Proxy For Infection Research Articles

Higher infection risk for JAK inhibitors tofacitinib and baricitinib compared to subcutaneous biological DMARDs.

Rheumatoid arthritis (RA) is usually treated with disease modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs) and more recently, Janus kinase inhibitors (JAKi). Randomized trials suggest similar infection risks for JAKi and bDMARDs, but real-world data are scarce. From a nationally representative prescription database, adult RA patients starting a new JAKi or bDMARD between August 1st, 2018, and January 31st, 2021, were included. Prescriptions of antibiotic, antiviral or antifungal medication were used as proxy for infections. Infection incidence rates (IR) were compared between JAKi and bDMARDs and infection risks were estimated using multilevel Poisson regression adjusted for follow-up time and potential confounders and stratified for age < 65 and ≥ 65 years. In 14,989 patients, we identified 20,050 treatment episodes with either JAKi or bDMARDs. The infection IR was significantly higher in JAKi (48/100 patient years) compared bDMARDs (35/100 patient years, adjusted incidence rate ratio (IRR) 1.22, 95% CI 1.12-1.33). More herpes zoster infections were seen in JAKi compared to bDMARDs (adjusted IRR 2.65, 95% CI 1.94-3.60). No significant differences in infection IRs were found comparing JAKi baricitinib and tofacitinib. In older patients, infection IRs were higher, but IRRs were similar between age groups. In comparison to bDMARDs, JAKi are associated with a slightly higher infection risk and a higher risk of herpes zoster specifically. In older patients, infection IRs are higher but similar infection risks for JAKi and bDMARDs are observed. No differences in infection risk between tofacitinib and baricitinib were found. Key Points • Compared to bDMARDs, JAKi are associated with a slightly higher infection risk for all ages • An increased risk of herpes zoster in patients who use JAK inhibitors was confirmed • No significant differences in infection incidence were found between tofacitinib and baricitinib.

Improved Innate Immune Function in Patients with Chronic Lymphocytic Leukemia Treated with Targeted Therapy in Clinical Trials.

Patients with chronic lymphocytic leukemia (CLL) have increased risk of severe infections. Although adaptive immune dysfunction is well described, clinical tools for identifying patients at risk are lacking, warranting investigation of additional immune components. In contrast to chemotherapy, targeted agents could spare or even improve innate immune function. Therefore, we investigated innate immune phenotypes and function in patients with CLL before and during targeted treatment. Baseline and consecutive blood samples were collected from patients with CLL treated with acalabrutinib (n = 17) or ibrutinib+venetoclax (n = 18) in clinical trials. Innate immune function was assessed by TruCulture, a whole-blood ligand-stimulation assay quantifying cytokine release in response to standardized stimuli. Innate immune phenotypes were characterized by flow cytometry. As a proxy for infections, we mapped antimicrobial use before and during treatment. At baseline, patients with CLL displayed impaired stimulated cytokine responses to the endotoxin lipopolysaccharide (LPS) along with deactivated monocytes, enrichment of myeloid-derived suppressor cells and metamyelocytes, and elevated (unstimulated) proinflammatory cytokines. Two/three cycles of acalabrutinib or ibrutinib normalized LPS-stimulated responses, in parallel with decreased duration of infections. Innate immune profiles and elevated proinflammatory cytokines further normalized during longer-term acalabrutinib or ibrutinib+venetoclax, paralleled by decreased infection frequency. Innate immune impairment and infection susceptibility in patients with CLL were restored in parallel during targeted therapy. Thus, targeted treatment may reduce the risk of infections in CLL, as currently under investigation in the PreVent-ACaLL phase 2 trial of acalabrutinib+venetoclax for high-risk CLL (NCT03868722).

Toward a molecular microbial blood test for tuberculosis infection

The World Health Organization's aim to end the global tuberculosis (TB) epidemic by 2050 cannot be achieved without taking measures to identify people with asymptomatic Mycobacterium tuberculosis (Mtb) infection and offer them an intervention to reduce the risk of disease progression, such as preventive antimicrobial therapy. Implementation of this strategy is limited by the fact that existing tests for Mtb infection, which use immunosensitization to Mtb-specific antigens as a proxy for infection, have low positive predictive value for progression to TB. A blood test that detects Mtb deoxyribonucleic acid (DNA) could allow preventive therapy to be targeted at individuals with microbiological evidence of persistent infection. In this review, we summarize recent advances in the development of molecular microbial blood tests for Mtb infection and discuss potential explanations for discordance between their results and those of immunodiagnostic tests in adults with recent exposure to an infectious index case. We also present a roadmap for further development of molecular microbial blood tests for Mtb infection, and highlight the potential for research in this area to provide novel insights into the biology of Mtb infection and yield new tools to support efforts to control the global TB epidemic.

