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Niels Obel,1,2 Matthew P Fox,3 Malte M Tetens,2 Lars Pedersen,4 Tyra Grove Krause,5 Henrik Ullum,5 Henrik Toft Sørensen4 1Department of Infectious Disease Epidemiology and Prevention, Statens Serum Institut, Copenhagen, 2300, Denmark; 2Department of Infectious Diseases, Copenhagen University Hospital – Rigshospitalet, Copenhagen, 2100, Denmark; 3Departments of Epidemiology and Global Health, School of Public Health, Boston University, Boston, MA, USA; 4Department of Clinical Epidemiology, Aarhus University, Aarhus N, 8200, Denmark; 5Statens Serum Institut, Copenhagen, 2300, DenmarkCorrespondence: Niels Obel, Department of Infectious Disease Epidemiology and Prevention, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark, Tel +4532683252, Email niob@ssi.dkBackground: Observational studies of SARS-CoV-2 vaccine effectiveness are prone to confounding, which can be illustrated using negative control methods.Methods: Nationwide population-based cohort study including two cohorts of Danish residents 60– 90 years of age matched 1:1 on age and sex: A vaccinated and a non-vaccinated cohort, including 61052 SARS-CoV-2 vaccinated individuals between 1 March and 1 July 2021 and 61052 individuals not vaccinated preceding 1 July 2021. From these two cohorts, we constructed negative control cohorts of individuals diagnosed with SARS-CoV-2 infection or acute myocardial infarction, stroke, cancer, low energy fracture, or head-trauma. Outcomes were SARS-CoV-2 infection, negative control outcomes (eg, mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear), and death. We used Cox regression to calculate adjusted incidence and mortality rate ratios (aIRR and aMRR).Results: Risks of SARS-CoV2 infection and all negative control outcomes were elevated in the vaccinated population, ranging from an aIRR of 1.15 (95% CI: 1.09– 1.21) for eye examinations to 3.05 (95% CI: 2.24– 4.14) for malignant melanoma. Conversely, the risk of death in the SARS-CoV-2 infected cohort and in all negative control cohorts was lower in vaccinated individuals, ranging from an aMRR of 0.23 (95% CI: 0.19– 0.26) after SARS-CoV-2 infection to 0.50 (95% CI: 0.37– 0.67) after stroke.Conclusion: Our findings indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be subject to substantial confounding. Therefore, randomized trials are essential to establish vaccine efficacy after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.Plain Language Summary: Why was this study done: After the emergence of new SARS-CoV-2 variants and the rollout of multiple booster SARS-CoV-2 vaccines, the impact of vaccination on risk of SARS-CoV-2 infection and death after the infection has mainly been explored in observational studies. We used negative control methods to investigate whether confounding affects the results of observational SARS-CoV-2 vaccine effectiveness studies.Findings: We used Danish registry data obtained during the SARS-CoV-2 vaccine roll-out to conduct a nationwide, matched population-based cohort study of Danish residents 60– 90 years in which we compared vaccinated individuals with non-vaccinated individuals. Compared with unvaccinated individuals, vaccinated individuals had increased risks of SARS-CoV2 infection but also had increased risks of all negative control outcomes (mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear). The risk of death after SARS-CoV2 infection was lower in the vaccinated cohort, as was the risk of death after acute myocardial infarction, stroke, cancer, low energy fracture, and head-trauma.Meaning: The negative control methods indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be prone to substantial confounding which may impact the observed associations. This bias may both lead to underestimation of vaccine effectiveness (increased risk of SARS-CoV2 infection among vaccinated individuals) and overestimation of the vaccine effectiveness (decreased risk of death after of SARS-CoV2 infection among vaccinated individuals). Our results highlight the need for randomized vaccine efficacy studies after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.Keywords: COVID-19, vaccines, cohort studies, bias, confounding factors, epidemiologic

Objectives: To investigate receipt of antibiotics among patients with neuroborreliosis after initial antibiotic treatment, likely attributable to posttreatment symptoms., Methods: We performed a nationwide, matched, population-based cohort study in Denmark (2009-2021). We included all Danish patients with neuroborreliosis, i.e. a positive Borrelia burgdorferi intrathecal antibody index test and a cerebrospinal fluid leukocyte count ≥10 × 10 6 /l, and initially treated with doxycycline. To form a comparison cohort, we randomly extracted individuals from the general population matched 1:10 to patients with neuroborreliosis on date of birth and sex. The main outcome was receipt of doxycycline, and the secondary outcome was receipt of phenoxymethylpenicillin. We calculated short-term (<1 year) and long-term (≥1 year) hazard ratios (HR) with 95% confidence intervals (95%CI)., Results: We included 463 patients with neuroborreliosis and 2,315 comparison cohort members. Compared with the comparison cohort members, patients with neuroborreliosis initially treated with doxycycline had increased receipt of additional doxycycline within 1 year (HR: 38.6, 95%CI: 17.5-85.0) and ≥1 years (HR: 3.5, 95%CI: 1.9-6.3). Compared with comparison cohort members, patients with neuroborreliosis had no increased receipt of phenoxymethylpenicillin (<1 year HR 1.0, 95%CI: 0.7-1.3; ≥1 years HR 1.2, 95%CI: 0.9-1.5)., Conclusions: After initial antibiotic treatment, patients with neuroborreliosis have increased receipt of doxycycline particularly within one year after initial antibiotic therapy but also subsequently. The lack of increased receipt of phenoxymethylpenicillin suggests that the receipt of doxycycline was not merely due to differences in healthcare-seeking behaviour, increased risk of early Lyme borreliosis due to exposure, or differences in antibacterial usage in general.

