCa cells . MechaniONECUT2 is a transcription factor identified as a master regulator of AR networks in mCRPC. ONECUT2 suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA . ONECUT2p53 interferes with AR signaling through binding to the AR promoter and suppressing AR expression. Enhanced p53 protein level negatively regulates the AR mRNA and protein levels in LNCaP cells. Knock down of p53 enhances AR protein expression in LNCaP cells . MutatioAnother AR-bypass pathway is the activation of the AKT-mTOR pathway by p66Shc, which is an oxidase previously shown to promote androgen-independent cell growth through generation of reactive oxygen species (ROS) and being elevated in PCa tumor samples. P66Shc is also known as a sensor for oxidative stress-induced apoptosis and as a longevity protein in mammals. Interestingly, in cancer p66Shc seems to activate AKT, mTOR, ERK, and Rac1 . Since pMicroRNAs (miRNAs) are endogenous small non-coding RNAs that act as a tumor suppressor or oncogene post-transcriptionally. Emerging evidence has discovered the importance of aberrant expression of miRNAs that are involved in the development of CRPC. Deregulated miRNA mediate drug resistance through different mechanisms such as reducing apoptosis by downregulating E2F1, enhancing CSC properties to facilitate tumorigenicity and chemoresistance, promoting the EMT process to increase PCa aggressiveness. For example, upregulation of miR 221/-222 via targeting p27/Kip1, HECTD2, and RAB1A are responsible for 90% of CRPC .Cisplatin is commonly used as a chemotherapy agent for the treatment of cancer. Chemotherapy of patients with cisplatin is initially effective, but patients eventually develop resistance . The lncIn CRPC, the overexpression of cytokines such as IL-6 is known to promote tumor progression and drug resistance ,134,135.The IL-6 signaling pathway is seemingly important in the regulation of growth and drug resistance of PCa cells and it helps cancer cell survival. A phase I study with patients scheduled for radical prostatectomy received either siltuximab or no drug. Tumor samples of siltuximab treated patients showed a decrease in  phosphorAnother pathway that involves STAT3 is an aberrant TGF-β pathway that plays a major function in the occurrence of DRPC and induction of epithelial-mesenchymal transition (EMT) because members of TGF-β family induce the expression of Snail . Snail iMoreover, reduced or loss of AR expression results in activation of IL-6 signaling, which activates STAT3. Activation of STAT3 is associated with enhanced Sox2, CD44, Nanog, Musashi-1, and integrin α2β1 that are stemness regulators. Thus, this may lead to a cancer stem cell (CSC) phenotype. Mounting the CSC repertoire results then in an unwanted sustained malignancy of human PCa tumors and is suggested to be responsible for the emergence of DRPC and tumor relapse . Epidermal growth factor receptor (EGFR) is involved in regulating cellular growth and function. The EGF ligand causes activation of EGFR by autophosphorylation, which leads in multiple downstream signaling . The mRNThe AR is a critical genomic and non-genomic factor in PCa pathogenesis. Adaptive AR signaling and occurrence of therapy resistant signaling are selected through therapy leading to CRPC and DRPC with unwanted further PCa progression. It emerges that many different adaptive and bypass pathways can lead to DRPC, which emphasizes the need for personalized medicine . AR-depe


Among the 50 patients considered as unhealed, on the contrary, radiological imaging showed an improvement in imaging in 39 patients (78%) and a worsening in 11 patients (22%). Our study showed that there was no correlation between the clinical condition of patients and their follow-up radiological imaging in the context of PVO.No recommendations are established for monitoring pyogenic vertebral osteomyelitis (PVO). Thus, the realization of systematic follow-up radiological imaging is controversial. The objective of this study was to evaluate the interest in follow-up radiological imaging in patients with PVO. We conducted a retrospective cohort analysis of patients with PVO who had both baseline and follow-up radiological imaging. We classified the follow-up images into two groups, improvement/stability, and deterioration, compared with the baseline data. For each patient, we compared their radiological imaging follow-up to their clinical-biological condition assessed at the same time. Eighty-six patients were included. The mean age was 68 years (±13). A total of 99 radiological imaging examinations at diagnosis and at follow-up were analyzed, 69 Magnetic Resonance Imaging (MRI), and 30 Computerized Tomography (CT scans). The mean delay between the follow-up radiological imaging and clinical evaluation was 2.8 +/− 2.1 months. Of the 36 patients with clinical and biological recovery, 24 patients (67%) had improved radiological imaging and 12 patients (34%) had radiological worsening (new abscesses ( Pyogenic vertebral osteomyelitis (PVO), also called spondylodiscitis, septic discitis, and spinal osteomyelitis , represeThe follow-up radiological imaging of patients with PVO is not standardized. It is, therefore, common that some physicians prescribe systematic follow-up MRI. Although some authors have suggested specific monitoring criteria in MRI , the corThe objective of this study was to evaluate the interest in a follow-up of radiological imaging in patients with PVO.We conducted a retrospective analysis of patients with PVO between January 2010 and August 2019 from the University Hospital of Besançon (France). The diagnosis of PVO was confirmed by a positive microbiologically sample  and typical radiological features  or Computerized Tomography ). The duration of follow-up was defined by the date of the patient’s post-antibiotic consultation, for which a clinical examination, a biological assessment, and radiological imaging were performed.Only patients with the same radiological imaging (MRI or CT scan) at diagnosis and follow-up were analyzed. The images were analyzed by two different physicians blind to clinical and biological data. Follow-up images were compared to those taken at diagnosis and were classified into two groups: improvement/stability group or deterioration group. The following radiological imaging parameters were assessed: soft tissue infiltration, epidural, para-vertebral and intra-muscular abscesses, and epiduritis. Patients were classified in the deterioration group when worsening of at least one of the radiological imaging parameters was observed; otherwise, they were classified in the improvement/stability group. Then each follow-up radiological imaging was compared to the clinical-biological status of the patient assessed at the time of the examination. To assess the clinical status of patients, we retrospectively extracted clinical information from patients’ medical records. Patients were considered cured if they had recovered from their clinical condition prior to infection, and the CRP had to be less than 10 mg/L.t-test. All statistical tests were two-tailed, and p < 0.05 was considered statistically significant. Statistical analyses were computed by SPSS 22.0 .Statistical analysis. All variables were examined by univariate analysis using the chi-square or Fisher’s exact test, as appropriate. Continuous variables were analyzed by Student’s Staphylococcus aureus (34%), gram-negative bacilli (20%), and Streptococcus (19%). The level of spinal involvement was predominantly lumbar (We included 86 patients. The mean age was 68 years (±13 years), 58 were men. Among these patients, 21 had a history of spinal surgery, 9 of them with osteosynthesis. The most frequently reported germs were methicillin-sensitive y lumbar .p < 0.001) and 10 (12%) with neurological impairment (p < 0.001). The average CRP at diagnosis was 65 mg/L versus 26 mg/L at follow-up (p = 0.01)  patients presented with spinal pain, and 29 (34%) had a neurological deficiency, whereas at the follow-up assessment, there were 21 (24%) patients with spinal pain ( = 0.01) .A total of 99 diagnosis images and 99 follow-up images from 86 patients were analyzed, 69 MRIs, and 30 CT scans.p = 0.037) or MRI . Epiduritis was significantly less frequent at follow-up, only with MRI   .Of the 36 patients with clinical and biological recovery, 24 patients (67%) showed an improvement of radiological images, and 12 patients (34%) showed radiological deterioration. Among the 50 patients considered as unhealed, on the contrary, radiological imaging showed an improvement in radiological lesions in 39 patients (78%) and a worsening in 11 patients (22%) .n = 11, 45%). In unhealed patients, all parameters, abscess, epiduritis, and soft tissue infiltration had a similar reduction of approximately 30% , four required abscess drains because of the increase or persistence of abscess without any associated neurological deficit. Of these four patients, only one was classified as completely healed. Two patients underwent a laminectomy, and two patients a corporectomy.Of the 21 patients with a history of spinal surgery, six were considered cured, with only one image classified in the deterioration group. Among the 15 patients considered unhealed, 12 follow-up images showed the condition to be improving/stable, and three were worsening.Our results are consistent with those previously reported in the literature regarding PVO. Thus, our patients were mainly men; there was a predominance of staphylococci responsible for the infection and a higher frequency of lumbar involvement .To our knowledge, this is one of the first studies comparing several follow-up radiological imaging modalities of patients with PVO with the clinical and biological status of the patients at the same time. Our study shows that there was no correlation between the patient’s clinical and biological status and his follow-up radiological imaging on average 3 months after first imaging, regardless if an MRI or a CT scan was performed.Although the majority of previous studies suffer from their small sample size ,9,10, ouPrevious studies have reported that patients with PVO may have worsened bone and disc damage on MRI despite clinical improvement. In