Mendelian randomisation identifies priority groups for prophylactic EBV vaccination

BackgroundEpstein Barr virus (EBV) infects ~ 95% of the population worldwide and is known to cause adverse health outcomes such as Hodgkin’s, non-Hodgkin’s lymphomas, and multiple sclerosis. There is substantial interest and investment in developing infection-preventing vaccines for EBV. To effectively deploy such vaccines, it is vital that we understand the risk factors for infection. Why particular individuals do not become infected is currently unknown. The current literature, describes complex, often conflicting webs of intersecting factors—sociodemographic, clinical, genetic, environmental-, rendering causality difficult to decipher. We aimed to use Mendelian randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of EBV.MethodsWe mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal.ResultsOur GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed shorter time in education, an increase in number of sexual partners, and a lower age of smoking commencement, to be causal risk factors for EBV serostatus.ConclusionsGiven the current interest and likelihood of a future EBV vaccine, these factors can inform vaccine development and deployment strategies by completing the puzzle of causality. Knowing these risk factors allows identification of those most likely to acquire EBV, giving insight into what age to vaccinate and who to prioritise when a vaccine is introduced.

Childcare attendance and risk of infections in childhood and adolescence.

It has been suggested that the transiently increased infection risk following childcare enrolment is compensated by decreased infection risk later in childhood and adolescence. We investigated how childcare enrolment affected rates of antimicrobial-treated infections during childhood and adolescence. In a register-based cohort study of all children born in Denmark 1997-2014 with available exposure information (n = 1 007 448), we assessed the association between childcare enrolment before age 6 years and infection risks up to age 20 years, using antimicrobial exposure as proxy for infections. Nationwide childcare and prescription data were used. We estimated infection rates and the cumulative number of infections using adjusted Poisson regression models. We observed 4 599 993 independent episodes of infection (antimicrobial exposure) during follow-up. Childcare enrolment transiently increased infection rates; the younger the child, the greater the increase. The resulting increased cumulative number of infections associated with earlier age at childcare enrolment was not compensated by lower infection risk later in childhood or adolescence. Accordingly, children enrolled in childcare before age 12 months had experienced 0.5-0.7 more infections at age 6 years (in total 4.5-5.1 infections) than peers enrolled at age 3 years, differences that persisted throughout adolescence. The type of childcare had little impact on infection risks. Early age at childcare enrolment is associated with a modest increase in the cumulative number of antimicrobial-treated infections at all ages through adolescence. Emphasis should be given to disrupting infectious disease transmission in childcare facilities through prevention strategies with particular focus on the youngest children.

Urogenital schistosomiasis among pre-school and school aged children in four districts of north western Tanzania after 15 years of mass drug administration: Geographical prevalence, risk factors and performance of haematuria reagent strips.

Urogenital schistosomiasis remains as a public health problem in Tanzania and for the past 15 years, mass drug administration (MDA) targeting primary school children has remained as the mainstay for its control. However, after multiple rounds of MDA in highly risk groups, there are no data on the current status of Schistosoma haematobium in known endemic areas. Furthermore, the performance of commonly used diagnostic test, the urine reagent strips is not known after the decline in prevalence and intensities of infection following repeated rounds of treatment. Thus, after 15 of national MDA, there is a need to review the strategy and infection diagnostic tools available to inform the next stage of schistosomiasis control in the country. A analytical cross-sectional study was conducted between October and November, 2019 among pre-school (3-5years old) and school aged children (6-17 years old) living in four (4) districts with low (<10%) and moderate (10%-<50%) endemicity for schistosomiasis as per WHO classification at the start of the national control programme in 2005/06, with mean prevalence of 20.7%. A total of 20,389 children from 88 randomly selected primary schools participated in the study. A questionnaire was used to record demographic information. A single urine sample was obtained from each participant and visually examined for macrohaematuria, tested with a dipstick for micro-haematuria, to determine blood in urine; a marker of schistosome related morbidity and a proxy of infection. Infection intensity was determined by parasitological examination of the urine sample for S. haematobium eggs. Overall, mean infection prevalence was 7.4% (95%CI: 7.0-7.7, 1514/20,389) and geometric mean infection intensity was 15.8eggs/10mls. Both infection prevalence (5.9% versus 9%, P<0.001) and intensity (t = -6.9256, P<0.001) were significantly higher in males compared to females respectively. Light and heavy infections were detected in 82.3% and 17.7% of the positive children respectively. The prevalence of macrohaematuria was 0.3% and that of microhaematuria was 9.3% (95%CI:8.9-9.7). The sensitivity and specificity of the urine reagent strip were 78% (95%CI: 76.1-79.9) and 99.8% (95%CI: 99.7-99.9). Having light (P<0.001) and heavy infection intensities (P<0.001) and living in the study districts increased the odd of having microhaematuria. Predictors of S. haematobium infection were being male (P<0.003), microhaematuria (P<0.001), and living in the three study districts (P<0.001) compared to living at Nzega district. The findings provide an updated geographical prevalence which gives an insight on the planning and implementation of MDA. Comparing with the earlier mapping survey at the start of the national wide mass drug administration, the prevalence of S. haematobium infection have significantly declined. This partly could be attributed to repeated rounds of mass drug administration. The urine reagent strips remain as a useful adjunct diagnostic test for rapid monitoring of urogenital schistosomiasis in areas with low and high prevalence. Based on prevalence levels and with some schools having no detectable infections, review of the current blanket mass drug administration is recommended.