Objectives: To assess whether bipolar disorders are associated with the risk of HIV infection and whether the risk of bipolar disorders is increased among people with HIV (PWH) and their siblings., Design: Nationwide, population-based, combined matched nested case-control and cohort study of PWH of Danish origin (1995-2021), a comparison cohort from the background population, matched on date of birth and sex, and sibling cohorts., Methods: Conditional logistic regression and Cox regression was used to calculate adjusted odds ratios (aORs) for HIV infection and hazard ratios (HRs) among PWH for bipolar disorder and receipt of lithium., Results: We included 5322 PWH and 53,220 comparison cohort members. In the case-control study, bipolar disorder was associated with an increased risk of HIV infection (aOR: 1.9, 95% confidence interval (CI): 1.2-3.0), especially when injection drug use was the route of infection (aOR: 7.6, 95% CI: 2.0-28.9). In the cohort study, we observed an increased risk of bipolar disorders among PWH, especially in the first 2 years of observation (HR: 4.2, 95% CI: 2.4-7.4), whereas the risk of receipt of lithium was lower and the CI crossed 1. The 20-year risk of bipolar disorders for PWH was approximately 1%. Siblings of PWH also had an increased risk of bipolar disorder, but not to the same degree as PWH and not of receipt of lithium., Conclusions: Bipolar disorders are associated with the risk of HIV infection, and PWH have increased risk of bipolar disorder and receipt of lithium beyond what familial factors could explain., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Few studies have investigated the risk of psychiatric neurodevelopmental disorders (PNDD) after childhood meningitis., Methods: Nationwide population-based cohort study (Denmark, 1995-2021) of children with positive cerebrospinal fluid for bacteria or enterovirus, stratified on age as young infants (0 to <90 days, n  = 637) or older children (≥90 days to <17 years, n  = 1,218). We constructed a comparison cohort from the general population ( n  = 18,550), and cohorts of siblings of participants. As risk estimates of PNDD we calculated age- and sex-adjusted hazard ratios (aHRs) with 95% confidence intervals (95%CI)., Results: Children with bacterial meningitis had increased risks of PNDD, especially learning and intellectual developmental disorders (young infants: aHR 4.2, 95%CI: 2.4-7.1; older children: aHR 1.5, 95%CI: 1.0-2.3), attention deficit disorder (ADHD) (young infants: aHR 2.8, 95%CI: 1.5-5.2; older children: 1.4, 95%CI: 0.9-2.2) and redemption of ADHD medication (young infants: aHR 2.2, 95%CI: 1.0-4.7; older children: 1.5, 95%CI: 1.0-2.3). Young infants with bacterial meningitis additionally had increased risks of autism spectrum disorders (aHR 1.9, 95%CI: 0.9-4.1) and behavioural and emotional disorders (aHR 2.0, 95%CI: 1.0-3.9). In young infants, the excess risk of PNDD was especially observed in premature children. Siblings of older children with bacterial meningitis also had increased risks of PNDD. Children with enteroviral meningitis at any age did not have increased risks of PNDD or redemption of ADHD medication., Conclusions: Bacterial meningitis in childhood is associated with subsequent diagnosis of PNDD, while enteroviral meningitis is not. The association appears to be partly explained by prematurity and familial and socioeconomic factors.

Objectives: To identify diagnostic opportunities, we investigated healthcare-seeking behaviour among patients with Lyme neuroborreliosis (LNB) within 28 weeks before diagnosis., Methods: We conducted a population-based, nationwide matched nested case-control study (Denmark, 2009-2021). As cases, we included all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis). We randomly selected controls from the general population and matched 10:1 on date of birth and sex. Exposures were assignment of diagnostic codes for symptoms, contact to medical specialties, medical wandering, and undergoing diagnostic procedures. We calculated the weekly and 3-month proportions of individuals with exposures and calculated absolute risk differences with corresponding 95% CI., Results: We included 1056 cases with LNB and 10 560 controls. Within 3 months before diagnosis, the most frequent assigned symptoms were pain (difference: 13.0%, 95% CI: 10.9-15.1). Cases with LNB exhibited increased contact with most specialties, particularly general practitioners (difference: 48.7%, 95% CI: 46.0-51.4), neurology (difference: 14.3%, 95% CI: 11.7-16.8), and internal medicine (difference: 11.1%, 95% CI: 8.7-13.5), and medical wandering (difference: 17.1%, 95% CI: 14.3-20.0). Common diagnostic procedures included imaging of the brain (difference: 10.2, 95% CI: 8.3-12.1), the spine (difference: 8.8%, 85% CI: 7.0-10.6), and the abdomen (difference: 7.2%, 95% CI: 5.4-9.1). The increase in healthcare-seeking behaviour was observed ≤12 weeks preceding diagnosis., Discussion: Pain appears to be an ambiguous symptom of LNB, potentially contributing to delays in establishing the correct diagnosis. It would be difficult to identify patients with LNB more effectively as the increased healthcare-seeking behaviour preceding diagnosis is distributed across many medical specialties., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Bacterial meningitis can cause a life-threatening increase in intracranial pressure (ICP). ICP-targeted treatment including an ICP monitoring device and external ventricular drainage (EVD) may improve outcomes but is also associated with the risk of complications. The frequency of use and complications related to ICP monitoring devices and EVDs among patients with bacterial meningitis remain unknown. We aimed to investigate the use of ICP monitoring devices and EVDs in patients with bacterial meningitis including frequency of increased ICP, drainage of cerebrospinal fluid (CSF), and complications associated with the insertion of ICP monitoring and external ventricular drain (EVD) in patients with bacterial meningitis., Method: In a single-center prospective cohort study (2017-2021), we examined the frequency of use and complications of ICP-monitoring devices and EVDs in adult patients with bacterial meningitis., Results: We identified 108 patients with bacterial meningitis admitted during the study period. Of these, 60 were admitted to the intensive care unit (ICU), and 47 received an intracranial device (only ICP monitoring device N = 16; EVD N = 31). An ICP > 20 mmHg was observed in 8 patients at insertion, and in 21 patients (44%) at any time in the ICU. Cerebrospinal fluid (CSF) was drained in 24 cases (51%). Severe complications (intracranial hemorrhage) related to the device occurred in two patients, but one had a relative contraindication to receiving a device., Conclusions: Approximately half of the patients with bacterial meningitis needed intensive care and 47 had an intracranial device inserted. While some had conservatively correctable ICP, the majority needed CSF drainage. However, two patients experienced serious adverse events related to the device, potentially contributing to death. Our study highlights that the incremental value of ICP measurement and EVD in managing of bacterial meningitis requires further research., (© 2024. The Author(s).)