contrast, a soft tissue lesion tended to improve and was one of the first signs of improvement in MRI. It has also been shown that gadolinium contrast enhancement could persist for more than four months, although its intensity may be reduced. Contrast enhancement was undetectable after 2 years of follow-up ,16.The persistence of contrast enhancement on follow-up MRI despite clinical improvement has also been described ,18. The 18F]FDG-PET/CT if follow-up imaging is required, the same imaging modality will be preferred. In these situations, the [18F]FDG-PET/CT allows the determination of residual infection after treatment [It seems interesting to consider our results and previous data in order to optimize the follow-up of patients with spondylodiscitis. Thus, apart from a neurological aggravation, follow-up radiological imaging should not be systematic. Clinical evaluation associated with infectious markers would allow sufficient follow-up to assess the evolution of the disease. However, the accuracy of infectious biomarkers during spondylodiscitis has not been extensively studied. Carragee et al. reported that a 25% decrease in erythrocyte sedimentation rate (ESR) during the first month of antibiotic therapy was rarely associated with management failure . HoweverThe limitations of our study are mainly based on its retrospective and monocentric nature. The analysis of CT scans is another limitation to be considered. Indeed, CT scans are less sensitive than MRI for analyzing the abnormalities described in our study, especially epiduritis. However, this bias was minimized by comparing the same radiological imaging modality to baseline and during follow-up. Moreover, our study was carried out in a university hospital center that handles cases that are sometimes more complicated or atypical than those encountered in other centers.In conclusion, our results support the fact that follow-up radiological imaging during PVO does not correlate with the clinical status of the patient. Its use, apart from proven clinical complications, could complicate the management by providing contradictory data with respect to the clinical observation performed by the physician. Thus, apart from a modification of the clinical examination, notably neurological and aggravation of clinical or biological infectious parameters, follow-up radiological imaging does not seem to be relevant and useful in the follow-up of patients with PVO. Clinical and biological evaluation seems sufficient to determine whether or not the patient is cured. Many images are made during the follow-up with a questionable cost/effectiveness ratio.


In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation.ClinicalTrials.gov (NCT04381936).This randomised, controlled, open-label, platform trial , is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death .Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days . Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days  and National Institute of Health Research. The majority of SARS-CoV-2 infections are either asymptomatic or result in only mild disease.Hypoxic respiratory failure in patients with COVID-19 is associated with evidence of systemic inflammation, including release of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumour necrosis factor α, and elevated concentrations of D-dimer, ferritin, and C-reactive protein (CRP).7Tocilizumab is a recombinant humanised anti-IL-6 receptor monoclonal antibody that inhibits the binding of IL-6 to both membrane and soluble IL-6 receptors, blocking IL-6 signalling and reducing inflammation. Tocilizumab is licensed in the UK as an intravenous treatment for patients with rheumatoid arthritis and for people with chimeric antigen receptor T-cell-induced severe or life-threatening cytokine release syndrome. Randomised trials of tocilizumab in COVID-19 have so far shown mixed results for 28-day mortality: seven small trials reported no benefit and the somewhat larger REMAP-CAP trial reported a benefit in patients requiring organ support.Evidence before this studyWe searched MEDLINE, Embase, and MedRxiv from inception up to March 5, 2021, for clinical trials or meta-analyses evaluating the effect of interleukin-6 inhibitor treatment on patients with COVID-19 using the search terms (“COVID-19” OR “COVID” OR “SARS-CoV-2” OR “2019-nCoV” OR “coronavirus”) AND (“tocilizumab” OR “sarilumab” OR “interleukin-6 inhibitor” or “IL-6 inhibitor”).We identified eight relevant randomised trials that compared tocilizumab with usual care or placebo in hospitalised patients with COVID-19. All were assessed as at low risk of bias. Of these trials, only the REMAP-CAP trial in critically ill patients found a significant reduction in 28-day mortality with tocilizumab. A meta-analysis of these eight trials, which included a total of 439 deaths among 2379 patients showed no significant difference in 28-day mortality .Added value of this studyThe Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is the largest randomised trial of the effect of tocilizumab in hospitalised patients with COVID-19. We found that in 4116 COVID-19 patients with hypoxia and a raised C-reactive protein, tocilizumab reduced 28-day mortality, increased the probability of discharge within 28 days, and, among patients who were not receiving invasive mechanical ventilation at randomisation, reduced the probability of progression to the composite outcome of invasive mechanical ventilation or death. The benefits were in addition to corticosteroids and consistent in all subgroups, regardless of the amount of respiratory support.Implications of all the available evidenceOur finding shows that tocilizumab improves survival and other clinical outcomes in a broad group of patients hospitalised with COVID-19 and that these benefits are additional to those of corticosteroids.website. This report is limited to adult patients. The randomised assessment of tocilizumab in children younger than 18 years is ongoing.The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an investigator-initiated, individually randomised, controlled, open-label, platform trial to evaluate the effects of potential treatments in patients hospitalised with COVID-19. Details of the trial design and results for other possible treatments have been published previously.Patients admitted to hospital were eligible for the study if they had clinically suspected or laboratory confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at substantial risk if they were to participate in the trial. Written informed consent was obtained from all patients, or their legal representative if they were too unwell or unable to provide consent.Data were collected at study entry using a web-based case report form that included demographics and major comorbidities . All eliUp to 21 days after the main randomisation and regardless of treatment allocation, RECOVERY trial participants with clinical evidence of progressive COVID-19  could be considered for randomisation to tocilizumab versus usual care alone. Baseline data collected for this randomisation included amount of respiratory support, markers of progressive COVID-19 , suitability for the study treatment, and treatment availability at the site . For somPatients who were eligible for randomisation to tocilizumab were assigned to either usual standard of care or usual standard of care plus tocilizumab in a 1:1 ratio by means of web-based simple (unstratified) randomisation with allocation concealed until after randomisation. Allocated treatment was prescribed by the managing doctor. Roche Products  supported the trial through provision of tocilizumab. Participants and local study staff were not masked to the allocated treatment. The steering committee, investigators, and all others involved in the trial were masked to the outcome data during the trial.Patients allocated to tocilizumab were to receive tocilizumab as a single intravenous infusion over 60 min. The dose of tocilizumab was established by bodyweight . A second dose could be given 12–24 h later if, in the opinion of the attending clinician, the patient's condition had not improved.A single online follow-up form was completed when participants were discharged, had died, or at 28 days after the initial randomisation, whichever occurred earliest . InformaOutcomes were assessed at 28 days after randomisation to tocilizumab versus usual care alone, with further analyses specified at 6 months. The primary outcome was all-cause mortality. Secondary outcomes were time to discharge from hospital, and, among patients not receiving invasive mechanical ventilation at randomisation, receipt of invasive mechanical ventilation  or death. Prespecified subsidiary clinical outcomes were use of non-invasive respiratory support , time to successful cessation of invasive mechanical ventilation , and use of renal dialysis or haemofiltration. Prespecified safety outcomes included cause-specific mortality and major cardiac arrhythmia. Information on suspected serious adverse reactions was collected in an expedited fashion to comply with regulatory requirements.In accordance with the statistical analysis plan . Observed effects within subgroup categories were compared by means of a χEstimates of rate and risk ratios are shown with 95% CIs. All p values are two-sided and are shown without adjustment for multiple testing. The full database is held by the study team which collected the data from study sites and did the analyses at the Nuffield Department of Population Health, University of Oxford .Before commencement of the randomisation to tocilizumab versus usual care, the trial steering committee determined that if 28-day mortality in the usual care group was above 25% then recruitment of around 4000 patients to this comparison would provide 90% power at two-sided p=0·01 to detect a proportional reduction in 28-day mortality of one-fifth. Consequently, Roche Products provided sufficient treatment for 2000 patients to receive tocilizumab. The trial steering committee, masked to the results, closed recruitment to the tocilizumab comparison at the end of Jan 24, 2021, as over 4000 patients had been randomly assigned.ClinicalTrials.gov (NCT04381936).For the primary outcome of 28-day mortality, the results from RECOVERY were subsequently included in a meta-analysis of results from all previous randomised trials of tocilizumb versus usual care in patients with COVID-19. For each trial, we compared the observed number of deaths among patients allocated tocilizumab with the expected number if all patients were at equal risk . For RECOVERY, these were taken as the log-rank observed minus expected statistic and its variance but for other trials, where the exact timing of each death was not available, these were calculated from standard formulae for 2 × 2 contingency tables. We then combined trial results using the log of the mortality rate ratio calculated as the inverse-variance weighted average S/V with variance 1/V (and hence with 95% CI S/V ±1·96/√V), where S is the sum over all trials of (O–E) and V is the sum over all trials of v.Neither the funders of the study nor Roche Products had any role in study design, data collection, data analysis, data interpretation, or writing of the report. Roche Products supported the study through the supply of tocilizumab and reviewed the draft publication for factual accuracy relating to tocilizumab.Between April 23, 2020, and Jan 24, 2021, 4116 (19%) of 21 550 patients enrolled into the RECOVERY trial at one of the 131 sites in the UK participating in the tocilizumab comparison were eligible for random assignment. 