Higher mortality associated with the SARS-CoV-2 Delta variant in the Western Cape, South Africa, using RdRp target delay as a proxy: a cross-sectional study.

Background: The SARS-CoV-2 Delta variant (B.1.617.2) has been associated with more severe disease, particularly when compared to the Alpha variant. Most of this data, however, is from high income countries and less is understood about the variant's disease severity in other settings, particularly in an African context, and when compared to the Beta variant. Methods: A novel proxy marker, RNA-dependent RNA polymerase (RdRp) target delay in the Seegene Allplex TM 2019-nCoV (polymerase chain reaction) PCR assay, was used to identify suspected Delta variant infection in routine laboratory data. All cases diagnosed on this assay in the public sector in the Western Cape, South Africa, from 1 April to 31 July 2021, were included in the dataset provided by the Western Cape Provincial Health Data Centre (PHDC). The PHDC collates information on all COVID-19 related laboratory tests, hospital admissions and deaths for the province. Odds ratios for the association between the proxy marker and death were calculated, adjusted for prior diagnosed infection and vaccination status. Results: A total of 11,355 cases with 700 deaths were included in this study. RdRp target delay (suspected Delta variant) was associated with higher mortality (adjusted odds ratio [aOR] 1.45; 95% confidence interval [CI]: 1.13-1.86), compared to presumptive Beta infection. Prior diagnosed infection during the previous COVID-19 wave, which was driven by the Beta variant, was protective (aOR 0.32; 95%CI: 0.11-0.92) as was vaccination (aOR [95%CI] 0.15 [0.03-0.62] for complete vaccination [≥28 days post a single dose of Ad26.COV2.S or ≥14 days post second BNT162b2 dose]). Conclusion: RdRp target delay, a proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting.

A Pilot Study on Covid and Autism: Prevalence, Clinical Presentation and Vaccine Side Effects.

Background: Several neurobiological mechanisms have been proposed to support the hypothesis of a higher COVID-19 risk in individuals with autism spectrum disorder (ASD). However, no real-world data are available on this population. Methods: We compared the period prevalence (March–May 2020) and symptom presentation of COVID-19 infections between a sample of individuals with severe ASD (n = 36) and the staff personnel (n = 35) of two specialized centers. Anti-SARS-Cov-2 antibody positivity was used as a proxy of infection. Additionally, we evaluated vaccine side effects in the same groups. Results: No significant difference was found between the prevalence of COVID-19 positivity between autistic participants and staff personnel. Levels of antibodies against the spike protein and the receptor binding domain were not significantly different between autistic and staff participants. The level of antibodies against the N-terminal domain were higher in autistic individuals. There was a significant difference between the prevalence of symptomatic COVID-19 in autistic participants (9.1%) compared to staff personnel (92.3%). The most frequent side effect among autistic participants was light fever. Conclusions: The present study provides preliminary data on COVID-19 transmission and presentation in ASD. Our data do not support the hypothesis of a higher susceptibility and severity of COVID-19 in people with ASD.

An Infection-Tolerant Mammalian Reservoir for Several Zoonotic Agents Broadly Counters the Inflammatory Effects of Endotoxin.