Background: Lyme borreliosis is a tick-borne disease caused by the bacterium Borrelia burgdorferi (Bb) sensu lato complex. Previous studies have suggested an association between Lyme borreliosis and heart failure, which have been suggested to be a possible manifestation of Lyme carditis. We aimed to investigate the risk of heart failure among individuals tested for serum Bb antibodies, and serum Bb seropositive individuals., Methods: We performed a matched nationwide cohort study (Denmark, 1993-2020) and included 52,200 Bb seropositive individuals, and two age- and sex-matched comparison cohorts: 1) 104,400 Bb seronegative comparison cohort members, and 2) 261,000 population controls. We investigated the risk associated with 1) being tested for serum Bb antibodies, and 2) being Bb seropositive. Outcomes were: 1) a composite of heart failure, cardiomyopathy, and/or myocarditis diagnosis, and 2) redemption of cardiovascular medicine used for treatment of heart failure. We calculated short-term odds ratios (aOR) (within 1 month) and long-term hazard rates (aHR) (after 1 month) adjusted for age, sex, diabetes, pre-existing heart failure, and kidney disease., Results: Compared with the population controls, individuals tested for Bb antibodies, regardless of the test result, had increased short-term risk of heart failure, cardiomyopathy, and myocarditis (aOR 8.3, 95 %CI: 6.7-10.2), and both increased short- and long-term risk of redemption of cardiovascular medicine (aOR 4.3, 95 %CI: 3.8-4.8, aHR 1.13, 95 % CI: 1.11-1.15). The Bb seropositive individuals had no increased short- or long-term risk of any outcome compared with Bb seronegative comparison cohort members., Conclusions: In conclusion, Bb antibody tests seemed to be performed in the diagnostic work-up of heart failure, but Bb seropositivity was not associated with heart failure., Competing Interests: Conflict of interest MMT has received travel grants outside this work from GlaxoSmithKline Pharma A/S. RBD has advisory board activity with Pfizer. JHS reports institutional research grant from Medtronic (outside this study), speakers’ honorarium from Medtronic and membership of an advisory board in Medtronic. AML reports speakers’ honorarium/travel grants/advisory board activity and unrestricted grant from Gilead, speakers honorarium /travel grants from GSK, speaker's honorarium/advisory board activity from Pfizer outside this work. None of the authors report any conflict of interests in connection with this article., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Radicular pain is the most predominant symptom among adults with Lyme neuroborreliosis (LNB) but the duration preceding and following diagnosis remains unknown. We aimed to investigate whether patients with LNB have increased obtainment of analgesics before and after diagnosis and for how long., Methods: We performed a nationwide, population-based, matched cohort study (2009-2021). all Danish residents with LNB (positive Borrelia burgdorferi intrathecal antibody index test and cerebrospinal fluid pleocytosis) were included. To form a comparison cohort, individuals from the general population were randomly extracted and matched 10:1 to patients with LNB on age and sex. Outcomes were obtainment of simple analgesics, antiepileptics, tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, tramadol, and other opioids. We calculated monthly and six-monthly proportions of individuals with obtainment of analgesics and absolute risk differences., Results: 1,056 patients with LNB and 10,560 comparison cohort members were included. An increased proportion of patients with LNB obtained analgesics from 3 months before study inclusion, especially simple analgesics, tramadol, and other opioids. Within the 0-1-month period after study inclusion, patients with LNB most frequently obtained simple analgesics (15 %), antiepileptics (11 %), and tramadol (10 %). Thereafter, obtainment of analgesics declined within a few months. A slightly larger proportion of patients with LNB obtained antiepileptics up to 2.5 years after diagnosis., Conclusions: Up to 3 months preceding diagnosis, LNB was preceded by increased obtainment of analgesics, which suggests diagnostic delay. Importantly, most patients with LNB did not obtain analgesics after the immediate disease course, although obtainment remained more frequent up to 2.5 years after., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Survival among people with HIV (PWH) has vastly improved globally over the last few decades but remains lower than among the general population. We aimed to estimate time trends of survival among PWH and their families from 1995 to 2021., Methods: We conducted a registry-based, nationwide, population-based, matched cohort study. We included all Danish-born PWH from 1995 to 2021 who had been on antiretroviral therapy for 90 days, did not report intravenous drug use, and were not co-infected with hepatitis C (n = 4168). We matched population controls from the general population 10:1 to PWH by date of birth and sex (n = 41,680). For family cohorts, we identified siblings, mothers, and fathers of PWH and population controls. From Kaplan-Meier tables with age as time scale, we estimated survival from age 25. We compared PWH with population controls and families of PWH with families of population controls to calculate mortality rate ratios adjusted for sex, age, comorbidities, and education (aMRR)., Findings: The median age of death among