2022 patients were randomly allocated to tocilizumab and 2094 were randomly allocated to usual care. The mean age of these participants was 63·6 years (SD 13·6). At randomisation, 562 (14%) of 4116 patients were receiving invasive mechanical ventilation, 1686 (41%) of 4116 were receiving non-invasive respiratory support , and 1868 (45%) of 4116 were receiving no respiratory support other than simple oxygen therapy  of 2022 randomly assigned patients in the tocilizumab group and 2049 (98%) of 2094 patients in the usual care group. Among patients with a completed follow-up form, 1647 (84%) of 1964 allocated to tocilizumab and 77 (4%) of 2049 of those allocated to usual care received at least one dose of tocilizumab  of 2094 patients in the usual care group; rate ratio 0·85; 95% CI, 0·76–0·94; p=0·0028; Allocation to tocilizumab was associated with a significant reduction in the primary outcome of 28-day mortality compared with usual care alone . Treatment with tocilizumab improved survival and the chances of discharge from hospital by 28 days, and reduced the chances of progressing to require invasive mechanical ventilation. These benefits were consistent across all patient groups studied, including those receiving invasive mechanical ventilation, non-invasive respiratory support, or no respiratory support other than simple oxygen. The benefits of tocilizumab were clearly seen among those also receiving treatment with a systemic corticosteroid, which is now usual standard of care for COVID-19 patients requiring treatment with oxygen.5 mg/L. TPrevious trials have provided some evidence that tocilizumab might shorten time to discharge or reduce progression to invasive mechanical ventilation or death.NCT04315298) are not yet published.The RECOVERY results support the use of tocilizumab. Our results show that the benefits of tocilizumab extend to a broad group of patients receiving oxygen, with or without other forms of respiratory support, and that those benefits include a reduction in the need for invasive mechanical ventilation and renal replacement therapy. Since complicating bacterial infections are infrequent in the early hospitalisation period of COVID-19, this recognised concern in relation to the use of tocilizumab would be lessened with earlier use.Strengths of this trial included that it was randomised, had a large sample size, and included patients requiring various amounts of respiratory support  and has 99% completeness of follow-up for the primary outcome. CRP was chosen as the biomarker for inflammation in this study since it is widely used and affordable worldwide, it is correlated with serum IL-6 concentrations, and early clinical studies of COVID-19 had reported it to be associated with severity and prognosis, with a value of greater than 50 mg/L associated with severe disease and a concentration of around 75 mg/L distinguishing fatal from non-fatal cases.The RECOVERY trial has shown that for patients hospitalised with severe COVID-19, treatment with tocilizumab reduces mortality, increases the chances of successful hospital discharge, and reduces the chances of requiring invasive mechanical ventilation. These benefits are additional to those previously reported for dexamethasone. These findings require an update to clinical guidelines, which has already begun, and efforts to increase the global availability and affordability of tocilizumab.30recoverytrial@ndph.ox.ac.ukCorrespondence to: Prof Peter W Horby and Prof Martin J Landray, RECOVERY Central Coordinating Office, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK policy and procedures see https://www.ndph.ox.ac.uk/data-accessFor online. As described in the protocol, the trial steering committee will facilitate the use of the study data and approval will not be unreasonably withheld. De-identified participant data will be made available to bona fide researchers registered with an appropriate institution within 3 months of publication. However, the steering committee will need to be satisfied that any proposed publication is of high quality, honours the commitments made to the study participants in the consent documentation and ethical approvals, and is compliant with relevant legal and regulatory requirements . The steering committee will have the right to review and comment on any draft manuscripts before publication. Data will be made available in line with the policy and procedures. Those wishing to request access should complete the form.The protocol, consent form, statistical analysis plan, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, and other relevant study materials are available policy of not accepting honoraria or consultancy fees directly or indirectly from industry.The authors have no conflict of interest or financial relationships relevant to the submitted work to disclose. No form of payment was given to anyone to produce the manuscript. All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. The Nuffield Department of Population Health at the University of Oxford has a staff


Glioblastoma (GBM) is the most common adult glioma. Differentiating post-treatment effects such as pseudoprogression from true progression is paramount for treatment. Radiomics has been shown to predict overall survival and MGMT (methylguanine-DNA methyltransferase) promoter status in those with GBM. A potential application of radiomics is predicting pseudoprogression on pre-radiotherapy (RT) scans for patients with GBM. A retrospective review was performed with radiomic data analyzed using pre-RT MRI scans. Pseudoprogression was defined as post-treatment findings on imaging that resolved with steroids or spontaneously on subsequent imaging. Of the 72 patients identified for the study, 35 were able to be assessed for pseudoprogression, and 8 (22.9%) had pseudoprogression. A total of 841 radiomic features were examined along with clinical features. Receiver operating characteristic (ROC) analyses were performed to determine the AUC (area under ROC curve) of models of clinical features, radiomic features, and combining clinical and radiomic features. Two radiomic features were identified to be the optimal model combination. The ROC analysis found that the predictive ability of this combination was higher than using clinical features alone (mean AUC: 0.82 vs. 0.62). Additionally, combining the radiomic features with clinical factors did not improve predictive ability. Our results indicate that radiomics is potentially capable of predicting future development of pseudoprogression in patients with GBM using pre-RT MRIs.  Imaging is a primary diagnostic tool upon which medical decisions are made, and magnetic resonance imaging (MRI) is commonly used to monitor post-treatment effects for central nervous system (CNS) tumors. There is more information within images than is initially seen, however. Radiomics is the transformation of images to mineable data . The proOne category of tumor that could benefit from the clinical applications of radiomics is gliomas. Gliomas are the most common primary CNS malignancy in adults and are separated into grades I-IV according to the World Health Organization (WHO) . GlioblaFollowing completion of treatment, imaging with brain MRIs is scheduled per NCCN guidelines. Pseudoprogression is a transient radiologic finding frequently encountered in the post-radiotherapy (RT) setting that often imitates true progression, with or without clinical effects . VaryingDeveloping pseudoprogression is partially due to inherent features of tumors. For example, pseudoprogression is more commonly seen in patients with MGMT promoter methylation and IDH-1 mutations ,11,12,13Most efforts attempting to distinguish pseudoprogression from true progression on follow-up imaging utilize known parameters, including tumor size, edema changes from T1- and T2-weighted sequences, and diffusion and perfusion indices. Collectively, these parameters have proven insufficient to reliably discriminate pseudoprogression from true progression . Thus, rThe clinical potential of radiomics has not been reached, and the amount of clinically relevant data in the field is sparse . Our goaThis study was approved by the institutional review board . Our database included patients with pathologically proven glioblastoma between 2009 and 2018. Patients with GBM who had pre-RT MRIs were included. Of the 72 patients fitting these parameters, 35 reached final analysis due to others not having pseudoprogression data. Data were gathered via a retrospective chart review in a single department at a Midwest medical school, and they included demographics, pathologic characteristics, treatment, recurrence history, and pre-RT MRI images. Clinical features included age, gender, location of tumor, and extent of resection. These features were selected