Animals that are competent reservoirs of zoonotic pathogens commonly suffer little morbidity from the infections. To investigate mechanisms of this tolerance of infection, we used single-dose lipopolysaccharide (LPS) as an experimental model of inflammation and compared the responses of two rodents: Peromyscus leucopus, the white-footed deermouse and reservoir for the agents of Lyme disease and other zoonoses, and the house mouse Mus musculus Four hours after injection with LPS or saline, blood, spleen, and liver samples were collected and subjected to transcriptome sequencing (RNA-seq), metabolomics, and specific reverse transcriptase quantitative PCR (RT-qPCR). Differential expression analysis was at the gene, pathway, and network levels. LPS-treated deermice showed signs of sickness similar to those of exposed mice and had similar increases in corticosterone levels and expression of interleukin 6 (IL-6), tumor necrosis factor, IL-1β, and C-reactive protein. By network analysis, the M. musculus response to LPS was characterized as cytokine associated, while the P. leucopus response was dominated by neutrophil activity terms. In addition, dichotomies in the expression levels of arginase 1 and nitric oxide synthase 2 and of IL-10 and IL-12 were consistent with type M1 macrophage responses in mice and type M2 responses in deermice. Analysis of metabolites in plasma and RNA in organs revealed species differences in tryptophan metabolism. Two genes in particular signified the different phenotypes of deermice and mice: the Slpi and Ibsp genes. Key RNA-seq findings for P. leucopus were replicated in older animals, in a systemic bacterial infection, and with cultivated fibroblasts. The findings indicate that P. leucopus possesses several adaptive traits to moderate inflammation in its balancing of infection resistance and tolerance.IMPORTANCE Animals that are natural carriers of pathogens that cause human diseases commonly manifest little or no sickness as a consequence of infection. Examples include the deermouse, Peromyscus leucopus, which is a reservoir for Lyme disease and several other disease agents in North America, and some types of bats, which are carriers of viruses with pathogenicity for humans. Mechanisms of this phenomenon of infection tolerance and entailed trade-off costs are poorly understood. Using a single injection of lipopolysaccharide (LPS) endotoxin as a proxy for infection, we found that deermice differed from the mouse (Mus musculus) in responses to LPS in several diverse pathways, including innate immunity, oxidative stress, and metabolism. Features distinguishing the deermice cumulatively would moderate downstream ill effects of LPS. Insights gained from the P. leucopus model in the laboratory have implications for studying infection tolerance in other important reservoir species, including bats and other types of wildlife.

649 Cervical epithelial organ-on-chip: a platform to study cellular remodeling of the cervix

To develop an organ-on-chip for the cervical epithelial layer (CE-OOC) for testing the intercellular interactions between the epithelial cells from distinct regions of the cervix and their contributions in maintaining the integrity of the cervix during infection and inflammation often associated with spontaneous preterm birth. The CE-OOC is composed of two chambers connected by microchannels to culture ectocervical (Ecto) and endocervical (Endo) epithelial cells and recreated the cervical epithelial layer (Fig 1A-B). Using CE-OOC, we tested the effect of lipopolysaccharide (LPS; a proxy for infection), and tumor necrosis factor-alpha (TNFα; a proxy for inflammation), on cell fate (apoptosis and necrosis [flow cytometry] and senescence [senescence associated β-galactosidase staining], cellular migration, and epithelial-to-mesenchymal transition [EMT] using cytokeratin-18 [epithelial marker] and vimentin [mesenchymal marker] immunostaining) as well as on the secretion of inflammatory cytokines (IL-6 and IL-8 multiplex assay) inside the CE-OOC for 96 h. The ectocervical and the endocervical epithelial cells were successfully cultured in a CE-OOC for 96 h (Fig 1C). Using this OOC, we determined that LPS and TNFα induced irreversible EMT but only LPS increased the migration of Ecto and Endo. Co-culture allowed bidirectional cellular migration through microchannels that led to the development of the transformation zone. This mimicked, endocervical cells migrating towards the ectocervix, as seen in vivo. Apoptosis, necrosis, and senescence were significantly increased by LPS and TNFα treatments in both cell types (Fig 2A-B). LPS and TNFα increased the IL6- and IL-8 production by Ecto and Endo. CE-OOC established an in vitro model that recapitulated the ectocervical, the transformation zone, and the endocervical epithelial region of the cervix. This model allowed us to study the pathological effects of infection and inflammation in the distinct zones of the cervix. This CE-OOC can be used to study the epithelial layer in cervical remodeling during pregnancy and parturition.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