PWH increased from 27.5 years in 1995-1997 to 73.9 years (2010-2014), but thereafter survival increased only marginally. From 2015 to 2021, mortality was increased among PWH (aMRR 1.87 (95% CI: 1.65-2.11)) and siblings (aMRR: 1.25 (95% CI: 1.07-1.47)), mothers (aMRR: 1.30 (95% CI: 1.17-1.43)), and fathers (aMRR: 1.15 (95% CI: 1.03-1.29)) of PWH compared to their respective control cohorts. Mortality among siblings of PWH who reported heterosexual route of HIV transmission (aMRR: 1.51 (95% CI: 1.16-1.96)) was higher than for siblings of PWH who reported men who have sex with men as route of HIV transmission (aMRR 1.19 (95% CI: 0.98-1.46))., Interpretation: Survival among PWH improved substantially until 2010, after which it increased only marginally. This may partly be due to social and behavioural factors as PWH families also had higher mortality., Funding: Preben and Anna Simonsen's Foundation and Independent Research Fund Denmark., Competing Interests: Malte Mose Tetens has received travel grants outside this work from GlaxoSmithKline Pharma A/S, and funding of salary from the Research Fund of Copenhagen University Hospital–Rigshospitalet. The remaining authors declare no conflicts of interest., (© 2024 The Authors.)

Objectives: To investigate the short- and long-term risks of atrioventricular block and other cardiac conduction disorders associated with being tested for Borrelia burgdorferi (Bb) antibodies or Bb seropositivity as measures of confounding by indication and Bb infection, respectively., Methods: We performed a nationwide population-based matched cohort study (Denmark, 1993-2021). We included 52 200 Bb-seropositive individuals (stratified as only Bb-IgM-seropositive [n = 26 103], only Bb-IgG-seropositive [n = 18 698], and Bb-IgM-and-IgG-seropositive [n = 7399]) and two age- and sex-matched comparison cohorts: 104 400 Bb-seronegative individuals and 261 000 population controls. We investigated the risk associated with being tested for serum Bb antibodies and being Bb seropositive. Outcomes were atrioventricular block and other conduction disorders. We calculated short-term odds ratios (aOR) (within 1 month), and long-term hazard ratios (aHR) (after 1 month) adjusted for age, sex, diabetes, chronic heart failure, and kidney disease with 95% CI., Results: Compared with population controls, individuals tested for Bb antibodies had increased short- and long-term risks of atrioventricular block (aOR 47.9, 95% CI: 30.0-76.7, aHR 1.3, 95% CI:1.2-1.3), and other conduction disorders (aOR 18.2, 95% CI: 10.1-32.8, aHR 1.2, 95% CI: 1.1-1.4). Compared with Bb-seronegative individuals, only Bb-IgM-and-IgG-seropositive individuals had increased short-term risk of atrioventricular block (aOR: 2.1, 95% CI: 1.5-3.1)., Discussion: The results suggest that Bb antibody testing is included in the diagnostic work-up of conduction disorders. Finally, that Bb seropositivity is not associated with other conduction disorders than atrioventricular block or with increased long-term risk of conduction disorders., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: We compared characteristics and outcomes of individuals who in the cerebrospinal fluid (CSF) were positive for herpes simplex virus (HSV) or varicella-zoster virus (VZV)-intrathecal antibody index test ([AI]-positive) vs. individuals who were PCR-positive for HSV type 1 (HSV1), type 2 (HSV2), and for VZV., Methods: Nationwide cohort study of all Danish residents with positive CSF-AI or -PCR for HSV or VZV (1995-2021). We calculated short- and long-term risks as age-, sex-, and comorbidity-adjusted odds ratios (aOR), adjusted hazard ratios (aHR), and absolute risk differences with 95% CIs., Results: Compared with individuals with positive PCR for HSV1 (n = 321), HSV2 (n = 497), and VZV (n = 1054), individuals with a positive AI for HSV (n = 177) and VZV (n = 219) had CSF pleocytosis less frequently (leucocyte count >10/μL: HSV-AI: 39%, VZV-AI: 52%, HSV1-PCR: 81%, HSV2-PCR: 92%, VZV-PCR: 83%), and were less frequently diagnosed with central nervous system infection ([aOR {95%CI}]: HSV-AI vs. HSV1-PCR: [0.1 {0.1, 0.2}], HSV-AI vs. HSV2-PCR: [0.1 {0.0, 0.1}], VZV-AI vs. VZV-PCR: [0.2 {0.2, 0.3}]). Individuals with a positive HSV-AI or VZV-AI had increased risk of demyelinating disease ([aOR {95%CI}; aHR {95%CI}]: HSV-AI vs. HSV1-PCR: [4.6 {0.9, 24.5}; aHR not applicable], HSV-AI vs. HSV2-PCR: [10.4 {2.3, 45.9}; 12.4 {2.3, 66.0}], VZV-AI vs. VZV-PCR: [aOR not applicable; 10.3 {1.8, 58.8}]). Disability pension was less frequent among HSV-AI than HSV1-PCR cohort members (5-year risk difference: -23.6%, 95%CI: -35.2, -11.8), and more frequent among VZV-AI than VZV-PCR cohort members (5-year risk difference: 16.8%, 95%CI: 5.0, 28.7)., Discussion: AI-positive individuals differ from PCR-positive individuals in several aspects. AI appears unspecific for current central nervous system infections., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: In a nationwide, matched cohort study, we aimed to investigate risks of haematologic cancers among individuals tested for Borrelia burgdorferi (Bb) antibodies, and among serum Bb seropositive individuals., Methods: We identified all Bb seropositive individuals in Denmark (1993-2020) (n = 52 200) and constructed two age- and sex-matched comparison cohorts: (a) Bb seronegative controls (n = 104 400) and (b) background population controls (n = 261 000). We calculated short-term OR (aOR) (<1 month of study inclusion), and long-term