independent of and in combination with radiomic features to evaluate their utility in predicting pseudoprogression. Radiomic data were extracted exclusively from pre-RT imaging and analyzed to determine pseudoprogression prediction. Pseudoprogression was determined by reviewing post-RT imaging and clinical notes. Pseudoprogression was defined as post-treatment findings on imaging that either resolved spontaneously or with steroids on subsequent imaging.Pre-RT T1 MRI images with gadolinium-based contrast agents were taken before radiation therapy. These contrast-enhanced T1 MRI images were used for radiomic analysis. The radiomic features analyzed were from pre-RT scans only. Pre-treatment imaging was chosen for this analysis due to the concept that development of pseudoprogression is likely multi-factorial but partially due to tumor features such as the amount/nature of new vasculature, growth rate, association with tumor stroma, and the genetic profiles of the malignancies. The ability to extract and analyze these differences through a radiomic analysis may be compromised by post-treatment effects in the tumor. Sequential images  were acquired following RT. These post-radiation MRI images were used to assess pseudoprogression. Only patients with regular follow-up and sufficient numbers of post-radiation MRIs for pseudoprogression assessment were included in the final analysis. Pseudoprogression was diagnosed from a consensus of the CNS oncology treatment team, which includes certified neuroradiologists, radiation oncologists, neurosurgeons, and medical oncologists. All MRI images were acquired on a 1.5 T Ingenia MRI scanner by Philips Medical Systems. Slice thickness ranged from 1 to 2.5 mm, with most using 1 mm slices. Regions of interest, manually drawn by one of two attending radiation oncologists according to the tumor boundary on the contrast-enhanced T1-weighted pre-RT MRIs, were used for analysis. Segmentation based on contrast-enhanced T1 imaging without use of T2 flair imaging was chosen for multiple reasons: (1) consistency in segmentation across patients and amongst the radiation oncologists providing the segmentation; (2) pseudoprogression often occurs in the treated regions receiving full radiation dose, which is a volume based on the contrast-enhanced T1 imaging regardless of which guidelines the respective radiation oncologist used for treatment planning; and (3) the flair portion of an MRI in the setting of glioblastoma is of unclear etiology, potentially representing tumor infiltration, benign edema, or recent seizure activity. Our intention was to analyze radiomic features based on characteristics of the tumors, focusing on the area of greatest likelihood to be attributable to the malignancy (contrast-enhancing region). To avoid bias field distortions and data heterogeneity bias, a bias field correction using N4 and an image normalization using histogram matching was performed using the 3D Slicer software on the MRI images before feature extraction.3 voxel size and a bin width of 25 were used for feature extraction. The features are defined in compliance with feature definitions as described by the Imaging Biomarker Standardization Initiative (IBSI) [From each segmented tumor, 841 radiomic features were extracted from the segmented 3D volume using the radiomics module on 3D Slicer 4.9  and visue (IBSI)  and can The data analysis, described with more details in the following sections, was performed by using R (version 3.3.2) .To investigate the overall relationship of radiomic features, a heatmap analysis was performed. Hierarchical clustering was conducted with the average method based on the correlation distance for both radiomic features and patients. Patients were grouped into two clusters, and each cluster has a unique pattern.p-value rejects the assumption, which means the tested feature can provide information for the prediction of pseudoprogression. Since hundreds of radiomic features were tested independently, false discovery rates (FDRs) were calculated to reduce the impact of the multiple testing problem. Those features with FDR-adjusted p-values smaller than 0.1 were selected. They were then clustered to group highly correlated features (cutoff = 0.9) into clusters, and only the feature with the lowest FDR adjusted p-value was kept within each cluster to reduce collinearity. Lastly, sequential floating forward selection (SFFS) was then used to select features, which gave the highest area under the receiver operating characteristic (ROC) curve (AUC) value with a random forest machine learning model. The PRAUC values were also calculated from the precision-recall ROC curves.For the radiomic prediction, feature selection was performed with the following steps. A univariate ANOVA analysis was performed to select potential features contributing to the classification. In the ANOVA analysis, patients with pseudoprogression and those without were assumed to have equal means for the tested radiomic feature, indicating that the feature provides little information for differentiating the two groups. A significant The prediction model was trained with random forest to optimize the AUC. The performance of the model was evaluated by 1000-time 3-fold cross-validations, yielding 3000 AUC values from the test datasets. The statistical distributions of these 3000 AUC values were used to describe the performance of the model. Due to the uneven patient distribution between the pseudoprogression and non-pseudoprogression groups (8:27), a stratified 3-fold cross-validation was used, i.e., the ratio of positives to negatives of the data in each group was restricted in order to have the same ratio as in the whole dataset. Therefore, subsets are representative of all strata of the whole dataset. Three top-ranked radiomic features from feature selection were used to generate 1-feature, 2-feature, and 3-feature radiomic models, yielding a total of 7 different models. The model with the highest average AUC value was selected as the final radiomic model. A one-tailed t-test was conducted to compare each of the other models with this model, with a null assumption that the other comparing model is better than the selected model. The model performance of the following three signatures were evaluated: the radiomic signature , the single-feature models yielded mean AUCs between 0.6 and 0.7, while the two-feature and three-feature models yielded AUCs above 0.7. The two-feature model combining features 2 and 3 achieved the highest mean AUC of 0.82. The ROC analysis comparing the clinical-based model, the radiomics-based model, and the combined model yielded mean AUCs of 0.62, 0.82, and 0.80 from the 1000 rounds of stratified 3-fold cross-validations, respectively; this suggests that the radiomic signature was superior to the clinical signature and is similar to the combined model at predicting the development of pseudoprogression. A comparison of the average ROC curves and precision-recall ROC curves of the three models is shown in In this study, our objective was to identify radiomic features to predict pseudoprogression in GBM patients using pre-RT MRI imaging as a pilot feasibility study. A radiomic model was constructed using 1000 times 3-fold cross-validations, which achieved a mean AUC of 0.82 on the 3000 test datasets with a random forest model using a combination of two selected features. These two radiomic features were then compared with four clinical features and a model including both radiomic and clinical features through ROC analyses with an additional 1000-round 3-fold cross-validations. The radiomic model resulted in a mean AUC of 0.82, which was higher than the clinical model (0.62). Combining radiomic and clinical features did not improve the model performance, resulting in a mean AUC of 0.80. These results demonstrate the potential of radiomics in predicting pseudoprogression using pre-RT MRIs.These results fit within the context of previously published works using advanced imaging analyses, including radiomics and radiogenomics in differentiating pseudoprogression from true progression ,21,22,23Our study investigated the ability of radiomics to predict pseudoprogression. Pseudoprogression remains an important phenomenon in GBM as its differentiation from true treatment failure is imperative for patient management. Pseudoprogression can often be managed with observation alone, while true progression requires therapeutic alteration or consideration of discontinuation of care ,28. A prLimitations of our study include the relative unknown nature of molecular sub-types within our population, including MGMT and IDH-1 statuses, which have been shown to be linked to a higher incidence of pseudoprogression and thus may confound our data ,12. Due Despite these limitations, results from current studies support the potential clinical applications of radiomics to predict pseudoprogression. As patients are followed closely with imaging, the value in differentiating changes on these scans with reliable predictability would be immense.Future directions of this work include larger scaled studies with a validating database to confirm these results. In addition, expanding radiomic analyses to post-RT scans, and combining pre-RT and post-RT radiomic features, such that intrinsic tissue factors and post-treatment changes can be incorporated into predictive algorithms to identify pseudoprogression, could prove worthwhile. Furthermore, studies involving molecular marker status to control for these variables would be valuable as well.Glioblastoma is the most common glioma in adults, and pseudoprogression is a well-defined post-treatment effect frequently encountered. Using radiomic data from pre-radiation therapy MRI images, an optimal signature of two radiomic features out-performed clinical features alone in predicting the development of future pseudoprogression. Additionally, when combining radiomic features with clinical features, performance did not improve. Further large-scale studies are needed to validate our findings, but the results indicate the potential of radiomic features to predict future development of pseudoprogression in GBM patients using pre-radiation therapy MRIs.


