Intervertebral Disc Degeneration (IDD) is a heterogeneous spinal disease whose underlying molecular mechanism is unclear.This study aimed to identify, profile, and analyze microRNAs (miRNAs) related to IDD.Microarray Gene Expression IDD data (GSE63492) were downloaded from Gene Expression Omnibus datasets. We employed Weighted Gene Co-Expression Network Analysis (WGCNA) to construct a miRNA co-expression network, and the miRNAs related to the IDD stage were detected. The number of differentially expressed miRNAs between normal and degenerated nucleus pulposus tissues was calculated. Twenty-three clinical specimens were used to validate the expression of miRNAs using qRT-PCR.WGCNA identified 48 miRNAs significantly related to the IDD stage, and 94 miRNAs that were significantly different between normal and degenerated nucleus pulposus tissues. We selected 32 overlapping miRNAs and identified 347 corresponding target genes. The integrative analysis revealed the biological function and pathways of these targeted genes. Analysis of clinical specimens validated that hsa-miR-4534 was upregulated in IDD, whereas hsa-miR-1827 and hsa-miR-185-5p were downregulated in IDD.This study has identified a subset of miRNAs that are related to IDD pathogenesis and hub miRNAs that are keys to the IDD co-expression network, which may potentially be utilized as indicators for treatment. Currentet al. provided a few potential networks among competing endogenous RNAs (ceRNAs) related to IDD and mainly emphasized the interactions among lncRNAs, miRNAs, and mRNAs . We obtained degenerative nucleus pulposus samples from IDD patients. Non-degenerative specimens were collected from cadaveric donors. Samples gathered from graded I (Pfirrmann grading) [The GSE63492 miRNA expression dataset  was obtagrading)  cadaveri2.2A co-expression network of miRNAs was built by weighted gene co-expression network analysis (WGCNA)  using th2.3t-test implemented in the LIMMA package [The GSE63492 data were initially pretreated using the Bioconductor package in the R language prior to differential analysis. Briefly, we converted the probe-level data into expression values. Then, the expression values of all probes in every sample were reduced to a single value by calculating the average expression value. Any missing data were imputed, followed by quantile normalization of the complete data. The differential expression of miRNAs between normal and degenerated nucleus pulposus tissues was estimated using a Student’s  package . The miR2.4The target genes of the overlapping miRNAs were queried in the databases: TargetScan , miRDB , and miR2.5Validation experiments were performed to examine miRNA expression in intervertebral disc tissues and were approved by the ethics committee of the Third Affiliated Hospital of Guangxi Medical University. The protocol for collecting intervertebral disc tissues followed the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects . In addi1).The protocol for the detection of intervertebral discs using MRI was discordant with that of a previous report . This st2.61). qRT-PCR was performed to quantify miRNA expression on a 7500 real-time PCR instrument  using a final volume of 20 μL. The reaction conditions included 1 cycle at 95°C for 5 minutes; 15 cycles at 95°C for 25 seconds, 64°C for 20 seconds, 72°C for 20 seconds; and a final 31 cycles at 93°C for 25 seconds, 64°C for 20 seconds, 72°C for 20 seconds. Relative miRNA expression levels were analyzed using the ∆∆CT method with data normalization to U6 expression.Total RNA was extracted from fresh intervertebral disc tissues  with TRIzol regent  following the manufacturer's instruction. RNA purity and concentration were determined by an ultraviolet spectrophotometer . A sequence of each hsa-miR-1827, hsa-miR-4534, and hsa-miR-185-5p was retrieved from miRbase database. The primers of three miRNAs are listed in . Four significant modules were identified using the WGCNA approach; the colors of these modules were brown, green, turquoise, and yellow . By module-trait analysis of WGCNA, we analyzed the clinical features of IDD patients  with the miRNAs . Six modules were identified; only the yellow module was associated with the IDD stage (p = 0.004). Table S1 shows the miRNAs that are significantly associated with the IDD stage. However, no significant correlation was observed between sex and all the modules .Using a WGCNA approach, we constructed a miRNA co-expression network for all miRNAs in the GSE63492 dataset. We selected seven miRNAs as soft-thresholding powers to construct a miRNA co-expression network , we identified 94 miRNAs that were differentially expressed compared to normal and degenerated nucleus pulposus tissues, of which 38 miRNAs were upregulated and 56 were downregulated (Table S2). The heat map of the top 20 differentially expressed miRNAs is presented in . Overlapping miRNAs were obtained by merging the stage-related miRNAs from WGCNA and differentially miRNAs, and 32 overlapped miRNAs were finally identified .Using selected criteria . Further analysis using ClueGo revealed that the target genes were of the following biological functions: posttranscriptional regulation of gene expression (GO:0010608), myeloid cell differentiation (GO:0030099), and regulation of cell-substrate adhesion (GO:0010810) . The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways are as follows: HIF-1 signaling pathway (KEGG:04066), cell cycle (KEGG:04110), and hepatitis B (KEGG:05161) .By searching the databases TargetScan, miRanda, and MirTarget, we identified 347 target genes of the overlapping miRNAs, and the miRNA–mRNA interaction is depicted in 3.42). qRT-PCR analysis revealed that the relative expression of hsa-miR-4534 markedly increased in IDD compared to controls, while the expression levels of hsa-miR-1827 and hsa-miR-185-5p decreased in IDD compared to controls . These findings coincided with the results of miRNA profiling.We selected three miRNAs  that had the highest number of the targeted genes and were validated by qRT-PCR assay with clinical specimens. There were 23 intervertebral disc tissues, including 18 IDD tissues and 5 control tissues, with no significant differences between IDD and controls regarding patient age and sex  analysis revealed the biological function of the miRNA target genes, and KEGG analysis uncovered cell cycle-related pathways, indicating that these miRNAs may affect the process of IDD by regulating the target genes. Aberrant cycles can lead to apoptosis of nucleus pulposus cells ; hence, The present study found that hsa-miR-1827, hsa-miR-4534, and hsa-miR-185-5p are significantly associated with IDD development. However, recent studies have only mainly explored their role in cancers. For example, hsa-miR-1827 has been reported to be downregulated in highly invasive lung cancer sub-cell lines, and the overexpression of miR-1827 inhibits lung cancer cell migration via targeting RBX1 and CRKL . The funin vivo and in vitro experiments. Fourth, the effect of miRNAs should be further investigated via their target genes; however, due to insufficient research funds, functional studies were not performed. Therefore, further investigations on the function of these targeted genes are warranted.The present study performed a comprehensive analysis of the miRNA profiles in IDD using microarray data, thereby improving our understanding of their involvement in IDD pathogenesis by regulating target genes. However, some clear limitations need to be noted. First, this microarray data only assessed 10 samples, and this small sample size reduces the robustness in detecting more significant miRNAs. Second, the clinical features of the IDD in this study are limited, and some other important clinical features, such as injuries and nutrition, were not analyzed, and thus we could not explore their correlation to miRNA expression. Third, this study solely performed a bioinformatics analysis of miRNA microarray data, and the results were not validated using The present study provides a system biology perspective in characterizing miRNA expression in IDD. We have identified some miRNAs that are both differentially expressed and closely related to the IDD stage. The function of hub miRNAs in the co-expression network analysis is also elucidated, suggesting their potential use as therapeutic targets for IDD. Further experimental studies validating the role of these miRNAs in IDD should be performed.