hazard ratios (aHR) (>1 month after study inclusion) adjusted for age and sex. We stratified seropositive individuals on only Bb-IgM seropositive (n = 26 103), only Bb-IgG seropositive (n = 18 698), and Bb-IgM-and-IgG seropositive (n = 7399)., Results: Compared with the background population, individuals tested for Bb antibodies had increased short-term (aOR: 12.6, 95% CI: 10.1-15.6) and long-term (aHR: 1.3, 95% CI: 1.2-1.4) risk of haematologic cancers. The Bb seropositive individuals had no increased risk of haematologic cancers compared with those who tested negative for Bb, except that Bb-IgM-and-IgG seropositive individuals had increased long-term risk of chronic lymphatic leukaemia (aHR: 2.0, 95% CI: 1.2-3.4)., Discussion: Our results suggest that Bb antibody testing is included in the work-up of unspecific symptoms preceding diagnosis of haematologic cancers. Bb-IgM-and-IgG seropositivity was associated with a two-fold increased long-term risk of chronic lymphatic leukaemia, which warrants further investigation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Human immunodeficiency virus (HIV) infection is associated with depression. However, previous studies have not addressed familial factors., Methods: Nationwide, population-based, matched cohort study of people with HIV (PWH) in Denmark between 1995 and 2021 who were matched on sex and date of birth with a comparison cohort randomly selected from the Danish population. Family-related factors were examined by inclusion of siblings of those in the cohorts. We calculated hazard ratios (HRs) for depression, receipt of antidepressants, electroconvulsive therapy (ECT), and suicide, as well as the yearly proportions of study cohorts with psychiatric hospital contact due to depression and receipt of antidepressants from 10 years before to 10 years after study inclusion., Results: We included 5943 PWH and 59 430 comparison cohort members. Median age was 38 years, and 25% were women. We observed an increased risk of depression, receipt of antidepressants, ECT, and suicide among PWH in the 2 first years of observation (HR, 3.3; 95% confidence interval [CI]: 2.5-4.4), HR, 3.0 (95% CI: 2.7-3.4), HR, 2.8 (95% CI: .9-8.6), and HR, 10.7 (95% CI: 5.2-22.2), thereafter the risk subsided but remained increased. The proportions of PWH with psychiatric hospital contact due to depression and receipt of antidepressants were increased prior to and especially after HIV diagnosis. Risk of all outcomes was substantially lower among siblings of PWH than among PWH (HR for receipt of antidepressants, 1.1; 95% CI: 1.0-1.2)., Conclusions: PWH have an increased risk of depression. Family-related factors are unlikely to explain this risk., Competing Interests: Potential conflicts of interest. A. M. L. reports unrestricted research grants from Gilead and speaker honoraria/advisory board activity from Gilead, GSK, and Pfizer, with no relation to the current study; consulting fees from AbbVie and MSD (paid to institution); participation on a data and safety monitoring board for Novo Nordisk (paid to author); grants or contracts outside this work to institution from the Lundbeck Foundation and Novo Nordisk; payment or honoraria for lectures unrelated to this work from MSD, Pfizer, and GSK; and support for attending meetings from MSD, Chiesi, and Advanz. I. S. J. reports grants or contracts to institution from Odense University Hospital and consulting fees (to author) from Pfizer. M. M. T. reports a grant or contract from the Research Fund of Copenhagen University Hospital—Rigshospitalet (PhD scholarship) and travel grants for participation in a conference from GSK Pharma A/S. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Reproductive health in women with human immunodeficiency virus (HIV) (WWH) has improved in recent decades. We aimed to investigate incidences of childbirth, pregnancy, spontaneous abortion, and induced abortion among WWH in a nationwide, population-based, matched cohort study., Methods: We included all WWH aged 20-40 years treated at an HIV healthcare center in Denmark from 1995 to 2021 and a matched comparison cohort of women from the general population (WGP). We calculated incidence rates per 1000 person-years and used Poisson regression to calculate adjusted incidence rate ratios (aIRRs) of childbirth, pregnancy, spontaneous abortion, and induced abortion stratified according to calendar periods (1995-2001, 2002-2008, and 2009-2021)., Results: We included 1288 WWH and 12 880 WGP; 46% of WWH were of African origin, compared with 1% of WGP. Compared with WGP, WWH had a decreased incidence of childbirth (aIRR, 0.6 [95% confidence interval, .6-.7]), no difference in the incidence of pregnancy (0.9 [.8-1.0]) or spontaneous abortion (0.9 [.8-1.0]), but an increased incidence of induced abortion (1.9 [1.6-2.1]) from 1995 to 2021. The aIRRs for childbirth, pregnancy, and spontaneous abortion increased from 1995-2000 to 2009-2021, while the aIRR for induced abortion remained increased across all time periods for WWH., Conclusions: From 1995 to 2008, the incidences of childbirth, pregnancy, and spontaneous abortion were decreased among WWH compared with WGP. From 2009 to 2021, the incidence of childbirth, pregnancy, and spontaneous abortion no longer differed among WWH compared with WGP. The incidence of induced abortions remains increased compared with WGP., Competing Interests: Potential conflicts of interest. N. W. reports unrestricted research grants from AbbVie and Gilead, consulting fees from AbbVie and MSD, and participation on a data and safety monitoring board for Novo Nordisk. A. M. L. reports unrestricted research grants from Gilead and speaker honoraria/advisory board activity from Gilead, GSK, and Pfizer, with no relation to the current study; consulting fees from AbbVie and MSD (both as clinical investigator; paid to institution); and participation on a data and safety monitoring board for Novo Nordisk (paid to author). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Studies on brain abscess are hampered by single-centre design with limited sample size and incomplete follow-up. Thus, robust analyses on clinical prognostic factors remain scarce. This Danish nationwide, population-based cohort study included clinical details of all adults (≥18 years) diagnosed with brain abscess in the Danish National Patient Registry from 2007 through 2014 and the prospective clinical database of the Danish Study Group of Infections of the Brain covering all Danish departments of infectious diseases from 2015 through 2020. All patients were followed for 6 months after discharge. Prognostic factors for mortality at 6 months after discharge were examined by adjusted modified Poisson regression to compute relative risks with 95% confidence intervals (CI). Among 485 identified cases, the median age was 59 years [interquartile range (IQR 48-67)] and 167 (34%) were female. The incidence of brain abscess increased from 0.4 in 2007 to 0.8 per 100 000 adults in 2020. Immuno-compromise was prevalent in 192/485 (40%) and the clinical presentation was predominated by neurological deficits 396/485 (82%), headache 270/411 (66%), and fever 208/382 (54%). The median time from admission until first brain imaging was 4.8 h (IQR 1.4-27). Underlying conditions included dental infections 91/485 (19%) and ear, nose and throat infections 67/485 (14%), and the most frequent pathogens were oral cavity bacteria (59%), Staphylococcus aureus (6%), and Enterobacteriaceae (3%). Neurosurgical interventions comprised aspiration 356/485 (73%) or excision 7/485 (1%) and was preceded by antibiotics in 377/459 (82%). Fatal outcome increased from 29/485 (6%) at discharge to 56/485 (12%) 6 months thereafter. Adjusted relative risks for mortality at 6 months after discharge was 3.48 (95% CI 1.92-6.34) for intraventricular rupture, 2.84 (95% CI 1.45-5.56) for immunocompromise, 2.18 (95% CI 1.21-3.91) for age >65 years, 1.81 (95% CI 1.00-3.28) for abscess diameter >3 cm, and 0.31 (95% CI 0.16-0.61) for oral cavity bacteria as causative pathogen. Sex, neurosurgical treatment, antibiotics before neurosurgery, and corticosteroids were not associated with mortality. This study suggests that prevention of rupture of brain abscess is crucial. Yet, antibiotics may be withheld until neurosurgery, if planned within a reasonable time period (e.g. 24 h), in some clinically stable patients. Adjunctive corticosteroids for symptomatic perifocal brain oedema was not associated with increased mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Epilepsy in patients with brain abscess is frequent, but risk factors and prognosis remain undetermined. This study examined risk factors of epilepsy among survivors of brain abscess and associated prognosis., Methods: Nationwide, population-based healthcare registries were used to compute cumulative incidences and cause-specific adjusted hazard rate ratios (adj. HRRs) with 95% CIs for epilepsy among 30-day survivors of brain abscess from 1982 through 2016. Data were enriched with clinical details by medical record review of patients hospitalized from 2007 through 2016. Adjusted mortality rate ratios (adj. MRRs) were examined using epilepsy as a time-dependent variable., Results: The study included 1,179 30-day survivors of brain abscess among whom 323 (27%) developed new-onset epilepsy after a median of 0.76 years (interquartile range [IQR] 0.24-2.41). At admission for brain abscess, the median age was 46 years (IQR 32-59) in patients with epilepsy compared with 52 years (IQR 33-64) in those without epilepsy. The proportion of female individuals was similar in patients with and without epilepsy (37%). Adj. HRRs for epilepsy were 2.44 (95% CI 1.89-3.15) for aspiration or excision of brain abscess, 2.37 (1.56-3.60) for alcohol abuse, 1.75 (1.27-2.40) for previous neurosurgery or head trauma, 1.62 (1.17-2.25) for stroke, and 1.55 (1.04-2.32) for age group 20-39 years. Cumulative incidences were increased in patients with alcohol abuse (52% vs 31%), aspiration or excision of brain abscess (41% vs 20%), previous neurosurgery or head trauma (41% vs 31%), and stroke (46% vs 31%). Analysis using clinical details from medical record review of patients from 2007 through 2016 demonstrated adj. HRRs of 3.70 (2.24-6.13) for seizures at admission for brain abscess and 1.80 (1.04-3.11) for frontal lobe abscess. By contrast, adj. HRR was 0.42 (0.21-0.86) for occipital lobe abscess. Using the entire registry-based cohort, patients with epilepsy had an adj. MRR of 1.26 (1.01-1.57)., Discussion: Important risk factors of epilepsy were seizures during admission for brain abscess, neurosurgery, alcoholism, frontal lobe abscess, and stroke. Epilepsy was associated with an increased mortality. Antiepileptic treatment may be guided by individual risk profiles, and a specialized follow-up is highlighted by an increased mortality in survivors with epilepsy., (© 2023 American Academy of Neurology.)