The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a Patient-Reported Outcome Measure (PROM) used to evaluate the health status of patients with heart failure (HF) but has predominantly been tested in settings serving predominately white, male, and economically well-resourced populations. We sought to examine the acceptability of the shorter version of the KCCQ (KCCQ-12) among racially and ethnically diverse patients receiving care in an urban, safety-net setting.We conducted cognitive interviews with a diverse population of patients with heart failure in a safety net system to assess their perceptions of the KCCQ-12. We conducted a thematic analysis of the qualitative data then mapped themes to the Capability, Opportunity, Motivation Model of Behavior framework.We interviewed 18 patients with heart failure and found that patients broadly endorsed the concepts of the KCCQ-12 with minor suggestions to improve the instrument’s content and appearance. Although patients accepted the KCCQ-12, we found that the instrument did not adequately measure aspects of health care and quality of life that patients identified as being important components of managing their heart failure. Patient-important factors of heart failure management coalesced into three main themes: social support, health care environment, and mental health.Patients from this diverse, low-income, majority non-white population experience unique challenges and circumstances that impact their ability to manage disease. In this study, patients were receptive to the KCCQ-12 as a tool but perceived that it did not adequately capture key health components such as mental health and social relationships that deeply impact their ability to manage HF. Further study on the incorporation of social determinants of health into PROMs could make them more useful tools in evaluating and managing HF in diverse, underserved populations.The online version contains supplementary material available at 10.1186/s41687-022-00410-9. Heart failure (HF) is a common, progressive, fatal disease with a prevalence expected to increase by 40% over the next 10–15 years , 3. PatiThe goal of this project is to address this health equity gap through the examination of how a racially/ethnically diverse, low-income sample of patients with HF perceive the KCCQ-12. This qualitative inquiry explores how this PROM resonates with diverse patients, including how lived experiences directly impact HF self-management and influence their symptom reporting.This study enrolled patients receiving outpatient primary or cardiology care at an academic, urban, safety-net system that serves one in eight San Franciscans regardless of immigration or insurance status. The San Francisco Health Network’s (SFHN) Cardiology Clinic at Zuckerberg San Francisco General Hospital (ZSFG) delivers over 4,000 annual visits. Patients have primarily Medicaid or Medicare or are uninsured. Patients were eligible if they met all of the following criteria: (1) spoke English; (2) were between the ages 24–85; (3) received care at primary care or Cardiology clinics at the ZSFG location; (4) diagnosed with HF; and (5) did not have a significant cognitive or visual impairment. We invited eligible individuals to participate in person at ZSFG or by mail, email, or phone. All study visits beginning April 2020 were virtual given the COVID-19 pandemic. Patients provided consent and self-reported demographics. Those who completed an interview with our study team received $25 in cash or gift card for their time. The UCSF Institutional Review Board (IRB) (#18-26769) and the FDA IRB (2019-CDRH-019) approved this study.To characterize and understand how a diverse sample of HF patients interpreted items and responses within the KCCQ, we presented the KCCQ-12 , an abbrTrained interviewers  conducted cognitive interviews using a semi-structured interview guide  to code transcripts . Using acapability to entail both the patient’s psychological and physical capacity, plus having the necessary knowledge and skills to engage. Opportunity involves those external factors that impact behavior. Finally, motivation includes those factors that prompt and guide behavior, including conscious and unconscious processes. We developed a list of thematic codes based on the interview guide domains and topics then transcripts were re-reviewed along with notes and memos to determine broader thematic codes. Through this process, we developed sub-themes to capture participant experiences.For the deductive coding, we applied the behavioral Capability, Opportunity, Motivation model of Behavior (COM-B) model  to exploIn total, we conducted 18 qualitative interviews with heart failure patients from April 2019 to September 2020. The mean age was 52 years, 33% were women, and 78% were non-White. Complete baseline demographics are in Table Study patients shared a range of experiences managing their heart failure condition as well as a variety of feedback on the KCCQ-12 [original (n = 12) and tablet (n = 6) and reading level-adapted (n = 6) versions]. Table Applying the COM-B framework  to the ith-grade reading level for patient-reported outcome measures. Therefore, we adapted it to recommended reading levels and explored patient perceptions of the literacy-appropriate version , self-efficacy and knowledge, social interference, and quality of life , 18. TheSocial determinants of health deeply impact patient experience and outcomes and are disproportionately present in patients with HF as compared to the general population. For example, depression is more common in patients with HF and portends a worse prognosis , 23. SimUsing the COM-B framework , we idenSeveral limitations exist in the current study. We conducted interviews in a single safety-net health system hospital limiting external generalizability. However, this study touches on key demographic groups not typically represented in clinical studies. Only English-speaking patients were included, which unfortunately excluded non-English speaking patients in the SFHN, most commonly Spanish and Cantonese. This is an area of ongoing study. We employed the KCCQ-12 rather than the original 23-item KCCQ, which does have an item on depression and an item on sexual function. Based on our patients’ feedback, though, inclusion of these items would not have sufficiently addressed those SDOH deficiencies described above. Finally, the COVID-19 pandemic necessitated that the final 6 months of the study be conducted remotely via telephone or video conferencing. Given the socioeconomic makeup of our patient population, this likely impacted who was able to participate. Shelter-in-place requirements increased patient isolation and impacted patients’ feedback of the KCCQ-12. COVID-19 has exaggerated health disparities –32, and Patients from a diverse, low-income, majority non-white population in a safety net health care system experience unique challenges and circumstances that impact their ability to manage disease. It is important that future studies continue to enroll such patients, as SDOH disproportionately affects them negatively and impacts public health outcomes. In this study, patients were receptive to the KCCQ-12 as a tool but perceived that it did not adequately capture their illness experience because it did not assess key SDOH such as mental health and social relationships that deeply impact their ability to manage HF. Further study on the intersection of PROMs and SDOH reporting could investigate how to best use standardized patient reporting in evaluating and managing HF in diverse, underserved populations.Additional file 1: Table 1. Participant Perceptions of KCCQ-12.Additional file 2: Table 2. Patient-Reported Impacts on Quality of Life.