The SARS-CoV-2 mRNA vaccine has been reported to cause various adverse reactions, including the development or exacerbation of autoimmune diseases, but the adverse reactions and the effects of the vaccines on disease activity in patients with rheumatoid arthritis (RA) remain unknown. We therefore investigated the arthritis condition in RA patients after SARS-CoV-2 vaccination.RA patients who visited our hospital from January to April 2022 completed a questionnaire regarding adverse reactions to the SARS-CoV-2 vaccine. We compared the frequency and duration of post-vaccination arthralgia between RA patients and health care workers in our hospital. For the RA patients who reported post-vaccination arthralgia, we collected medical records for the 6 months after vaccination.Of the 1198 vaccinated RA patients, 256 (21.4%) had systemic inflammatory symptoms, 18 (1.5%) had allergies including urticaria and asthma, and 37 (3.1%) had arthralgia. A few patients had extra-articular manifestations such as acute exacerbation of interstitial lung disease. Compared with health care workers, RA patients more frequently developed arthralgia, and the arthralgia was longer lasting than that in controls: only 9 (0.8%) of the 1117 health care workers reported arthralgia, and all cases resolved within 3 days. Data from 31 of the 37 RA patients with post-vaccination arthralgia were further analyzed; in these patients, disease activity was highest after 2 months, and 10 patients required additional DMARDs within 6 months. The proportion of concomitant use of PSL at vaccination was higher in these patients. No patients on biological DMARDs or targeted synthetic DMARDs prior to vaccination needed additional DMARDs or a change of regimen.RA patients had more frequent and longer-lasting arthralgia after vaccination than healthy subjects, and one-third of patients with post-vaccination arthralgia required additional DMARDs. Although the SARS-CoV-2 mRNA vaccine was administered safely in most RA patients, in some patients RA symptoms may worsen after vaccination. Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus discovered in Wuhan, China in December 2019  is an autoimmune disease affecting the joints, estimated to affects approximately 0.5% to 1% of the global population. Given the large number of individuals affected by RA, it is crucial to understand the characteristics of adverse events of SARS-CoV-2 mRNA vaccine and their effects on disease activity in RA patients. Vaccines often cause arthralgia as an adverse event, but so far few data on the clinical course of arthralgia after vaccination in RA patients have been available.Therefore, we investigated the adverse events and the course of arthralgia after SARS-CoV-2 mRNA vaccination in RA patients in this study. This study aimed to clarify the characteristics of adverse events by SARS-CoV-2 vaccine and the impact on disease activity in patients with RA.We administered a questionnaire about vaccination to RA patients who visited Sasebo Chuo Hospital from 11 January 2022 to 22 April 2022. A total of 1265 RA patients responded to our questionnaire and were enrolled in this study. All patients had a current diagnosis of RA based on the 2010 American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) classification criteria for RA . We alsoWe collected patient data, including the date and type of vaccination, the disease duration of RA, positivity of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), and the use of disease-modifying antirheumatic drugs (DMARDs) at the time of vaccination in RA patients who reported having post-vaccination arthralgia in the questionnaire. This study was approved by the ethics committee of Sasebo Chuo Hospital .To evaluate the adverse symptoms after vaccination, a comprehensive questionnaire including information about the vaccine and subsequent symptoms was developed. The questionnaire included items about the vaccination status and number of doses of respondents, and symptoms such as fever, headache, allergy, and the appearance or worsening of arthralgia that had appeared within 2 weeks after vaccination  and the Clinical Disease Activity Index (CDAI) from the pre-vaccination to the 6-month post-vaccination visit.GraphPad prism software  was used for the statistical analyses. Normal distribution of the data was confirmed using the Kolmogorov-Smirnov test. Continuous variables were compared by Student’s paired t-test or Wilcoxon matched-pairs signed rank test (non-parametric), and the categorical variables were compared by Fisher’s exact test. All data are expressed as the medians and interquartile ranges or the numbers and percentages. A P values<0.05 were considered statistically significant.The demographic characteristics and adverse events of RA patients and health care workers are summarized in We next compared the frequency and duration of arthralgia following vaccination between patients and healthy individuals Table 1.Our present analysis specifically focused on the RA patients who were already diagnosed with RA at the vaccination. Thus, among the 37 RA patients who experienced arthralgia, 4 patients newly diagnosed as RA after vaccination and the 2 patients lack of the vaccination date were excluded and the clinical course of these 31 RA patients was reviewed from the pre-vaccination to the 6-month post-vaccination visit. Their median age of them was 64 years old (IQR 51.5–70), 21 (67.7%) were female, and 31 (100%) received with two doses of vaccination. Twenty-five patients were RF-positive (80.6%), and 19 patients were ACPA-positive (61.3%). Systemic inflammatory symptoms were observed after vaccination in 11 patients (29.7%) and allergic symptoms were observed in 1 patient (2.7%). Arthralgia worsened only after the first vaccination in 2 patients, only after the second vaccination in 13 patients, and after both vaccinations in 10 patients; the relation between arthralgia and the two vaccinations was unknown in 6 patients. Twenty-three patients received the Pfizer-BioTech COVID-19 vaccine (BNT162b2), 1 patient received the Moderna COVID-19 vaccine (mRNA-1273), and 11 patients were not sure which vaccine they received. Pre-vaccination treatment included 8 cases of biological DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs), 21 cases of MTX and 6 cases of other conventional synthetic DMARDs (csDMARDs). Seven patients were concomitantly using PSL Table 3.Disease activity was elevated in some patients; the mean value was highest at 2 months after vaccination but was not significantly changed from pre-vaccination levels at the 6-month follow-up . The results revealed no significant difference in clinical characteristics between these two groups of RA patients , 6 patients received an increased dose of MTX, and 1 patient had additional iguratimod. The course of CDAI in patients with additional or increased doses of DMARDs (n=10) and those without additional DMARDs (n=21) is shown in To investigate the factors associated with persistent worsening arthralgia, we compared the baseline characteristics between RA patients whose treatment remained unchanged during 6 months after vaccination and RA patients whose treatment needed to be changed specifically to suppress arthralgia Table 3.In this study, we first investigated the adverse events of SARS-CoV-2 mRNA vaccine. The RA patient group had fewer systemic inflammatory symptoms but more arthralgia than the health care worker group. The lower occurrence of systemic inflammatory symptoms in the RA group might derive from the difference of age at the vaccination, because systemic inflammatory symptoms after vaccination are more common among younger people , 11. AddThe prevalence of arthralgia after receiving the SARS-CoV-2 vaccine has been reported to be 0.83–46.4% in the general population –16. In aInterestingly, not only the frequency but also the duration of arthralgia differed between the two groups. Arthralgia disappeared within 3 days in all health care workers who reported it, whereas arthralgia in RA patients often persisted for longer days. It is controversial whether the SARS-CoV-2 vaccine exacerbates autoimmune diseases including RA , 18. WhiThe limitations of this study were the short observation period and the possibility of recall bias, as the RA patients and the health care worker group were administered questionnaires at different periods. In addition, we did not analyze the comorbidities of autoimmune disease, such as Sjogren syndrome and systemic lupus erythematosus. These autoimmune conditions can also contribute to arthralgia and may potentially be influenced by vaccination. This is not only for RA patients, but also for health care workers. Furthermore, the clinical course of unvaccinated RA patients has not been studied, so we have not been able to confirm whether vaccinated RA patients experience more flare-ups.Many of the patients who had worsening arthralgia and whose records for the following 6 months were collected were vaccinated with Pfizer’s vaccine; relatively few received Moderna’s vaccine. Indeed, most people in Japan at that time were vaccinated with the Pfizer-BioTech vaccine, not the Moderna vaccine. Therefore, this study cannot discuss differences in adverse events due to vaccine type.In conclusion, our study provides evidence that RA patients experience more frequent and longer-lasting arthralgia as a result of SARS-CoV-2 vaccination. Most of the RA patients were able to receive the vaccine safely. However approximately one-third of RA patients who had arthralgia after vaccination required additional DMARDs within the following 6 months. We should be prepared for this tendency for more prolonged and frequent arthralgia as compared with the general population; in some RA patients, prescription of additional DMARDs post-vaccination may be necessary to manage the increased disease activity. Further research and larger-scale studies are warranted to explore strategies for minimizing arthralgia and optimizing vaccination outcomes in RA patients.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by the ethics committee of Sasebo Chuo Hospital . The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.AT: Writing – original draft. NI: Writing – original draft. SK: Writing – review & editing. TA: Writing – review & editing. KT: Writing – review & editing. YU: Writing – review & editing, Supervision. AK: Writing – review & editing, Supervision. KE: Writing – review & editing, Conceptualization, Supervision.