Background: The impact of pre-antiretroviral treatment (ART) HIV-RNA on time to successful virological suppression and subsequent failure in HIV patients remains poorly investigated., Methods: We used the Swedish InfCareHIV database and the Danish HIV Cohort Study to evaluate impact of pre-ART HIV-RNA on primary virological suppression (HIV-RNA < 50 copies/ml) and risk of secondary virological failure (two consecutive HIV-RNA > 200 copies/ml or one >1000 copies/ml). The study included 3366 Swedish and 2050 Danish ART naïve individuals who initiated ART in the period 2000-2018. We used Kaplan-Meier estimates and Cox regression analyses to estimate absolute risks and hazard ratios., Results: In both cohorts, more than 95% of patients with a pre-ART HIV-RNA <100 000 copies/ml obtained virological suppression within the first year after ART initiation contrasting 74% (Sweden) and 86% (Denmark) in those with HIV-RNA >1 000 000 copies/ml. Almost all patients obtained virological suppression after four years irrespective of pre-ART HIV-RNA. In contrast, we observed no substantial impact of pre-ART HIV-RNA on risk of virological failure once virological suppression was obtained., Conclusion: High pre-ART HIV-RNA is strongly associated with increased time to successful virological suppression, but pre-ART HIV-RNA has no impact on risk of subsequent virological failure., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: It is unknown whether patients diagnosed with brain abscess have an increased risk of psychiatric disorders., Methods: In this nationwide, population-based matched cohort study from Denmark, we compared the incidence of psychiatric disorders, use of psychiatric hospitals, and receipt of psychiatric medications between patients diagnosed with brain abscess and individuals from the general population, matched on date of birth, sex, and residential area., Results: We included 435 patients diagnosed with brain abscess and 3909 individuals in the comparison cohort: 61% were male and median age was 54 years. Patients diagnosed with brain abscess were more likely to suffer from comorbidity. The risk of a hospital diagnosis of psychiatric disorders was increased the first 5 years of observation. In the subpopulation, who had never been in contact with psychiatric hospitals or received psychiatric medication before study inclusion, the risk of developing psychiatric disorders was close to that of the background population, especially when we excluded dementia from this outcome. There was a substantial increase in the receipt of anxiolytics and antidepressants. The difference in the proportion of individuals who received anxiolytics and antidepressants increased from 4% (95% confidence interval [CI], 0%-7%) and 2% (95% CI, -1% to 5%) 2 years before study inclusion to 17% (95% CI, 12%-21%) and 11% (95% CI, 7%-16%) in the year after study inclusion., Conclusions: Patients with brain abscess without prior psychiatric disorders or receipt of psychiatric medicine are not at increased risk psychiatric disorders diagnosed in psychiatric hospitals, but they have an increased receipt of psychiatric medication., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Clinical guidelines disagree on the diagnostic usefulness of Borrelia burgdorferi (Bb) serum antibodies (serum-Bb) in investigation of Lyme neuroborreliosis (LNB). We investigated the association between serum-Bb and Bb intrathecal antibody index (Bb-AI) and rates of seroconversion and seroreversion after LNB., Methods: Danish residents who had a Bb-AI and corresponding serum-Bb measured between 1994 and 2020 were identified at all Danish departments of clinical microbiology. We used descriptive statistics to examine the proportions of positive Bb-AI combined with positive or negative serum-Bb antibody tests. Next, the rate of seroconversion and seroreversion among those with positive Bb-AI and either an initial negative or positive serum-Bb was estimated., Results: We included 34 609 individuals with a Bb-AI and corresponding serum-Bb. The proportion of individuals with positive Bb-AI who had negative serum-Bb was 16.8% (95% CI, 15.1-18.6). The proportion of individuals with positive serum-Bb IgM, serum-Bb IgG, or serum-Bb IgM and IgG antibodies who had positive Bb-AI was 10.6% (95% CI, 9.5-11.8), 24.7% (95% CI, 23.0-26.4), and 45.0% (95% CI, 42.4-48.0), respectively. The proportion of children (<18 years) with positive serum-Bb IgM and IgG antibodies who had a positive Bb-AI was 59.7% (95% CI, 53.4-65.8). The proportion of individuals with positive Bb-AI with initial negative or positive serum-Bb antibodies who seroconverted or seroreverted within 2 years was 17.3% (95% CI, 6.9-27.8) and 23.2% (95% CI, 19.1-27.7), respectively., Conclusions: Serum-Bb antibodies could not predict results of Bb-AI. A fifth of both seronegative and seropositive individuals with positive Bb-AI seroconverted or seroreverted within 2 years., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Data on the clinical presentation are scarce and prognostic factors of herpes simplex virus type 2 (HSV-2) meningitis remain unknown., Methods: Prospective, nationwide, population-based database identifying all adults treated for HSV-2 meningitis at departments of infectious diseases in Denmark from 2015 to 2020. Unfavorable outcome was defined as Glasgow Outcome Scale (GOS) scores of 1-4 and Extended GOS scores of 1-6. Modified Poisson regression was used to compute relative risks with 95% confidence intervals for unfavorable outcome., Results: HSV-2 meningitis was diagnosed in 205 patients (76% female; median age [interquartile range (IQR)], 35 [27-49] years) yielding an incidence of 0.7/100 000 population/y. Common symptoms were headache (195 of 204 patients [95%]), photophobia