MP58-14 IMMUNOCOMPROMISED PATIENTS ARE NOT AT ELEVATED RISK OF INFLATABLE PENILE PROSTHESIS EXPLANT

INTRODUCTION AND OBJECTIVE: Infection of inflatable penile prostheses (IPP) occurs in 1-3% of cases and is associated with significant morbidity. Immunocompromised men may be at higher risk of infection. We explored reoperation rates [removal, revision or replacement] in immune deficient men to determine if immunocompromised patients are at higher risk of device complications. METHODS: We analyzed men who underwent initial IPP insertion from 2000 to 2016 in the New York Statewide Planning and Research Cooperative System (SPARCS) database, a de-identified, comprehensive, all-payer administrative database that collects patient, physician, and hospital data in New York state. Immune deficient patients were identified using billing codes and sub-stratified into categories of chronic steroid use, organ transplant, use of immune modulating drugs, and other congenital or acquired immune deficiencies (NOS). Immunocompromised men were propensity score matched in a 1:3 fashion with immune competent men based on age, race, insurance, comorbid conditions, procedure year, hospital volume, and disease status using multivariable logistic regression. RESULTS: 234 immune deficient patients were identified who received an IPP between 2000 and 2016. 177 (76.7%) were post-transplant, 29 (12.6%) on chronic steroids, and 29 (12.6%) NOS). Patients on immune modulators were not reportable and subgroup analysis for men on chronic steroids or with immunocompromise NOS was not possible due to sample size. After propensity score matching, we analyzed 230 immunocompromised men and 690 controls. Overall, there were no differences between age, comorbidities, race, type of insurance, year of implant or hospital center volume between cases and controls. Reoperation rate was similar at 90 days (5.0% versus 6.4%, p=0.35), 1 year (8.8% versus 10.0%, p=0.35), and 3 years (11.0% versus 14%, p=0.26) between immunocompromised men and controls. Reoperation rates remained similar in our subgroup analysis of transplant patients (Table 1). CONCLUSIONS: Reoperation rates are similar between immunocompromised men and immune competent controls overall and in men with transplants. Using reoperation rate as a proxy for infection, we conclude that immune status does not place men at higher risk for post IPP infection.Source of Funding: None

Does an Antimicrobial Incision Drape Prevent Intraoperative Contamination? A Randomized Controlled Trial of 1187 Patients

The risk of periprosthetic joint infection (PJI), a serious complication after arthroplasty, has not changed for years. Interventions such as eradication of Staphylococcus aureus and antibiotic bone cement are used to diminish infection risk but despite these efforts, the percentage of infection in TKA remains constant. Antimicrobial drapes have a dual action, acting both as a physical and antimicrobial barrier to counter bacterial contamination of the surgical wound. To study the effect of antimicrobial drapes, we used intraoperative contamination as a proxy for infection in our investigation. (1) Do antimicrobial surgical drapes reduce the risk of intraoperative microbial contamination in patients undergoing primary knee arthroplasty? (2) Are other factors such as sex, season, age, type of arthroplasty and duration of surgery associated with an increased risk of contamination in patients undergoing primary knee arthroplasty? (3) Does loosening of the antimicrobial drape increase contamination risk? An investigator-initiated, two-arm, non-blinded, multicenter, randomized, controlled trial was performed at five different hospitals in the capital and central regions of Denmark. Twenty-four surgeons participated in the study. Participants were patients older than 18 years undergoing primary knee arthroplasty. We excluded patients with an iodine allergy, previous open knee surgery, previous septic arthritis, any antibiotics taken 4 weeks before surgery, and if they were unable to understand the implications of study participation. Patients were randomly assigned to operation with an antimicrobial drape (intervention group) or operation without (control group). We screened 1769 patients, of which 100 were ineligible and 10 declined to participate. In all, 94% (1659 of 1769) of patients consented and were randomized to the intervention group (51%, 838 of 1659) and control group (49%, 821 of 1659), respectively. In all, 36% (603 of 1659) of patients in the intervention group and 35% (584 of 1659) patients in the control group were available for final analysis. No crossover was performed, and analysis was done per-protocol. Patients were excluded due to logistic failures like lack of utensils, samples disappearing en route to the laboratory mainly caused by implementation of a new electronic patient chart (EPIC, Verona, WI, USA), and forgetful surgeons. Intraoperatively, we swabbed for bacteria at the surgical site and in a rinse from the surgeons' gloves. All samples were sent for cultivation, and colony forming units (CFUs) counts ≥ 1 were deemed contaminated. The primary outcome measure was the difference in the proportion of contaminated patients between the two randomized groups. Secondary outcome measures were the affiliation of sex, season, age, type of implant used, and duration of surgery on contamination risk. To investigate whether other factors were affiliated with contamination risk, we did a logistic regression to control for confounding variables, including sex, age, season, type of implant and duration of surgery. Use of iodinated drapes reduced contamination, with contamination detected in 10% (60 of 603) procedures where iodinated drapes were used compared with 15% (90 of 584) when they were not (odds ratio 0.61 [95% CI 0.43 to 0.87]; p = 0.005), with a relative risk reduction of 35% (95% CI 12.3 to 52.5) and a number needed to treat of 18 patients. After controlling for confounding variables such as sex, age, type of implant, and duration of surgery, we found that not using an antimicrobial drape increased contamination risk by a factor of 1.6 (95% CI 1.08 to 2.35; p = 0.02). Female sex and undergoing surgery in the central region were associated with lower odds of contamination (OR 0.55 [95% CI 0.39 to 0.8]; p = 0.002 and OR 0.45 [95% CI 0.25 to 0.8]; p = 0.006, respectively). Patients with more than a 10-mm separation of the drape from the skin had higher odds of contamination (OR 3.54 [95% CI 1.64 to 11.05]; p = 0.0013). The use of an antimicrobial drape resulted in lower contamination risk than operating without an antimicrobial drape. Our findings suggest that antimicrobial drapes are useful in infection prevention, but further studies are needed to investigate the effect of antimicrobial drapes on infection. Level I, therapeutic study.