Fungal infections in patients with COVID-19 was one of the most debated topics during the pandemic. To analyze the clinical characteristics and evolution of people living with HIV/ AIDS and coinfection with cryptococcus and COVID-19 (group A) or without it (group B).  This is an analytical and retrospective study. We reviewed medical records of patients with meningeal cryptococcosis between April 2020 and May 2021. We studied 65 people living with HIV/AIDS and with cryptococcosis infection diagnosed from April 2020 to May 2021. Fifteen patients with HIV/AIDS suffered from cryptococcosis and COVID-19, and out of these, 14 presented meningitis (group A), while 28 suffered from meningeal cryptococcosis, but did not have COVID-19 (group B).Cryptococcus antigens in cerebrospinal fluid, sensorium deterioration or mortality. The detection of Cryptococcus antigens in serum by lateral flow assay was highly effective to rapidly diagnose cryptococcosis in patients with HIV/AIDS who also developed COVID-19. Patients of both groups consulted for cryptoccocosis sometime after, in comparison with the pre-pandemic cases related to this infection. No statistically significant differences were observed between the two groups (A and B) considering: intracranial hypertension, presence of  Later, this virus caused an epidemic of an atypical pneumonia called Coronavirus Disease 2019 (COVID-19) ,The start of the pandemic raised the question about the evolution of SARS-CoV-2 infection in people living with HIV/AIDS, mainly those cases without antiretroviral treatment and low count of CD4+ lymphocytes. In this regard, these patients were initially considered at risk of suffering from severe clinical forms -The association between fungal infections and COVID-19 has been the subject of multiple publications, especially for cases of aspergillosis, candidiasis, and mucormycosis ,On the other hand, meningeal cryptococcosis in patients with HIV/AIDS is still one of the most frequent and serious opportunistic diseases in South America The aim of this study was to compare the clinical characteristics and evolution of people living with HIV/AIDS and meningeal cryptococcosis in the presence (group A) or absence (group B) of COVID-19 infection.This is an analytical and retrospective study. We reviewed the medical records of 65 patients with HIV/AIDS and cryptococcosis infection diagnosed between April 2020 and May 2021 in the Mycology Unit of our hospital.People living with HIV/AIDS with meningeal cryptococcosis.HIV-negative patients with cryptococcosis.People living with HIV/AIDS with extra-meningeal cryptococcosis.We recorded data on age, sex, signs and symptoms, comorbidities, antiretroviral treatment, a physicochemical study of cerebrospinal fluid, opening pressure, antigenic score, lymphocyte populations count, and risk factors for HIV infection.The HIV-positive patients who met the inclusion criteria were divided into two groups. Group A included the patients who suffered from COVID-19, and group B, the patients who did not .,Cryptococcus antigen detection in serum was performed by lateral flow assay  in patients with a CD4+ lymphocyte count down to 200 cells/μl -Blood culture by lysis centrifugation was performed with samples from every patient with HIV/AIDS. The samples were cultured in Sabouraud-honey agar medium at 28°C and brain-heart infusion agar at 37°C for three weeks. Cultures were checked twice a week For mycological examination, we took respiratory samples -sputum or bronchoalveolar lavage- from patients with respiratory symptoms or compatible images with pulmonary cryptococcosis. Likewise, we took a cerebrospinal fluid sample from patients with initial suspicion of central nervous system involvement.Cryptococcus antigen detection, cryptococcemia or pulmonary cryptococcosis underwent lumbar puncture to rule out or confirm meningeal involvement through mycological examination of cerebrospinal fluid.All patients with a positive result for Cryptococcus spp.All cerebrospinal fluid samples were microscopically tested with Indian ink and cultured on Sabouraud-honey agar, sunflower seed agar, and brain-heart infusion agar. Cultures were incubated at 28°C and 37°C for 15 days and were observed daily, seeking for colonies compatible with Mycological control of patients with meningitis was performed with cerebrospinal fluid cultures at 2-3 weeks after the diagnosis and was repeated until a negative result was obtained.Cryptococcus neoformans and Cryptococcus gattii was performed by their growth in canavanine-glycine-bromothymol blue and Salkin’s medium (cycloheximideglycine-phenol red) respectively The phenotyping of the isolates was carried out by studying their growth capacity at 37°C, the presence of capsule, urease activity and phenoloxidase production in sunflower seeds agar. Differentiation between Blood samples were taken from all patients at the time of diagnosis. Serum was separated and kept at -20°C until the time of determination.Cryptococcus capsular polysaccharide antigen in both serum and cerebrospinal fluid was carried out using the latex agglutination technique  according to the manufacturer’s instructions. Undiluted serum and 1:10; 1:100; 1:1000; 1:5,000 and 1:10,000 dilutions were used to determine the titer.The semiquantitative determination of Cryptococcus, from cerebrospinal fluid, in culture and COVID-19 diagnosed by qRT-PCR (positive for SARS-CoV2).COVID-19 coinfection was confirmed in patients who presented a positive qRT-PCR for SARS-CoV-2 from a nasopharyngeal swab within 30 days of meningeal cryptococcosis having been diagnosed. We also included patients who persisted with development of Erythrocyte sedimentation rate was evaluated on the device VES Matic Cube 300 (Diesse); D-dimer was determined by an enzyme-linked fluorescence assay using a VIDAS autoanalyzer; C-reactive protein, ferritin, and lactic dehydrogenase enzyme were analyzed on the Cobas C311 analytical platform by immunoturbidimetry and UV kinetic method for lactic dehydrogenase enzyme.The leukocyte count was performed in the Sysmex XN-1000 hematology counter . This can be used as an immune response severity index. The number of neutrophils, lymphocytes and the ratio between the two of them are markers of systemic inflammation.Cryptococcus antigen in cerebrospinal fluid greater than or equal to 1/5000, impaired sensorium and CD4+ lymphocyte count lower than 100 cells/mm3.In both groups we evaluated as severity criteria the following: intracranial hypertension, Continuous variables were expressed as mean or median. Depending on the data distribution, we applied Student’s ttest or the Mann-Whitney- Wilcoxon to evaluate the statistical differences between groups A and B. Categorical variables were expressed as percentages and Fisher’s exact test was calculated. Differences were considered statistically significant when the pvalue was inferior to 0.05. We used Statistix® 8.0 software for analysis.We conducted this study according to the protocol and good clinical practice standards established by the research ethics committee of the Hospital Francisco Javier Muñiz.A total of 15 patients with HIV/AIDS suffered from cryptococcosis and COVID-19. Fourteen had meningitis, and only one had positive antigenemia, found by lateral flow assay, with no other findings. Regarding gender, nine patients were men and six were women. The median age was 26.5 (range: 23-60).None of the patients showed good adherence to antiretroviral therapy. Two of them were aware of their immunocompromised state at the time of hospitalization, and the remaining 12 were aware of their disease but were not under antiretroviral therapy.Four patients presented pulmonary compromise compatible with COVID19 . Out of Cryptococcus neoformans. However, the pulmonary commitment by this microorganism was not confirmed in any patient, although we observed findings congruent with cryptococcosis in computed tomographies from three of them.Four patients had positive blood cultures for C. neoformans, from cerebrospinal fluid samples, at the time of death. Nevertheless, it was impossible to establish whether they died from COVID-19 and/or cryptococcosis.The three patients who died had positive cultures for C. neoformans VNI, according to phenotypic and genotypic identification.All isolates corresponded to the variety of Increased lactate dehydrogenase, dimer D and lymphopenia were the most frequent laboratory parameters in patients with COVID-19 and cryptococcosis . In patiThe main signs and symptoms of patients with meningeal cryptococcosis and COVID-19 in both groups are shown in SARS-CoV-2 infection can cause asymptomatic clinical pictures as well as highly variable presentations. From myalgia, arthralgia, and anosmia to severe bilateral pneumonia Cryptococcus antigen detection, by lateral flow assay, has been routinely performed in patients with a CD4+ lymphocyte count less than or equal to 200 cells/μl, before starting antiretroviral treatment to prevent immune reconstitution syndrome ,,Cryptococcus meningitis close to the time when the nasopharyngeal admission swab was performed. Only few cases of COVID-19 infection occurred during hospitalization , in both groups, compared with pre-pandemic data  We detected an increase in the percentage of heavily treatmentexperienced patients (28/42 - 66 %) and presence of Numerous authors support that the hyperinflammatory immune response induced by the SARS-CoV-2 virus plays a central role in the pathogenesis of the disease. In this work, we analyze the prognostic value of certain laboratory biomarkers in hospitalized patients with COVID-19. The recommendations suggest evaluating inflammatory markers such as: leukocyte differential count, erythrocyte sedimentation rate, D-dimer, ferritin, C-reactive protein, interleukin6, lactate dehydrogenase, procalcitonin, troponins and natriuretic peptides 3), increased leukocytes, a high absolute count of neutrophils, and increased neutrophil-to-lymphocyte ratio. It is important to mention that in this retrospective study interleukin6, procalcitonin, and cardiac biomarkers (troponins and natriuretic peptides) were not analyzed.Most severe cases of COVID-19 presented a low absolute count of lymphocytes  or without coinfection with COVID-19 (group B).