Low-dose CT Urography (LD-CTU) has become a standard procedure in urinary tract abnormalities in children, especially when MR Urography is not available. Standard one-phase CTU is performed in excretory phase. There is also a split-bolus technique, which combines two or even three phases during one scan and provides more clinical information without higher radiation exposure. It can be implemented for congenital anomalies of kidneys and urinary tract (CAKUT) in children, however, this application is not deeply discussed in scientific literature. Aim of this publication is to present the protocol and determine the role of LD-CTU in diagnostic imaging of CAKUT in children.Close to 300 CTUs in children were performed as a standard of care during the last 6 years in our Department. Diagnostic accuracy in suspected CAKUT was analyzed, depending on applied protocol − standard excretory CTU, multiphase CTU and two different one-phase split-bolus CTU protocols.Visualization of the urinary tract was adequate in all study protocols. However, more clinically significant information was received in vascular-excretory protocol, including vascular and renal anatomy. Radiation exposure was similar or even lower than in other study protocols.One-phase split-bolus CTU protocol is a novel approach in low-dose diagnostic imaging of CAKUT in children. Combination of vascular and excretory phases has been shown as very effective technique, especially in comprehensive anatomical assessment of the abnormality and qualification to surgical intervention. As considered by the ESPR and ESUR groups, the only indications for CT Urography (CTU) in children include: suspected nephrolithiasis, renal trauma, some tumors and complicated infections , 2. MR UCTU can be routinely performed in children with suspected congenital anomalies of kidneys and urinary tract (CAKUT) , especiaSplit-bolus technique has already been described as a method of radiation dose reduction in CTU , 2, 6, 7CTU is considered as reliable technique in diagnosis of CAKUT , 10. HowTo present the protocol and determine the role of LD-CTU in diagnostic imaging of CAKUT in children.During the last 6 years (2011-2016) we have performed 276 CTUs in 249 children. This number includes standard indications, mentioned above , but also suspected CAKUT.CTUs were performed with two different multidetector CT scanners (64-row Philips Brilliance and 320-row Toshiba Aquilion ONE).CTU was performed in 4 different protocols:− Protocol 1: one-phase excretory CTU − performed 15-20 minutes after injection of CM in dose 1 ml/kg;− Protocol 2: one-phase split-bolus CTU, with combination of parenchymal and excretory phases , 7 − 2-2− Protocol 3: one-phase split-bolus CTU, with combination of vascular and excretory phases  − protoc− Protocol 4: excretory phase was performed as a part of a multiphase study.Whenever possible, low acquisition parameters were used, to meet ESPR and ESUR criteria , 2 and oCTU protocol evolved in time, and in some cases it could slightly differ from mentioned above - this concerned especially doses of CM per phase and time intervals between CM bolus injections (i.e. it could be elongated in some patients with severe hydronephrosis).Examinations performed due to suspected CAKUT and follow-up studies performed after surgical repair were chosen to the final analysis − that is 226 CTUs in 205 patients . In most cases, CTU was performed if no correlation was observed between the results of different imaging studies  or before qualification for surgical repair of the abnormality. Whenever possible, CTU was performed as a one-phase study.In all study protocols, visualization of the urinary tracts was adequate to make the correct diagnosis and select an appropriate management method.Indications for the CTUs in all study protocols are listed in In the group of 105 children with hydronephrosis, 62 were qualified for surgical treatment, while the remaining group was qualified for further observation. There were 15 patients with suspected crossing vessel as the cause of hydronephrosis . Only Protocol 3 directly visualized the crossing vessel, while in Protocols 1 and 4 – there were only indirect signs, like compression of the ureter’s contour (none of 3 CTUs in Protocol 4 was performed with a vascular phase).In 50 patients with suspected duplication of the urinary tract, the abnormality was ruled out in 12 children . 24 patients were qualified to surgical repair (heminephrectomy). There were complications in 4 children, due to suspected post-operative urine leakage from the cut surface – preoperative CTUs were performed in Protocol 1 (two cases), Protocol 2 (one case) and Protocol 3 (one case). Urine leakage was confirmed in post-operative CTUs in 3 children  – surgical revision was performed in all patients. One CTU, performed in Protocol 1, ruled out the urine leakage.The role of CTU in children is different than in adults, where optimal distention and opacification of the collecting system, ureters and urinary bladder is essential for detection of urothelial cancer . In diagOur analysis of the diagnostic accuracy of CTUs performed in different protocols showed that all of them provide adequate visualization of the urinary tract. However, there is a significant difference when the complete urinary system must be assessed, including vascular and renal anatomy.One-phase excretory CTU (Protocol 1) is a standard procedure in CAKUT diagnosis . HoweverSplit-bolus technique has been already described as a method of radiation dose reduction in CTU , 2, 6, 7Combination of parenchymal and excretory phases (Protocol 2) in most analyzed cases did not bring more clinical information. Enhancement of renal parenchyma may reveal renal scars or focal lesions, however, this is not a main goal in suspected CAKUT. Renal scars will be evaluated in scintigraphy or MRU, while focal lesions are not routinely suspected in such patients. However, parenchymal enhancement can help to visualize general renal anatomy before planned surgical intervention.Combination of vascular and excretory phases (Protocol 3) provides the most complex visualization of the urinary system. It allows to asses abnormalities of the collecting system, with additional information about renal vascularity and general renal anatomy. It appears very useful especially before planned surgical intervention, e.g. heminephrectomy in duplicated collecting systems, where renal vessels and borders between both parts of the kidney should be evaluated . VasculaMultiphase CTU (Protocol 4) exposes the patient to higher radiation doses  and should not be routinely performed in children. Similar diagnostic accuracy can be obtained in one-phase studies.In our material, implementation of both split-bolus techniques (Protocol 2 and Protocol 3) allowed to more accurately assess the kidney anatomy and it was a milestone in planning the surgery, as assessed by the urologists. Due to additional visualization of renal vessels, Protocol 3 (combination of vascular and excretory phases) appears as more effective split-bolus CTU technique. It must be emphasized, however, that study protocol must suit the diagnostic problem. In case of suspected urine leakage after surgery (e.g. heminephrectomy), we suggest to perform the follow-up post-operative CTU in a single excretory phase (Protocol 1), as parenchymal enhancement in split-bolus technique may obscure the leakage.Our analysis showed that one-phase split-bolus LD-CTU protocol is a very effective and dose sparing technique in diagnosis of CAKUT in children. Additionally, it can be adapted to the standard indications agreed by the ESPR and ESUR groups , 2. In rThere were limitations to our study. We haven’t compared directly the image quality and dose reduction between the study protocols, or differences in diagnostic accuracy between both CT scanners. The main goal was to present advantages of one-phase split-bolus CTU technique. In comparison to multiphase studies, where the radiation dose multiplies with every additional phase, implementation of one-phase CTU protocol allowed to significantly reduce radiation dose. Furthermore, in comparison to different CTU protocols, diagnostic accuracy increased significantly when the one-phase split-bolus CTU with combination of vascular and excretory phases was implemented. This protocol is universal and can be adapted to every CT scanner, nevertheless, there are still many issues for further investigations, especially with protocol optimization . Also, the optimal use of CM should be evaluated, especially in terms of CM volume and time interval between CM bolus injections. From our experience, it is recommended to use at least 2 ml/kg of total dose of CM, divided half-and-half for vascular and excretory phases. Lower doses, like standard 1 - 1,5 ml/kg divided for both phases, could be not suffcient to appropriately enhance renal vessels, parenchyma and collecting system, especially in case of hydronephrosis.Low-dose one-phase split-bolus CTU protocol is a reliable technique to reduce radiation dose in children. Combination of vascular and excretory phases provides very precise picture of CAKUT, especially before planned surgical intervention. It can become a standard CTU protocol in children.