Formula feeding increases the risk of antibiotic prescriptions in children up to 2years: results from a cohort study.

Association between the use of infant formula and risks for infants' health is seldom studied in western countries. We set up a historical cohort based on record linkage analysis, combining the data from administrative databases providing individual data. Infants receiving the second dose of pediatric immunization between 2015 and 2017 were included. The main outcome measure was antibiotic prescriptions from enrolment up to 24months of age, by infant feeding category at enrolment. The extended Cox regression technique was used to account for recurrent events. The infants' cohort included 40,258 5-month-old infants; during the study period, 60,932 antibiotic prescriptions were filled. Compared with infants fully breastfed, children fed with both maternal milk and formula received 106 more antibiotic prescriptions per 1000 children/year, whereas infants receiving formula only had 138 excess prescriptions per 1000 children/year. The association with infant feeding was statistically significant and remained unchanged after adjustment for common confounders (adjusted hazard ratio, HR, for complementary feeding vs full breastfeeding 1.09; 95%CI 1.05 to 1.12; formula only versus full breastfeeding adj. HR 1.12; 95%CI 1.08 to 1.16).Conclusion: In our cohort, we observed a positive association between infant formula use considered a proxy of infections antibiotic prescription rate, considered a proxy of infections. The association followed a gradient.What is Known:• Formula feeding is associated with increased morbidity and mortality even in western countries, but still, it is common.• Information on formula are seldom unbiased; thus, public perception of risks is distorted.What is New:• In a large Italian cohort of infants, formula feeding at 5months of age results to be associated with an increased rate of antibiotic prescription (considered to be a proxy of infection) up to 24months of age: the association follows a dose-response relationship.• Record linkage analysis using administrative databases provides useful information at a limited cost.

Urogenital schistosomiasis elimination in Zanzibar: accuracy of urine filtration and haematuria reagent strips for diagnosing light intensity Schistosoma haematobium infections

BackgroundUrine filtration and microhaematuria reagent strips are basic standard diagnostic methods to detect urogenital schistosomiasis. We assessed their accuracy for the diagnosis of light intensity infections with Schistosoma haematobium as they occur in individuals living in Zanzibar, an area targeted for interruption of transmission.MethodsUrine samples were collected from children and adults in surveys conducted annually in Zanzibar from 2013 through 2016 and examined with the urine filtration method to count S. haematobium eggs and with the reagent strip test (Hemastix) to detect microhaematuria as a proxy for infection. Ten percent of the urine filtration slides were read twice. Sensitivity was calculated for reagent strips, stratified by egg counts reflecting light intensity sub-groups, and kappa statistics for the agreement of urine filtration readings.ResultsAmong the 39,207 and 18,155 urine samples examined from children and adults, respectively, 5.4% and 2.7% were S. haematobium egg-positive. A third (34.7%) and almost half (46.7%) of the egg-positive samples from children and adults, respectively, had ultra-low counts defined as 1–5 eggs per 10 ml urine. Sensitivity of the reagent strips increased significantly for each unit log10 egg count per 10 ml urine in children (odds ratio, OR: 4.7; 95% confidence interval, CI: 4.0–5.7; P < 0.0001) and adults (OR: 2.6; 95% CI: 1.9–3.7, P < 0.0001). Sensitivity for diagnosing ultra-light intensity infections was very low in children (50.1%; 95% CI: 46.5–53.8%) and adults (58.7%; 95% CI: 51.9–65.2%). Among the 4477 and 1566 urine filtration slides read twice from children and adults, most were correctly identified as negative or positive (kappa = 0.84 for children and kappa = 0.81 for adults). However, 294 and 75 slides had discrepant results and were positive in only one of the two readings. The majority of these discrepant slides (76.9% of children and 84.0% of adults) had counts of 1–5 eggs per 10 ml urine.ConclusionsWe found that many individuals infected with S. haematobium in Zanzibar excrete less than 5 eggs per 10 ml urine. These ultra-light infections impose a major challenge for accurate diagnosis. Next-generation diagnostic tools to be used in settings where interruption of transmission is the goal should reliably detect infections with ≤ 5 eggs per 10 ml urine.Trial RegistrationISRCTN, ISRCTN48837681. Registered 05 September 2012 - Retrospectively registered.