Sterilization rates for Asian-born men were not significantly higher than those of US-born men . This original quantitative analysis contributes to the literature demonstrating the health impact of discrimination on Asian-Americans and the disproportionate sterilization of racial minorities under state eugenics programs.During the twentieth century, state health authorities in California recommended sterilization for over 20,000 individuals held in state institutions. Asian immigrants occupied a marginalized position in racial, gender, and class hierarchies in California at the height of its eugenic sterilization program. Scholars have documented the disproportionate sterilization of other racialized groups, but little research exists connecting the racist, gendered implementation of Asian immigration restriction to the racism and sexism inherent in eugenics. This study examines patterns of coercive sterilization in Asian immigrants in California, hypothesizing higher institutionalization and sterilization rates among Asian-born compared with other foreign- and US-born individuals. We used complete count census microdata from 1910 to 1940 and digitized sterilization recommendation forms from 1920 to 1945 to model relative institutionalization and sterilization rates of Asian-born, other foreign-born, and US-born populations, stratified by gender. Other foreign-born men and women had the highest institutionalization rates in all four census years. Sterilization rates were higher for Asian-born women compared with US-born [Incidence Rate Ratio (IRR) = 2.00 ] and other foreign-born women ( The COVID-19 pandemic prompted increased xenophobia and racialized violence toward Asian-Americans and Asian immigrants in the United States. This surge in discrimination and hate crimes is unsurprising when tracing long-standing stereotypes of Asians as threats to public health. Historians have documented the development of legal, social, and scientific narratives portraying Asians, both foreign- and American-born, as unassimilable aliens and threats to the health of white populations . Public This is the first study to quantitatively analyze the eugenic sterilization of Asian immigrants in the twentieth century. The impact of California’s twentieth-century eugenic sterilization program on Asians merits closer examination given the racist implementation of eugenic programs and the sociopolitical position of Asians in California’s racial, gender, and class hierarchies at the time. Previous studies reported a disproportionate sterilization of Black people in North Carolina  and SpanOur study analyzes “Asian race” as a socially and historically constructed category rather than a biological reality . AlthougOzawa v. United States 1922), and Bhagat Singh Thind, an Indian man (United States v. Thind 1923)  . These cnd 1923) . By the nd 1923) .This condensed history demonstrates the formation of the socially constructed racial category of “Asian” during the eugenics era. Given this history, our paper uses nativity from China, Japan, Korea, India, and the Philippines—what we label “Asian-born”—as a proxy for the way these individuals were racialized by institutional authorities making decisions about whether they should be sterilized. This category derives meaning and power not from the shared continent of Asian immigrants’ countries of origins but from the shared experiences of Asian immigrants with discrimination and racialization in American society . AlthougProponents of eugenics blamed “bad genetics” for social issues, including criminality , sexual The varied pathways into state institutions included commitment by a family member such as a spouse or parent, forced placement by a juvenile official usually involving court proceedings, or transfer, particularly of young people, from a reform school . Less coThe advent of sterilization fundamentally shifted the institutionalization process and offered institutional authorities a mechanism to “safely” release some patients without fear they would reproduce . Thirty-Institutionalization in state hospitals for the insane or homes for the “feebleminded” constituted the primary setting for eugenic sterilization in California . In one California’s eugenic sterilization law granted institutional superintendents’ discretion to authorize the sterilization of any individual committed to a state institution. Given this intersection of institutionalization and sterilization in California, we analyze rates of both. We use sterilization request forms  created by institutional and state authorities for institutionalized individuals deemed “unfit” to reproduce. See the online supplementary material for Disability diagnoses and labels popular in the early twentieth century—like “feeblemindedness” or “dementia praecox”—often led to institutionalization. Racism, classism, sexism, and xenophobia not only shaped understandings of who was considered “unfit” but also the development and application of disability labels indicating mental illness or cognitive impairment . EugenicDisparaging associations of Asian race and disability developed before the height of the eugenics movement. Prior to the discovery that trisomy 21 caused the condition known as Down’s Syndrome, Dr. John Langdon Down theorized racial degeneration caused this condition to develop among Europeans. He compared the physical features of people with trisomy 21 to the physcial features of people from Mongolia and asserted “a very large number of congenital idiots are typical Mongols” , 2. “MonPublic health rhetoric expanded xenophobic “Yellow Peril” narratives, which positioned Asian immigration as threatening the US social order, into the realm of medicine. Nativists and eugenicists alike cast racialized Asian immigrants as inferior and undesirable by linking them to disability and illness. Officials believed Asians were hereditarily prone to diseases such as trachoma and syphilis and would eventually spread them to white populations . IncreasCalifornia institutional officials often blamed foreign-born populations for California’s supposed high insanity rates . During Race and gender are not mutually exclusive categories but instead exist as overlapping “structures of difference and disempowerment [that] reinforce one another” , 15. TheThe literature on both eugenic sterilization  and AsiaMen vastly outnumbered women among Asian immigrants in the United States, though the sex ratio became less skewed over time . In addiMany Asian women immigrated to the United States during the era of exclusion through exemption clauses allowing immigrant (pre-exclusion or exempt class) or US-born Asian men to bring over wives, children, or other family members . HoweverCalifornia officials were also preoccupied with the sexual and reproductive lives of Asian immigrant families. The gender imbalance among Asian immigrants led to widespread non-normative family structures that deviated from the “Western” nuclear ideal. The supposed prevalence of prostitutes and “concubines” in Chinese communities implied that neither Chinese women nor men respected the sanctity of marriage . Some ChSince eugenic definitions of “unfit” overlapped with racialized characteristics ascribed to Asian immigrants, we theorize Asian-born people had overall higher rates of institutionalization and eugenic sterilization from 1920 to 1945 compared with non-Asian-born people (other foreign- and US-born), with gender modifying the relationship; however, we postulate heterogeneity in institutionalization rates in Asian-born individuals by gender and nativity subgroup. Initial analysis prompted an additional post hoc hypothesis that the year of sterilization recommendation could modify the relationship between nativity and the sterilization rate for men.This retrospective population study used two datasets: complete-count US decennial census microdata  from 191Sterilization requests are assumed to be evidence of sterilization as an integral step in the state-sponsored sterilization process in California. These recommendations were the primary mechanism through which compulsory sterilizations were authorized in institutions, and all included requests were approved by the Department of Institutions. These forms contained demographic, personal, and familial information recorded by institutions. Sterilization records in the dataset were centralized from eleven California institutions during the 1920s transition from the California Commission in Lunacy to the California Department of Institutions. Two institutions were Homes for the Feebleminded (Sonoma and Pacific Colony), and nine were State Hospitals for the Insane . Dewitt and Modesto State Hospitals did not recommend any sterilizations until after 1945 and are therefore not included in the analysis.For more details about data collection and digitization, see the methodological supplement of In both datasets, we used data on birthplace to generate a three-category nativity variable: (i) US-born; (ii) Chinese-, Indian-, Japanese-, Korean-, or Filipino-born; or (iii) other foreign-born. US-born included people born in US territories granting birthright citizenship during the study period (e.g. Hawaii) but not US territories whose residents were excluded from citizenship (e.g. the Philippines).We restricted the census data to those with complete data on sex and birthplace.n1920 = 11,396, n1930 = 16,801, n1940 = 26,748) and overall population of California .Bivariate statistics were calculated for age, census year, institution, and sex by the nativity group for the institutionalized population  and nativity (n = 4282) information were excluded. Since sterilization recommendation forms did not systematically report race or ethnicity, we designated Chinese-, Indian-, Japanese-, Korean-, or Filipino-born individuals as part of a racialized “Asian-born” group (n = 287). A categorical nativity variable identified Asian-born people, other foreign- (n = 2303), and US-born people . The final analytic sample was n = 13,499.The sterilization dataset was restricted to 17,813 people recommended for sterilization from 1920 to 1945 corresponding with available US Census microdata from 1920, 1930, and 1940. Those missing sex , patient histories, diagnosis, legal provision, and consent. A Holm–Bonferroni correction for multiple testing was applied to all statistical tests of descriptives besides basic demographics. Additional methodological information for descriptive statistics can be found online.To estimate sterilization rates across nativity groups, we collapsed our microdata to generate counts of sterilization recommendations, by gender, nativity group, and year from 1920 to 1945. We similarly collapsed census microdata to generate counts of institutionalized persons in 1920, 1930, and 1940 by sex and nativity group. To generate intercensal year counts, we linearly interpolated the number of institutionalized people, by gender and nativity group, between census years. Counts from 1940 were extended forward to 1945. For hospitals established after 1920 (Pacific Colony in 1927 and Camarillo in 1933), institutionalized populations were interpolated back from the first census after opening.Because sterilization