How do COVID-19 hospitalizations for people experiencing incarceration or homelessness compare with those among the general US population?In a cross-sectional study using hospital discharge records from more than 800 hospitals, people experiencing incarceration who were evaluated in the emergency department had a higher frequency of hospitalization, invasive mechanical ventilation, mortality, and readmissions, as well as longer lengths of stay, compared with the general population. People experiencing homelessness who were evaluated in the emergency department had a higher frequency of hospitalization and readmissions, a lower frequency of invasive mechanical ventilation and mortality, and longer lengths of stay compared with the general population.This study suggests that expanding medical respite may reduce hospitalizations or shorten the length of stay for COVID-19 for people experiencing incarceration or homelessness who are disproportionately affected by the pandemic. People experiencing incarceration (PEI) and people experiencing homelessness (PEH) have an increased risk of COVID-19 exposure from congregate living, but data on their hospitalization course compared with that of the general population are limited.To compare COVID-19 hospitalizations for PEI and PEH with hospitalizations among the general population.This cross-sectional analysis used data from the Premier Healthcare Database on 3415 PEI and 9434 PEH who were evaluated in the emergency department or were hospitalized in more than 800 US hospitals for COVID-19 from April 1, 2020, to June 30, 2021.Incarceration or homelessness.Hospitalization proportions were calculated. and outcomes  among PEI and PEH were compared with outcomes for all patients with COVID-19 (not PEI or PEH). Multivariable regression was used to adjust for potential confounders.P < .001). Both PEI and PEH hospitalized for COVID-19 were more likely to be younger, male, and non-Hispanic Black than the general population. Hospitalized PEI had a higher frequency of IMV  and mortality  than the general population . Hospitalized PEH had a lower frequency of IMV  and mortality  than the general population. Both PEI and PEH had longer mean (SD) lengths of stay  and a higher frequency of readmission  than the general population .In total, 3415 PEI  and 9434 PEH  were evaluated in the emergency department for COVID-19 and were hospitalized more often  than the general population (624 470 of 1 257 250 [49.7%]) (In this cross-sectional study, a higher frequency of COVID-19 hospitalizations for PEI and PEH underscored the importance of adhering to recommended prevention measures. Expanding medical respite may reduce hospitalizations in these disproportionately affected populations. This cross-sectional study uses data from more than 800 hospitals to compare COVID-19 hospitalizations for people experiencing incarceration or homelessness with COVID-19 hospitalizations among the general population. For PEI, the government is required to provide health care; decisions on when and how to hospitalize patients vary by facility and jurisdiction.11 In this report, we examine COVID-19 emergency department visits and hospitalizations among PEI and PEH compared with the general population using a national electronic health record database.Gaps remain in understanding COVID-19 hospitalizations for PEI and PEH. Previous reports were isolated to a single state, were limited in sample size, or were unable to adjust for potential confounding demographic factors.12 We included all adults aged 18 years or older with COVID-19 who were evaluated in the emergency department or hospitalized and discharged during the period from April 1, 2020, through June 30, 2021. COVID-19 was defined using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification (ICD-10-CM) code U07.1 listed as either the primary or secondary diagnosis code.13 PEI and PEH were identified using ICD-10-CM codes listed as either the primary or secondary diagnosis code during any emergency department visit or hospitalization during the period from April 1, 2020, through June 30, 2021  and was conducted consistent with applicable federal law and CDC policy (45 CFR part 46). This study was exempt from institutional review board oversight and exempt from patient informed consent because the disclosed Premier Healthcare Database Special COVID-19 Release data are considered deidentified. This report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.14In this cross-sectional study, we analyzed data from the Premier Healthcare Database Special COVID-19 Release (release version 09/28/2021), an all-payer, hospital-based administrative database that contains hospital discharge records from more than 800 for-profit and nonprofit, community and teaching hospitals across the United States; the database is updated every 2 weeks.30, 2021 . People ICD-10-CM codes listed as a primary or secondary diagnosis code during any inpatient or outpatient encounter during the period from January 1, 2019, through the initial COVID-19 encounter  and disability .We defined hospitalization proportion as the number of patients hospitalized for COVID-19 out of the total number evaluated in the emergency department for COVID-19. Patient race and ethnicity were determined as recorded in the electronic health record. Underlying medical conditions were defined using d-dimer, C-reactive protein, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels.18 We examined the proportion of patients with laboratory abnormalities above or below the normal reference range as defined by each facility. Acute in-hospital complications  were defined using ICD-10-CM diagnosis or procedure codes listed as a primary or secondary diagnosis code during the same COVID-19 hospitalization , in-hospital mortality, length of stay, and 30-day readmission for COVID-19. We identified 7 laboratory test results associated with severe outcomes in COVID-19 based on meta-analyses: leukocytosis, lymphocytopenia, and elevated 2 tests (or Fisher exact tests for cell sizes <5) to determine whether PEI and PEH had the same frequencies as the general population.20 We then calculated intensive care unit admission, IMV, in-hospital mortality, length of stay, and 30-day readmission for COVID-19 for PEI and PEH compared with the general population using multivariable regression analyses. We obtained risk ratios using either a log binomial model (intensive care unit admission and IMV) or an alternative revised Poisson model when the log binomial model did not converge .21 We used a zero-truncated negative binomial model for length of stay, which was an overdispersed positive count data variable.22We examined frequencies of demographic characteristics and underlying medical conditions and conducted Pearson χP values were from 2-sided tests, and results were deemed statistically significant at P < .05.For the regression models, we calculated unadjusted, age-adjusted, and fully adjusted models. In the fully adjusted model, we adjusted for age, sex , race and ethnicity , health care professional region , health care professional urbanicity , pandemic wave , serious mental illness (yes or no), and disability status (yes or no), which were selected based on a priori understanding of the direction of causality. Payer source  and underlying medical conditions were not included in the final model because these factors are more likely predicated on incarceration and housing status rather than potential confounders. We accounted for clustering at the hospital level by calculating 95% CIs based on clustered SEs in log binomial models and revised Poisson models or by including a hospital random effect in zero-truncated negative binomial models. SAS software, version 9.4 (SAS Institute Inc) was used to conduct all statistical analyses. All P < .001) and PEH  than the general population (624 470 [49.7%]). PEI and PEH evaluated only in the emergency department for COVID-19 were more likely to be male  and non-Hispanic Black  and less likely to be non-Hispanic Asian  and of Hispanic ethnicity  than the general population . Several underlying medical conditions were more common among PEI and PEH with COVID-19 in the emergency department than among the general population, including chronic obstructive pulmonary disease, liver disease, tobacco use, substance use disorder, and serious mental illness.The analysis included discharge records from 892 hospitals. We identified 3415 PEI , 9434 PEH , and 1 257 250 patients in the general population with COVID-19 who were evaluated in the emergency department only or hospitalized . The proP < .001), whereas the health care location was more likely to be urban for PEH (5732 [94.2%]) than for the general population . Despite their younger age, there were fewer PEI  and PEH  hospitalized for COVID-19 with no underlying medical conditions compared with the general population (46 832 [7.5%]). Significant differences were seen for individual conditions. For example, the proportion of individuals hospitalized for COVID-19 with severe obesity was lower for PEI  and PEH  than for the general population (97 861 [15.7%]), whereas liver diseases were more frequent for PEI  and PEH  than for the general population (55 607 [8.9%]). Serious mental illness was higher among PEI  and PEH  than among the general population (24 588 [3.9%]).PEI and PEH hospitalized with COVID-19 were more likely to be younger , male , and non-Hispanic Black  and less likely to be non-Hispanic Asian , non-Hispanic White , and of Hispanic ethnicity  than the general population . The head-dimer and lactate dehydrogenase) were less frequent among PEI than among the general population. All 7 