Antibiotic use as a marker of acute infection and risk of first and recurrent venous thrombosis.

A role for transient infections in the aetiology of venous thrombosis (VT) has been suggested. This study aimed to determine whether individuals who receive antibiotic treatment (as a proxy for infections) have an increased risk of first and recurrent VT and whether infections should be seen as a provoking risk factor for VT. We used the self-controlled case series method to study the risk of first VT during antibiotic prescriptions. The risk of recurrent VT during antibiotic use was estimated by of time-dependent Cox-regression. A total of 2547 patients with a first VT were included and followed for a median of 5·9years for recurrence (1999-2010), in whom 114 first events occurred during antibiotic use. We found a five-fold increased risk of first VT during antibiotic treatment: [incidence-rate-ratio 5·0; 95% confidence interval (CI), 4·0-6·1]. Antibiotic use was associated with a 2·0-fold (95% CI, 1·1-4·0) increased risk of recurrent VT. Patients with an unprovoked first VT who used antibiotics shortly before this event, had a similar risk of recurrence as patients with a provoked first VT (adjusted hazard ratio 1·1; 95% CI, 0·7-1·7). Individuals who receive antibiotics have an increased risk of first and recurrent VT and infections should be considered a provoking risk factor for VT.

Association between statins and infections among patients with diabetes: a cohort and prescription sequence symmetry analysis.

PurposeA previous meta‐analysis of randomized trials did not confirm findings from observational studies that suggested that statins reduce the risk of infection. However, animal experiments indicate that statins may be more effective in reducing the risk and/or the severity of infection among patients with diabetes. Hence, we evaluated the effect of statins on antibiotic prescriptions (a proxy for infections) among patients with drug‐treated type 2 diabetes using two confounding‐reducing observational designs.MethodsWe conducted a prescription sequence symmetry analysis and a cohort study using the IADB.nl pharmacy prescription database. For the prescription sequence symmetry analysis, a sequence ratio was calculated. The matched cohort study, comparing the time to first antibiotic prescription between periods that statins are initiated and non‐use periods, was analyzed using stratified Cox regression.ResultsPrescription sequence symmetry analysis of 4684 patients with drug‐treated type 2 diabetes resulted in an adjusted sequence ratio of 0.86 (95% confidence interval [CI]: 0.81 to 0.91). Corresponding figures for the cohort analysis comparing 9852 statin‐initiation with 4928 non‐use periods showed similar results (adjusted hazard ratio: 0.88, 95%CI: 0.83 to 0.95).ConclusionsThese findings suggest that statins are associated with a reduced risk of infections among patients with drug‐treated type 2 diabetes. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Increased use of antimicrobial medication in bulimia nervosa and binge-eating disorder prior to the eating disorder treatment.

We examined the use of antimicrobial medication as a proxy for infections in large patient cohort treated for binge-eating disorder (BED), bulimia nervosa (BN), and anorexia nervosa (AN) over the five-year period preceding eating disorder treatment. Patients (N = 1592) at the Eating Disorder Unit of Helsinki University Central Hospital between 2000 and 2010 were compared with matched general population controls (N = 6368). The study population was linked to the prescription data of antibacterial, antifungal and antiviral medication from the Register on Reimbursed Prescription Medicine. Data were analyzed using regression models. Individuals with BN and BED had received more often antimicrobial medication prescriptions compared to their controls (OR: 1.7, 95% CI: 1.3-2.1; OR: 2.6, 95% CI: 1.4-4.6, respectively), while no significant difference emerged in AN (OR: 0.9, 95% CI: 0.7-1.0, p = 0.10). Of the main drug categories, the respective pattern was seen in antibacterial and antifungal medication, while increased use for antivirals appeared only in BN (OR: 1.6, 95% CI: 1.1-2.3). Measured with the mean number of prescriptions or mean Defined Daily Doses per individual, patients with BN, BED and males with AN had also higher total antimicrobial medication use. Indicating increased infections, we found elevated use of antimicrobial medication in BN, BED and in males with AN. Infections may be consequence of hyperglycemia, weight gain, or dysregulation of intestinal microbiota associated with core eating disorder behaviors. Or the other way round; changes in intestinal microbiota due to infections, inflammation, or antibacterial medications might contribute to eating disorders in multiple ways. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:542-552).