practices differed between males and females, we stratified all analyses on sex. To qualitatively demonstrate time trends, locally estimated scatterplot smoothing (LOESS) curves were constructed for annual population-based sterilization rates, stratified by nativity group and sex. We used Poisson regression to compare sterilization rates between nativity groups, using the annual number of sterilizations as the dependent variable, the number of institutionalized persons as the offset, and the nativity group as the independent variable. For regression coefficients estimating differences in sterilization rates by nativity, US-born was the reference group. A post hoc test evaluated whether regression coefficients for Asian- and other foreign-born people differed statistically. LOESS curves and regression models could not be adjusted for age or institution or disaggregated by the Asian nativity subgroup, as small cell sizes prevented the reliable interpolation of census denominators. A post hoc analysis for the effect modification of the sterilization rate model by time for men only in the form of a 1933 inflection point was conducted based on observations of LOESS curves.n = 4,282). The online supplement details our methods for generating lower and upper bound estimates.A sensitivity analysis was conducted to examine the potential impact of missing data on the results. Additional Poisson regressions modeled low and high estimates of the number of Asian-born patients among individuals missing nativity information . Across the four censuses, California’s Asian-born population was 79.14% male, whereas other foreign-born people were 57.26% and US-born people were 50.46% male. California’s US-born population increased each census year from 1910 to 1940, and its Asian-and other foreign-born population decreased from 1930 to 1940. The proportion of the population institutionalized across the four census years varied by nativity group, with the greatest proportion institutionalized among other foreign-born, followed by Asian- and then US-born persons.n1920 = 11,396, n1930 = 16,801, n1940 = 26,748) by nativity group  and chi-squared P-values. There were statistically significant differences in age distribution by nativity, with Asian-born institutionalized persons tending to be older than US-born but younger than other foreign-born people. A greater proportion of Asian-born patients were men (79.96%) than among other foreign-born (60.77%) or US-born (50.51%) people. The institutions housing the most Asian-born patients during census years were Stockton State Hospital (29.85% of Asian-born patients), Napa State Hospital (14.93%), Patton State Hospital (16.50%), and Mendocino State Hospital (15.15%). A greater proportion of Asian-born patients were institutionalized at Stockton than were other foreign- (21.66%) or US-born (13.13%) persons. Asian-born patients were primarily institutionalized in “Hospitals for the Insane” with only 2.00% of Asian-born patients at Sonoma and Pacific Colony. This proportion is lower than the 20.12% of US-born patients in Homes for the Feebleminded. The institutionalized population increased each census for all nativity groups.n = 13,499) by nativity group with P-values for chi-square tests of independence across nativity groups. A greater proportion of US-born people were recommended for sterilization at young ages (29.62% younger than 20) when compared with Asian-born populations (6.01% younger than 20). A larger proportion of Asian-born people recommended for sterilization were men (70.38%) than among other foreign- (59.88%) or US-born (49.63%) people.The institutions that sterilized the most Asian-born patients were Stockton (44.60% of Asian-born patients recommended for sterilization), Napa (17.07%), and Patton (19.51%). A greater proportion of Asian-born patients were sterilized at Stockton than were other foreign- (32.42%) or US-born (18.82%) persons. “Hospitals for the Insane” sterilized 95.82% of Asian- and 92.31% of other foreign-born patients recommended for sterilization. Although most US-born patients recommended for sterilization were also sterilized at “Hospitals for the Insane” (69.72%), the proportion of US-born patients sterilized at “Homes for the Feebleminded” (30.27%) was higher than for Asian- and other foreign-born patients.The number of sterilizations among US-born patients increased from 1920 to 1939 and then decreased slightly from 1940 to 1945. The number of sterilizations among Asian- and other foreign-born patients did not increase or decrease steadily across multiple periods. Descriptives for patient histories, diagnosis, legal provision, and consent are presented in P-value for difference in coefficients < 0.001). Asian-born men did not have significantly different rates of sterilization from US-born men [IRR = 0.95 ] but did have significantly higher sterilization rates than other foreign-born men . The online supplement presents sensitivity analysis LOESS curves in P < 0.001 for before and after 1933).Given the change in direction of relative sterilization rates for men by nativity group suggested by the LOESS curves, an indicator allowing different coefficients before and after 1933 was incorporated into another Poisson model for men . The infOur study presents novel quantitative evidence of disproportionate eugenic sterilization of Asian immigrants in twentieth-century California and follows Asian-American studies scholars in centering the experiences of Asian immigrants in the history of the United States. We connect the racist and gendered implementation of Asian immigration restriction to the racism and sexism inherent in eugenic theories and practices. Though Asian immigrant women constituted a small proportion of California’s population during the height of its sterilization program, we confirmed our hypothesis of higher rates of sterilization of Asian-born women compared with US- and other foreign-born women from 1920 to 1945. Asian-born men only showed higher sterilization rates prior to 1933, in partial agreement with our initial hypothesis, for reasons requiring additional research to illuminate.Contrary to our hypothesis of higher institutionalization rates of Asian immigrants, other foreign-born men and women consistently had the highest institutionalization rates across censuses while Asian-born men and women were generally institutionalized at similar rates to their US-born counterparts. However, disaggregating the Asian nativity group by national origin subgroup substantiated our expectation of heterogeneity in institutionalization rates by nativity subgroup.Asian-born men and women were institutionalized at similar rates to their US-born counterparts, except in 1920 when Asian-born women had a lower institutionalization and 1910 and 1940 when Asian-born men had higher institutionalization rates. Immigrants were often blamed for high “insanity rates” and overcrowding in institutions in California  and otheIndeed, further disaggregation of the Asian-born nativity group revealed in certain census years one national origin group drove the observed differences in aggregate institutionalization rates and could mask lower institutionalization rates of other groups. In 1910, Chinese-born men appeared to drive the higher institutionalization rate for Asian-born men compared with US-born men and mask the significantly lower rate for Japanese-born men. In 1940, Chinese-born men again contributed to the higher institutionalization rate of Asian-born men, now in conjunction with Indian-, Japanese-, and Korean-born men and masking the lower institutionalization rate for Filipino-born men relative to US-born men. Disaggregated rates for women revealed lower institutionalization rates for Japanese-born relative to US-born women in every census year except 1940. Our institutionalization rate findings for Japanese-born men and women parallel Our finding of disproportionate sterilization of Asian immigrant women across the study period and men prior to 1933 strengthens the evidence documenting a racialized implementation of eugenic sterilization previously demonstrated for other racialized groups: Latino/a/x people in California and Black people in North Carolina . UnfortuDistinct gender differences persisted in sterilization rates of Asian-born individuals. Asian-born women were sterilized at a rate twice that of US-born women and had an even greater disparity with other foreign-born women. Furthermore, disproportionate sterilization of Asian-born women occurred despite lower rates of institutionalization of this group; the institutionalization rates of Asian-born women were statistically similar or lower than the rates of US- and other foreign-born women in every census year examined. Women can be an extremely small numerical presence and still play central roles in their communities as In perhaps our most surprising finding, the sterilization rate of Asian-born men was not higher than the rate of other foreign- or US-born men until taking modification by the year of sterilization recommendation into account. This finding is somewhat consistent with other quantitative studies of eugenic sterilization in California  and otheThe greater effect size in the regression models for Asian-born women than in those for Asian-born men strongly contradicts the subordinate male target hypothesis under which Asian-born men would be the primary targets of racism toward Asian immigrants as perceived sexual and reproductive threats to the white US-born population . InterseThe specificity of the 1933 inflection point remains less easily explained and requires additional research to clarify. The relative sterilization rates clearly flipped for US- and Asian-born men in 1933 and led to our purely data-driven decision to use 1933 as the year in our inflection point models. We believe this shift is more than a demographic artifact of fluctuating labor needs and declining immigration of Asian male laborers due to exclusion laws because we account for changes in the institutionalized population with the inclusion of census denominators. Nevertheless, immigration restriction or momentous economic changes could have shifted how eugenicists and American society viewed Asian-born men as economic, social, and political “threats” to white Californians. For example, the Great Depression’s onset several years before and the Tydings–McDuffie act reclassifying Filipinos from US nationals to aliens ineligible for citizenship one year after the observed change in relative sterilization rates represents major transformations with the power to potentially change the application of eugenic sterilization to men of different groups. Although we can currently only speculate, the above two events in addition to other contextual factors such as population size, labor participation, political power, and community visibility constitute intriguing avenues of future research into historical eugenic sterilization.While nativity had less missingness than race, the missingness may still have biased the results. In sensitivity analyses imputing US nativity for all missing nativity data, Asian-born men exhibited lower sterilization rates than their US-born counterparts. The