laboratory test result abnormalities were significantly less frequent among PEH than among the general population.The overall frequency of in-hospital complications was lower for hospitalized PEI (1812 [83.5%]) and PEH (4400 [72.3%]) than for the general population (561 322 [89.9%]) . Two resICD-10-CM codes alone were similar  and experience in-hospital mortality  than the general population after adjusting for age and other covariates . PEH hosReadmission for COVID-19 within 30 days of hospital discharge was more common for PEI  and PEH  than for the general population (28 493 [4.6%]) . The mea24 In contrast, we calculated in-hospital measures using hospital admissions as the denominator; therefore, interpreting our findings requires understanding factors associated with both illness severity and reasons for hospitalization.This analysis expands on previous reports of COVID-19 hospitalization among PEI and PEH by using a large database of geographically diverse US hospitals and including a general population group for comparison. We found that PEI and PEH with COVID-19 who were evaluated in the emergency department were hospitalized more often, had longer lengths of stay, and had more frequent readmission than the general population. PEI hospitalized for COVID-19 had increased IMV and mortality compared with the general population. PEH hospitalized with COVID-19 had a less severe hospital course. Because we do not have population denominators for PEI or PEH, we cannot draw conclusions about population-level COVID-19 risk or severity compared with the general population. Previous population-based estimates have found that COVID-19 case rates and COVID-19 mortality rates were higher among PEI and PEH compared with the general population.10 Our findings additionally identified a higher proportion of PEI hospitalized with a longer length of stay and more frequent readmission. There are several possible explanations for why PEI referred to the emergency department are hospitalized with more severe illness. Some correctional facilities can provide basic medical treatment on site, which could reduce the need for hospitalization, particularly for less severe cases of COVID-19.25 The decision to transport an individual to a hospital is often made by a corrections medical director or contracted health care agency based on established preapproval processes.7 Correctional agencies must consider the costs and potential exposures for staff to provide transportation and in-hospital supervision. These factors could select for hospitalization of individuals with more severe cases. Individual PEI might perceive medical isolation space within correctional facilities as a form of punishment, akin to solitary confinement, which could lead to delayed presentation for illness. Facilities and clinicians should consider the institutional restrictions defined for this setting and ensure that these institutional barriers do not interfere with providing appropriate levels of health care to PEI.26 Several factors beyond illness severity may also be associated with longer duration of hospitalization for PEI. Hospitalizations might be extended if a correctional facility lacks medical rehabilitation space, equipment, or staffing to provide recuperative care at discharge or if delays occur in arranging staff to provide return transportation.Our finding of increased IMV among PEI hospitalized for COVID-19 compared with the general population is consistent with an earlier publication.27 Reducing jail and prison populations has allowed some facilities to provide the necessary medical isolation and quarantine spaces and has allowed for as much physical distancing as possible. Actions to prevent the spread of SARS-CoV-2 within the facility and between the community and the facility have been critical in lowering infection risk. Recommended infection, prevention, and control strategies include incorporating physical distancing and masking; reinforcing hygiene practices; intensifying facility cleaning and disinfection; conducting symptom and temperature screening for staff, visitors, and PEI; testing symptomatic and asymptomatic individuals; establishing appropriate medical isolation and quarantine cohorting; and offering vaccinations to staff and PEI.28 Strengthening partnerships between health departments and correctional facilities and agencies can help to effectively implement these infection, prevention, and control strategies.Our findings of severe COVID-19 illness among PEI underscore the importance of following recommended prevention measures. Because of overcrowding and limited availability of resources , correctional and detention centers have been urged to consider COVID-19–related risks when making bail decisions.11 There are at least 3 possible explanations for these findings. First, COVID-19 could exacerbate underlying conditions that lead to a higher frequency of hospitalization but not necessarily to a higher frequency of IMV or mortality for PEH compared with the general population. This possibility is supported by our finding that complications, such as acute congestive heart failure, hypertensive crisis, and diabetic ketoacidosis, were more common among PEH, whereas COVID-19 complications, such as respiratory and kidney complications, were more common in the general population. PEH with inadequate access to routine primary care may have undiagnosed or poorly controlled underlying medical conditions that are exacerbated by COVID-19. Second, PEH with asymptomatic COVID-19 might receive a diagnosis of COVID-19 during the workup for other conditions more often than the general population given the high use of the emergency department among this population.30 Third, PEH might be hospitalized for reasons associated with their housing status, such as an inability to recuperate or self-isolate while infectious. The inability to recuperate or self-isolate in a safe location might also lead to discharge delays and longer lengths of stay, as has been observed for PEH with other medical conditions.31For PEH, we found that individuals evaluated in the emergency department were admitted with COVID-19 more often but were less likely to require IMV and less likely to die compared with the general population, consistent with an earlier report from a smaller, single-center study.32 More recent studies have demonstrated the cost-effectiveness of medical respite programs.34 Expanding the availability of medical respite programs for PEH during the COVID-19 pandemic may have long-lasting benefits for PEH.Communities have developed solutions to address the lack of safe recuperation and isolation space. Medical respite care provides a safe location for PEH to recover from illness and offers medical and social services. A systematic review found that medical respite for PEH was associated with reduced future hospital admissions, lengths of stay, and readmissions.ICD-10-CM and admission codes. Our findings might not be generalizable to all PEI and PEH hospitalized for COVID-19, and ICD-10-CM codes are likely insufficient to identify all hospitalized PEI.36 We included admission codes in our PEI definition to broaden the scope, which provided more conservative estimates than ICD-10-CM codes alone. For PEH, ICD-10-CM codes are a more established method of identification but are underused, and hospitals might not have standardized methods for recording housing status in electronic health records. It remains unclear whether PEH identified through ICD-10-CM codes are generalizable to the broader population of hospitalized PEH.40 The ICD-10-CM codes for homelessness could be used preferentially for individuals who are admitted or who cannot be discharged for reasons associated with their housing status, which could bias our estimates away from the null. However, the importance of medical respite care for these populations remains. In addition, we were unable to deduplicate individuals who accessed care from multiple hospital systems; however, we expect that this small number would be offset by the large sample size. We relied on ICD-10-CM diagnoses to identify obesity and other underlying medical conditions, which likely resulted in an underestimation, but we expect that the underestimation would be similar for all 3 populations. Most hospitals did not report laboratory test results; however, the low reporting is consistent for all 3 populations, there was adequate sample size for analysis, and the findings are consistent with other outcomes . Last, although payer status and underlying medical conditions were not included in the fully adjusted model, we conducted sensitivity analyses that included these variables separately and found no meaningful changes in our results (eTable 4 in the This report has some limitations. The main limitation is our ability to identify PEI and PEH from In this cross-sectional study, PEI and PEH who presented to the emergency department with COVID-19 were hospitalized more often than the general population. Increased lengths of stay and readmission rates highlight the complex factors outside of COVID-19 illness with which PEI and PEH must contend and support the expansion of medical respite facilities. The high rates of COVID-19 hospitalizations among PEI and PEH reinforce the importance of COVID-19 prevention measures for these disproportionately affected populations. In the long term, reducing COVID-19 hospitalizations among PEI and PEH will require continued partnerships among homeless services, correctional facilities and agencies, health care professionals, and public health agencies to ensure that COVID-19 vaccinations and other prevention measures are implemented equitably for PEI and PEH.