Daycare attendance, breastfeeding, and the development of type 1 diabetes: the diabetes autoimmunity study in the young.

Background. The hygiene hypothesis attributes the increased incidence of type 1 diabetes (T1D) to a decrease of immune system stimuli from infections. We evaluated this prospectively in the Diabetes Autoimmunity Study in the Young (DAISY) by examining daycare attendance during the first two years of life (as a proxy for infections) and the risk of T1D. Methods. DAISY is a prospective cohort of children at increased T1D risk. Analyses were limited to 1783 children with complete daycare and breastfeeding data from birth to 2 years of age; 58 children developed T1D. Daycare was defined as supervised time with at least one other child at least 3 times a week. Breastfeeding duration was evaluated as a modifier of the effect of daycare. Cox proportional hazards regression was used for analyses. Results. Attending daycare before the age of 2 years was not associated with T1D risk (HR: 0.89; CI: 0.54–1.47) after adjusting for HLA, first degree relative with T1D, ethnicity, and breastfeeding duration. Breastfeeding duration modified this association, where daycare attendance was associated with increased T1D risk in nonbreastfed children and a decreasing T1D risk with increasing breastfeeding duration (interaction P value = 0.02). Conclusions. These preliminary data suggest breastfeeding may modify the effect of daycare on T1D risk.

Abalone withering syndrome: distribution, impacts, current diagnostic methods and new findings

Withering syndrome (WS) is a fatal disease of abalone caused by a Rickettsiales-like organism (WS-RLO). The causative agent, 'Candidatus Xenohaliotis californiensis', occurs along the eastern Pacific margin of North America in California, USA, and Baja California, Mexico. However, as infected abalones have been transported to Chile, China, Taiwan, Iceland, Ireland, Israel, Spain, Thailand and Japan, the geographical range of the etiological agent is suspected to be broad, especially where California red abalones Haliotis rufescens are cultured or in areas where native species have been exposed to this species. Susceptibility varies among species, with up to 99% losses of black abalone H. cracherodii in laboratory and field studies in the USA to no losses among the small abalone H. diversicolor supertexta in Thailand. Some populations that have suffered catastrophic losses due to WS have developed resistance to the disease. In addition, a newly identified phage hyperparasite of the WS-RLO may reduce pathogenicity and dampen associated losses. Diagnosis of WS requires the identification of infection with the pathogen (WS-RLO detected via in situ hybridization or histology coupled with PCR and sequence analysis) accompanied by morphological changes that characterize this disease (e.g. pedal and digestive gland atrophy, and digestive gland metaplasia). A quantitative PCR assay was developed and may be useful in quantifying pathogen DNA. Confirmation of infection cannot be done by PCR analysis alone but can be used as a proxy for infection in areas where the agent is established and is recommended for inclusion in health examinations. Avoidance of WS is best accomplished by the establishment of a health history and multiple health examinations prior to movement of animals.

Infection and childhood leukemia: review of evidence

OBJECTIVE : To analyze studies that evaluated the role of infections as well as indirect measures of exposure to infection in the risk of childhood leukemia, particularly acute lymphoblastic leukemia. METHODS : A search in Medline, Lilacs, and SciELO scientific publication databases initially using the descriptors “childhood leukemia” and “infection” and later searching for the words “childhood leukemia” and “maternal infection or disease” or “breastfeeding” or “daycare attendance” or “vaccination” resulted in 62 publications that met the following inclusion criteria: subject aged ≤ 15 years; specific analysis of cases diagnosed with acute lymphoblastic leukemia or total leukemia; exposure assessment of mothers’ or infants’ to infections (or proxy of infection), and risk of leukemia. RESULTS : Overall, 23 studies that assessed infections in children support the hypothesis that occurrence of infection during early childhood reduces the risk of leukemia, but there are disagreements within and between studies. The evaluation of exposure to infection by indirect measures showed evidence of reduced risk of leukemia associated mainly with daycare attendance. More than 50.0% of the 16 studies that assessed maternal exposure to infection observed increased risk of leukemia associated with episodes of influenza, pneumonia, chickenpox, herpes zoster, lower genital tract infection, skin disease, sexually transmitted diseases, Epstein-Barr virus, and Helicobacter pylori . CONCLUSIONS : Although no specific infectious agent has been identified, scientific evidence suggests that exposure to infections has some effect on childhood leukemia etiology.