corresponding version of the inflection point model resulted in statistically similar sterilization rates for Asian- and US-born men prior to 1933. However, imputing US nativity for all sterilization survivors missing nativity data still resulted in significantly higher sterilization rates for Asian-born relative to US-born women, albeit with a smaller effect size. The other set of sensitivity analyses extended the nativity distribution of sterilization survivors from Stockton State Hospital to all sterilization survivors missing nativity data. The Poisson regression models resulted in greater effect sizes in Asian-born women’s higher sterilization rates across the study period and Asian-born men’s sterilization rates before 1933.Nativity information was missing more often for women than for men: 26.12% of women versus 22.09% of men recommended for sterilization. This differential missingness likely contributed to wider variation in upper and lower sensitivity estimates for women compared with men. Yet our finding of higher sterilization rates of Asian-born relative to US- and other foreign-born women held even after accounting for missing data. Thus, our sensitivity analysis results strengthen the evidence for our conclusion that Asian-born women were sterilized at disproportionately higher rates compared with other foreign- and US-born women under California’s eugenic sterilization program.This study drew strength from its population-based design, ensuring adequate size for analysis. Despite small counts in both the census and sterilization recommendation datasets, LOESS analysis resulted in stable sterilization rates and regressions in acceptable model fit parameters. Using nativity instead of race allowed for less missing data, narrowed the population of interest and theoretical focus to immigrants, addressed some potential racial misclassification, and demonstrated the nuance of disaggregating subgroups comprising a racialized group. Another strength was examining both institutionalization and sterilization rates since California primarily sponsored the sterilization of institutional residents. In addition, this study identified differences in consent, diagnoses, and descriptive characteristics of Asian-born sterilization survivors. Finally, these findings can strengthen the foundation for continued quantitative and qualitative study of the United States’s history of eugenics and motivate new research questions.Unfortunately, we could not adjust models for age and institution because small cell counts prevented reliable interpolation between census years when incorporating additional variables. Statistically significant demographic differences between nativity groups and the population recommended for sterilization versus the institutionalized population suggest age and institution influence sterilization patterns, confounding the results. Asian individuals in some nativity subgroups resided in geographic and ethnic clusters in California , and if Additionally, large confidence intervals for institutionalization rates by nativity subgroup limit meaningful conclusions about nuances of national origin and institutionalization. Korean institutionalization rates appeared especially high compared with other nativity subgroups, though small numbers and possible misclassification due to the Japanese occupation of Korea in 1910–1945 mean these numbers should be interpreted cautiously. Moreover, we could not examine differential sterilization rates among nativity subgroups due to small cell sizes preventing a reliable interpolation of census denominators. Future research could explore the nuances of Asian subgroup differences in institutionalization and sterilization rates with more complex methods, such as surname analysis.Our assumption that a sterilization request form indicates a sterilization operation occurred may have misclassified some individuals who should have been part of the at-risk institutionalized population in the denominator rather than the population sterilized in the numerator. If misclassification was non-differential by nativity, it would bias the effect toward the null. The Spanish surname population, coded as other foreign- or US-born except some Filipino individuals with Spanish-influenced surnames, may have dampened the effect as well since they were another racialized group with sterilization rates disproportionate to their population share. Finally, using nativity to measure membership in a racialized Asian immigrant group may bias results toward the null due to “misclassifying” second-generation Asian-Americans. Due to perceptions of Asian-Americans as “perpetual foreigners,” they may have experienced similar discrimination in institutionalization and sterilization processes despite not being immigrants themselves.The historical rhetoric portraying Asians as perpetual foreigners and threats to public health bears unfortunate resemblance to increased racist and xenophobic rhetoric directed toward Asian-Americans and Asian immigrants during the COVID-19 pandemic. Asian-Americans have grown faster than any other major US racial group in the last two decades , increasMore recent reports of forced or coercive sterilization, such as California’s prison system sterilizing an estimated 148 incarcerated women without consent  and stersf-jul-21-354-File006_soad060Click here for additional data file.sf-jul-21-354-File007_soad060Click here for additional data file.sf-jul-21-354-File008_soad060Click here for additional data file.sf-jul-21-354-File009_soad060Click here for additional data file.


Coagulase-negative staphylococci tended to have a worse reinfection-free survivorship at five years . Furthermore, the patients with obesity tended to have reduced reinfection-free survivorship at five years . Overall, 5% (6/111) of the patients had blood count abnormalities with no treatment discontinuations. Conclusion: Two-stage revision arthroplasty with systemic oral linezolid treatment for resistant gram-positive PJI results in an infection control of 77% at the mid-term.Background: Increasing antibiotic resistance has been reported as an issue in the systemic treatment of periprosthetic joint infection (PJI). Linezolid offers the advantages of high oral bioavailability and little resistance; however, efficacy in the treatment of PJI varies considerably, and studies reporting consistent surgical treatment are scarce. Methods: This is a retrospective, single-center analysis of two-stage revisions performed between 2008 and 2017. We identified 111 patients who met the inclusion criteria. Oral linezolid was given for 28 days following 14 days of intravenous tailored antibiotics in resistant gram-positive PJI. A total of 64% of the patients had methicillin-resistant coagulase-negative staphylococci. The median follow-up was 43 (interquartile range (IQR) 30–57) months. Results: 22% (24/111) of the patients underwent surgery for subsequent infection. The 5-year infection-free survival probability was 77%  69–85). A total of 5% of the patients (6/111) had the same organism at the time of reinfection. The patients with infections caused by other organisms than  The pnfection . Previounfection ,18,19,20nfection .For instance, the largest studies on the use of linezolid-based antibiotic regimes ,22 for PFurthermore, a large proportion of studies included in a recent review used linezolid as a second-line treatment for recurrent infection or failure of previous systemic antibiotics, which is a substantial confounder for potentially lower treatment success .This study aims at reporting clinical and microbiological results as well as treatment details regarding the use of linezolid for the treatment of PJI in a large cohort of patients treated with a standardized surgical approach and analyzes risk factors for treatment failure.Demographic details on the patients included are given in A total of 22% (24/111) of the patients underwent surgery for subsequent infection after second-stage reimplantation of the same joint after a median follow-up of 7 months (IQR 4–11). A total of 25% (6/24) of the patients had a causative organism from the same species, including polymicrobial infections, suggesting possible persistence . A totalA total of 5% of the patients (6/111) had the same species at the time of reinfection compared to the initial culture results, suggesting a microbiological failure of the two-stage approach with systemic linezolid. However, none of the organisms in reinfected patients had developed resistance to linezolid.The 1-year infection-free survival probability amounted to 82% (95% CI 75–89), and the 5-year infection-free survival probability was 77% (95% CI 69–85) .p = 0.09). Furthermore, the patients with obesity had a reduced reinfection-free survivorship at five years .We found that the patients with infections caused by organisms other than ConS tended to have a worse reinfection-free survivorship at five years  and were of higher age .Additionally, the reinfected patients had a higher body mass index (BMI) , the type of intravenous systemic antibiotic treatment (p = 0.49), the type of local antibiotic added to the spacer (p = 0.5), diabetes (p = 0.24), McPherson systemic host grade (p = 0.58), McPherson extremity grade (p = 0.29), or the presence of fistulating infection (p = 0.64). In addition, the patient’s CCI (p = 0.68) and the number of previous surgeries (p = 0.13) were not associated with the risk of subsequent PJI.On the other hand, with the numbers available, there was no difference in infection-free survival depending on patient gender  of the patients had blood count abnormalities, and 3 patients had thrombopenia and leukopenia.Increasing antibiotic resistance particularly among CoNS PJI is an increasing challenge for clinicians . FurtherThe likelihood of successful infection control using a two-stage approach, including systemic linezolid treatment, has been investigated previously. One study  includedFurthermore, Eriksson et al.  investigRegarding microbiology findings, we found that the most common organism cultured was resistant coagulase-negative staphylococci, and the patients with a different organism than CoNS had a higher risk of relapse in comparison. The reasons for this are unclear given the retrospective study design. However, PJI caused by resistant CoNS is a major concern, although resistance patterns appear to vary tremendously, even in similar geographical regions . One stuIn the present study, patients with obesity had a higher risk of reinfection compared to patients with normal body weight. This is in line with findings from previous studies on two-stage revision. One study  includedWhile this is not a study on drug safety, we noted no discontinuations of oral linezolid treatment, and there were only 5% blood count abnormalities in the present cohort. In this study, linezolid was used for treatment continuation after intravenous treatment, and treatment duration was limited to 28 days, according to the pharmaceutical companies’ recommendations. Nonetheless, considering that longer treatment durations for PJI are desirable and may lead to favorable outcomes, including lifelong suppressive therapy in high-risk cases ,34,35,36While this is a large study with a relatively homogeneous patient cohort, its findings must be interpreted considering several limitations. First, it is retrospectively designed, and it is possible that some patients might have undergone treatment for PJI elsewhere; therefore, the reported infection risk should be viewed as a low-end result. Nevertheless, the median follow-up is almost four years, which exceeds many previous studies on PJI treatment with linezolid. Secondly, when analyzing risk factors for infection recurrence or treatment failure, this study is limited by the number of patients with individual risk factors. Furthermore, some risk factors, such as individual culture results or patient factors, might be present, but the study could still be underpowered to detect those. Thirdly, while we feel confident to report on some adverse events that could be attributed to linezolid treatment, this study is not a pharmaceutical or prospective trial., Patients were not prospectively supervised and the majority had blood counts performed on an individual basis by the general practitioner. Considering the higher risk of adverse events reported in previous studies, claims regarding drug safety should not be overstated based on our results.Fourthly, the outcome of two-stage chronic PJI depends on various factors, and systemic antibiotics are only considered as part of a multimodal treatment approach considering various factors, including intravenous systemic and local antibiotics. While we absolutely acknowledge these factors and their potential impact on our results, this study was unable to detect an effect on the survival and eradication of the infection based on the systemic antibiotic used or the presence of vancomycin in the spacer. Furthermore, multivariate analyses with larger datasets providing hazard ratios are needed to elucidate the potential interdependencies.After obtaining approval from our local ethics committee (reference number F-s-2019-041-f-S), we conducted a retrospective database search of our institution’s electronic database and reviewed all patients that underwent revision surgery of an infected hip or knee joint replacement between 2008 and 2017. Overall, 625 patients  completed a two-stage revision for chronic PJI, and 514 did not undergo treatment with linezolid.We included patients who underwent non-oncologic joint replacement as well as patients who underwent implant revision following oncological resection and implantation of tumor prostheses. We did not review patients with spinal infections, infected fractures, or osteosynthesis and osteomyelitis without foreign material present. Applying those criteria, we included 111 patients with a two-stage hip or knee revision for PJI with resistant gram-positive bacteria undergoing systemic linezolid treatment.In order to diagnose infection, we applied the criteria of the musculoskeletal infection society (MSIS) of 2011 , and priSystemic antibiotics were given for a minimum of six weeks and were generally administered every two weeks as an intravenous treatment, and the oral continuation treatment was performed in an outpatient setting for 4 weeks. In two-stage exchanges, intravenous therapy was given after reimplantation surgery for two further weeks until the final culture results from the reimplantation surgery remained negative. Otherwise, another four weeks of oral antibiotics were given.Failure was defined as a patient requiring further surgery due to infection. Furthermore, microbiological failure was defined as revision surgery for infection caused by the same species. On the other hand, infection control was defined as proposed by the consensus criteria by Diaz-Ledema et al. , which rPatient demographic details  and micrIn the present study, linezolid was used as an oral, outpatient continuation of previous intravenous therapy due to its excellent oral bioavailability and was administered for 28 days (maximum length of therapy according to the manufacturer). In some cases of infection caused by vancomycin-resistant enterococci, linezolid was already used during the hospital stay . Intravenous treatment was performed using vancomycin in 72% of the patients (80/111), flucloaxacillin or cephalosporines in 18% (20/111), and daptomycin in 7% (8/111).Linezolid was used as the first choice to treat resistant gram-positive infections if other oral alternatives (quinolones or cotrimoxazole) were tested to be resistant or if comorbidities or coexisting medications taken by individual patient did not allow for other oral antibiotics (five patients for cotrimoxazole and seven patients for leveofloxacin). A total of 600 mg of linezolid was given twice a day.A total of 14% of the patients (15/111) had combined oral therapy due to polymicrobial growth, and 10 patients received oral amoxicillin/clavulanic acid and 5 patients received ciprofloxacin.A combination with rifampicin was not generally used during spacer treatment because of relevant interaction and a reduction in linezolid blood levels caused by rifampicin ,44,45. WThe patients had a blood count performed after systemic antibiotic therapy during outpatient assessment prior to second-stage surgery and were questioned regarding treatment discontinuation or other complications.t-test or the Mann–Whitney u-test, respectively. Categorical variables were analyzed with the chi-squared test using cross tables. The reinfection-free implant survivorship was analyzed with the Kaplan–Meier method, and differences in survivorship were compared with the log-rank test. P was set at 0.05; all p-values were two-sided. The respective 95% confidence intervals (CIs) were calculated.A descriptive data analysis was conducted, and the distribution of the data was analyzed using the Shapiro–Wilk test or the Kolmogorov–Smirnov test. Parametric and non-parametric analyses were performed using Student’s A treatment approach using two-stage revision arthroplasty in combination with a systemic antibiotic regime consisting of intravenous treatment followed by oral linezolid treatment for resistant gram-positive PJI resulted in an infection control of 77% at mid-term follow-up with a low rate of discontinuation and adverse events. Future studies should investigate optimal combination therapy as well as the prolonged use of linezolid.


Whilst multi-morbidity is known to be a concern in people with cancer, very little is known about the risk of cancer in multi-morbid patients. This study aims to investigate the risk of being diagnosed with lung, colorectal, breast and prostate cancer associated with multi-morbidity.We investigated the association between multi-morbidity and subsequent risk of cancer diagnosis in UK Biobank. Cox models were used to estimate the relative risks of each cancer of interest in multi-morbid participants, using the Cambridge Multimorbidity Score. The extent to which reverse causation, residual confounding and ascertainment bias may have impacted on the findings was robustly investigated.p for trend < 0.001). These findings were robust to sensitivity analyses aimed at reducing the impact of reverse causation, residual confounding from known cancer risk factors and ascertainment bias.Of the 436,990 participants included in the study who were cancer-free at baseline, 21.6%  were multi-morbid (≥ 2 diseases). Over a median follow-up time of 10.9 [IQR 10.0–11.7] years, 9,019 prostate, 7,994 breast, 5,241 colorectal, and 3,591 lung cancers were diagnosed. After exclusion of the first year of follow-up, there was no clear association between multi-morbidity and risk of colorectal, prostate or breast cancer diagnosis. Those with ≥ 4 diseases at recruitment had double the risk of a subsequent lung cancer diagnosis compared to those with no diseases (HR 2.00 [95% CI 1.70–2.35] Individuals with multi-morbidity are at an increased risk of lung cancer diagnosis. While this association did not appear to be due to common sources of bias in observational studies, further research is needed to understand what underlies this association.The online version contains supplementary material available at 10.1186/s12889-023-16202-9. As the population ages, the incidence of both cancer and multi-morbidity (the coexistence of two or more chronic diseases) is increasing. Studies have shown that the majority of cancer patients have at least one other disease at cancer diagnosis, with 50%—90% being multi-morbid –4. MultiMulti-morbidity could impact cancer diagnosis through a number of pathways. Increased health care utilisation of multi-morbid patients  could rePrior research of the association between multi-morbidity and subsequent cancer diagnosis is limited. One previous study reported an increased risk of bladder and cervical cancer, but not other cancers, in multi-morbid individuals . Others The Cambridge Multi-morbidity Score (CMS)  was deveThe current study uses UK Biobank (UKB), a large prospective UK cohort, to investigate the association between multi-morbidity and the four most common cancers in the UK  and to determine the extent to which any association might be explained by ascertainment bias, shared risk factors or reverse causation bias.UKB is a large, prospective cohort study in which ~ 500,000 volunteers underwent a comprehensive baseline assessment between 2006–2010, providing in-depth data on socio-demographics, lifestyle and health, and a range of physical measures. Participants consented to linkage to their electronic health records for longitudinal follow-up of health outcomes. Full details of the UKB cohort are given elsewhere .Linkages have been undertaken to national cancer (data available from 1979 onwards) and death (2006 onwards) registries, hospital inpatient data (1997 onwards) and, for ~ 45% of the cohort, primary-care records (1938 – 2017).UKB received ethics approval from the National Information Governance Board for Health and Social Care and the National Health Service North West Multicentre Research Ethics Committee (21/NW/0157).In the current analysis, only UKB participants with no evidence of pre-existing cancer were included in the study.The CMS  is a wei"Has a doctor ever told you that you have had any serious medical conditions or disabilities?” and underwent a detailed nurse-led interview, where a full medical history was collected. This self-reported health data collected at recruitment was used to determine the CMS as the exposure for the main analysis. In sensitivity analyses aimed at assessing potential ascertainment bias, the main analyses were repeated used linked primary care data (in the subset of ~ 45% participants for whom these data were available) to identify health conditions included in the CMS that were recorded prior to recruitment .At recruitment, all UKB participants were asked via a touch-screen questionnaire Multi-morbidity at recruitment was defined in multiple ways, as follows: i) ≥ 2 diseases, ii) weighted CMS (using published weights ) categorCode lists for disease definitions are available at 10.5281/zenodo.7334984.The cancer registry data was used to identify cases during the follow-up period. Participants with a cancer diagnosis prior to recruitment (excluding non-melanoma skin cancer) were considered prevalent cases and excluded from the analysis. The first incident cancer diagnosis (excluding non-melanoma skin cancer) was identified for remaining participants. The four most commonly diagnosed cancers in UKB were selected as outcomes of interest because of their high public health impact and large numbers of incident cases. Prostate cancer was defined as ICD-10 code C61, breast cancer as C50, lung cancer as C33-34 and colorectal cancer as C18-20.Date of birth was estimated from month and year of birth. Townsend deprivation score (an area-based score denoting socio-economic deprivation of a participant’s residence at recruitment) was categorised into fifths. Region was defined as London; South East; South West; East Midlands; West Midlands; North East; North West; Yorkshire and the Humber; Scotland East; Scotland West; Wales. Ethnicity was characterised as white and non-white.2. Smoking was categorised as never; former; < 10 cigarettes daily; ≥ 10 cigarettes daily; current smoker with unknown number of cigarettes daily. Alcohol consumption was categorised as never; special occasions only; 1–3 times per month; 1–2 times per week; 3–4 times per week; daily or almost daily. Menopausal hormonal therapy (MHT) use was categorised as never or ever users (women only).Body mass index (BMI) was categorised as < 25; 25–30; ≥ 30 kg/mSelf-reported screening behaviour was categorised as never or ever attended breast or bowel cancer screening and prostate specific antigen (PSA) testing. To further assess the extent to which overall health care utilisation might influence the association between multi-morbidity and cancer diagnosis, the following data were extracted from the primary-care records at recruitment: rapid referral for cancer diagnostics (yes or no), number of consultations , number of spirometry measurements, number of blood pressure measurements, and number of PSA tests .th February 2020; Scotland 31st January 2021).Individuals contributed person-years to the analysis from their date of recruitment (2006–2010) until the earliest of: date of first cancer diagnosis (excluding non-melanoma skin cancer), loss to follow up , death, or end of follow up. End of follow up was defined as the date for which cancer registry data were considered complete , mean and standard deviation (SD) or proportions.Cox proportional hazards models, with attained age as the underlying time variable, were used to investigate the association between the multi-morbidity metrics at recruitment and subsequent cancer diagnosis during the follow-up period. Initial investigations compared these associations across follow-up intervals  and heterogeneity was assessed using likelihood ratio (LR) tests. All subsequent analyses focused on associations of multi-morbidity with cancer risk in the period 1 or more years after the recording of morbidity data (i.e. excluding the first year of follow-up) to minimise the impact of reverse causation.2statistics associated with multi-morbidity were estimated before and after adjustment for these confounders [2 of more than two-thirds after adjustment for all potential confounders was taken to indicate that the adjusted association could plausibly be due to residual confounding (caused by imperfect adjustment for the confounder(s) under study). Given the particularly strong association between smoking and lung cancer and other conditions included in the CMS, analyses of multi-morbidity with lung cancer was also restricted to never smokers to further investigate the possibility of residual confounding. To assess if ascertainment bias might have influenced the association, breast, colorectal, and prostate cancer models were adjusted for self-reported routine screening behaviour.Initial models were adjusted for year of birth, region, socio-economic status and ethnicity. Proportionality was checked by examining Schoenfeld’s residuals. To investigate the possibility of residual confounding (i.e. to determine if any association might be partly explained by the presence of shared risk factors), the models were further adjusted for BMI, alcohol consumption, smoking and MHT use. The change in LRχfounders . For theIn participants for whom primary care information were available the mean number of consultations, spirometry measurements, blood pressure measurements and PSA tests (men only) were calculated stratified by the number of diseases, in those without a cancer diagnosis. The association of multi-morbidity with cancer diagnosis among those with primary-care data was then further adjusted for the number of consultations  – and for prostate cancer, the number of PSA tests – to determine the extent to which healthcare usage might explain the associations.Where significant associations of multi-morbidity with cancer diagnosis were identified, associations between individual diseases within the CMS and cancer risk were investigated using the same methodology as for the multi-morbidity metrics. Multiple testing was adjusted for using the false discovery rate .Of the 502,411 participants in UKB, 34,161 (6.9%) had a prevalent cancer and were excluded from analysis. Over a median follow up time of 10.9 years (IQR 10.0 – 11.7)) 9,019 prostate, 7,994 breast, 5,241 colorectal, and 3,591 lung cancers were identified.The most common self-reported diseases within the CMS were hypertension (26.5%), asthma 11.6%), and thyroid disease (5.7%) ,, there was no association between multi-morbidity and colorectal, breast or prostate cancer Fig. . Additiop for trend < 0.001) , while 38.0%  did not have any of the CMS diseases recorded in their primary-care record (Supplementary Table p < 0.001), rapid referral for cancer diagnostic investigations and, for prostate cancer only, PSA testing. When analyses of multi-morbidity were conducted in this subset of participants with primary care data, with additional adjustment for markers of healthcare utilisation,, similar patterns of associations were observed regardless of whether multi-morbidity was based on primary care data or self-report. In particular, multi-morbidity was not associated with colorectal cancer or breast cancer but was positively associated with lung cancer (Table p for trend < 0.001)  had a primary-care record at recruitment, of which there were 4,096 incident prostate, 3,364 breast, 2,224 colorectal and 1,573 lung cancers diagnosed at least 12 months after recruitment. In contrast with self-reported conditions at recruitment, the most common diseases ascertained from primary-care data in the CMS were psoriasis and eczema (16.8%), anxiety (12.6%), and depression (14.4%). A third of participants were multi-morbid , coronary artery disease, constipation, diabetes, hypertension, inflammatory bowel disease, peptic ulcer disease, peripheral vascular disease, substance misuse and stroke or transient ischemic attack were all associated with incident lung cancer  are associated with increased inflammation –26, and As it is common for a number of conditions to be diagnosed on the cancer diagnostic pathway , and it Given the known contribution of certain modifiable lifestyle factors, such as obesity and smoking, to many of the diseases included in the CMS and some of the cancer outcomes, it is important to investigate if shared risk factors explain any observed associations. In this study, adjustment for potential shared risk factors suggests that residual confounding from these factors are unlikely to explain the associations. Further, the association between multi-morbidity and lung cancer was unaffected when limited to self-reported never-smokers, suggesting that this association is not fully explained by smoking. Although it is possible that passive smoking might have contributed to the increased risk, it is highly unlikely to explain all of the increased risk, given the magnitude of the association.The association with lung cancer was also evident when using primary-care data to ascertain multi-morbidity, despite the differences in the distributions of diseases between the two data sources, and there was no single condition that appeared to underlie this association. Furthermore, additional adjustment for metrics of health care utilisation  did not materially affect the association with lung cancer, indicating that it is unlikely to be explained by ascertainment bias. Further research on stage of lung cancer would be useful to confirm this is the case.Whilst no association was identified between multi-morbidity and prostate cancer using the self-reported health data, an inverse association was observed when using the primary-care data. Although this could be due to ascertainment bias , thPrevious research into multi-morbidity as a risk factor for cancer has been limited, with most research focussing on the association with survival following cancer diagnoses , 30, theThis study has many strengths, including the large sample, prospective analyses and use of a validated score. As far as we are aware, this is the first study to use a multi-morbidity score (the CMS ) to defiThis study has highlighted an increased risk of lung cancer diagnosis in those with multi-morbidity, which does not appear to be explained fully by reverse causality, residual confounding or ascertainment bias. This provides evidence to clinicians that their multi-morbid patients may be at increased risk of lung cancer, and provides evidence for health resource planners given the increasing prevalence of multi-morbidity in the U.K. However, what cannot be identified from the use of a score is which diseases or combinations of diseases might explain this association. Further research is required to assess whether there are any particular groups of multi-morbid patients that are at increased risk of lung cancer, any particular pre-existing morbidities that increase the risk of lung cancer diagnosis, and to elucidate the drivers of such associations. While the reasons for the increase in lung cancer risk among multi-morbid individuals are not yet clear, clinicians, health care planners and patients should be aware of the increased risk identified.Additional file 1: Supplementary Table 1. Prevalence of diseases included in Cambridge Multimorbidity Score in UK Biobank at baseline, by data source. Supplementary Figure 1. Association between disease count and risk of cancer diagnosis stratified by follow up time in UK Biobank. Supplementary Table 2. Association between self-reported derived multi-morbidity measures and risk of colorectal and prostate cancer diagnosis by follow-up time in UK Biobank. Supplementary Table 3. Association between self-reported derived multi-morbidity measures and risk of breast and lung cancer diagnosis by follow-up time in UK Biobank. Supplementary table 4. Association between multi-morbidity measures and risk of diagnosis of colorectal, breast, lung and prostate cancer. Supplementary Table 5. LRχ2 values for minimally and fully adjusted models for each cancer. Supplementary Table 6. Distribution of covariates by number of diseases in the UK Biobank subset with primary care data, restricted to those with at least 12 months follow up. Supplementary Table 7. Association between self-reported individual diseases at recruitment and risk of diagnosis of lung cancer.