or phonophobia (143 of 188 [76%]), and neck stiffness (106 of 196 [54%]). The median (IQR) time to lumbar puncture was 2.0 (1-4.8) hours, and the median cerebrospinal fluid (CSF) leukocyte count was 360 (166-670) × 10 × 6/L, with a mononuclear predominance of 97% (91%-99%). Lumbar puncture was preceded by brain imaging in 61 of 205 patients (30%). Acyclovir or valacyclovir was administered in 197 of 205 patients (96%) for a median (IQR) of 10 (7-14) days. Unfavorable outcome was observed in 64 of 205 patients (31%) at discharge and 19 of 181 (11%) after 6 months and was not associated with female sex (relative risk [95% confidence interval], 1.08 [.65-1.79]), age ≥35 years (1.28 [.83-1.97]), immunocompromise (1.07 [.57-2.03]), or CSF leukocyte count >1000 × 10 × 6/L (0.78 [.33-1.84])., Conclusions: HSV-2 meningitis often presented as meningeal symptoms in younger women. Unfavorable outcome at discharge was common and was not associated with sex, age, immunocompromise, or CSF leukocyte count. Sequelae persisted beyond 6 months in one-tenth of patients., Competing Interests: Potential conflicts of interests. M. M. T. reports grants or contracts from Independent Research Fund Denmark for a PhD scholarship (12 months) and was an invited speaker for Nordic Society of Clinical Microbiology and Infectious Diseases 2021 (paid flight and hotel). H. N. reports receiving grants or contracts from NovoNordiskFoundation for a randomized controlled trial for brain abscess in adults and receiving personal fees for serving on Advisory Board Denmark for MSD and GlaxoSmithKline, on the subject of coronavirus 2019 therapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: It remains unclear whether people with HIV (PWH) have increased risk of aneurysms. We aimed to investigate if the risk of subarachnoid haemorrhage, cerebral aneurysm, aortic aneurysm and other arterial aneurysms and dissections is increased in PWH compared with the general population., Design: We performed a nationwide population-based matched cohort study., Methods: We compared PWH with age-matched and sex-matched comparison cohort members to calculate incidence rate ratios (IRR) of subarachnoid haemorrhage, cerebral aneurysm, aortic aneurysm and other arterial aneurysms and dissections as well as surgery for these conditions., Results: We included all PWH, who were Danish residents and treated at a HIV healthcare centre between January 1995 and February 2018 ( n  = 6935) and an age-matched and sex-matched comparison cohort ( n  = 55 480). PWH had increased risk of subarachnoid haemorrhage (IRR 1.7, 95% CI, 1.1-2.6), but no increased risk of surgery for this condition. PWH had no increased risk of cerebral aneurysm or aortic aneurysm or surgery for these conditions. The risk of other arterial aneurysms and dissections was increased in PWH (IRR 2.0, 95% CI, 1.4-2.9), but this only applied for PWH who reported intravenous substance use as a route of HIV transmission (IRR 18.4, 95% CI, 9.3-36.6), and not for PWH without reported injection drug use (IRR 1.2, 95% CI, 0.73-1.7)., Conclusion: PWH were not at an increased risk of cerebral, aortic or other arterial aneurysms and dissections. Although PWH were at an increased risk of subarachnoid haemorrhage, subarachnoid haemorrhages were rare among PWH., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: The association of Lyme neuroborreliosis with the development of psychiatric disease is unknown and remains a subject of debate., Objective: To investigate the risk of psychiatric disease, the percentage of psychiatric hospital inpatient and outpatient contacts, and the receipt of prescribed psychiatric medications among patients with Lyme neuroborreliosis compared with individuals in a matched comparison cohort., Design, Setting, and Participants: This nationwide population-based matched cohort study included all residents of Denmark who received a positive result on an intrathecal antibody index test for Borrelia burgdorferi (patient cohort) between January 1, 1995, and December 31, 2015. Patients were matched by age and sex to a comparison cohort of individuals without Lyme neuroborreliosis from the general population of Denmark. Data were analyzed from February 2019 to March 2020., Exposures: Diagnosis of Lyme neuroborreliosis, defined as a positive result on an intrathecal antibody index test for B burgdorferi., Main Outcomes and Measures: The 0- to 15-year hazard ratios for the assignment of psychiatric diagnostic codes, the difference in the percentage of psychiatric inpatient and outpatient hospital contacts, and the difference in the percentage of prescribed psychiatric medications received among the patient cohort vs the comparison cohort., Results: Among 2897 patients with Lyme neuroborreliosis (1646 men [56.8%]) and 28 970 individuals in the matched comparison cohort (16 460 men [56.8%]), the median age was 45.7 years (interquartile range [IQR], 11.5-62.0 years) for both groups. The risk of a psychiatric disease diagnosis and the percentage of hospital contacts for psychiatric disease were not higher among patients with Lyme neuroborreliosis compared with individuals in the comparison cohort. A higher percentage of patients with Lyme neuroborreliosis compared with individuals in the comparison cohort received anxiolytic (7.2% vs 4.7%; difference, 2.6%; 95% CI, 1.6%-3.5%), hypnotic and sedative (11.0% vs 5.3%; difference, 5.7%; 95% CI, 4.5%-6.8%), and antidepressant (11.4% vs 6.0%; difference, 5.4%; 95% CI, 4.3%-6.6%) medications within the first year after diagnosis, after which the receipt of psychiatric medication returned to the same level as the comparison cohort., Conclusions and Relevance: In this population-based matched cohort study, patients with Lyme neuroborreliosis did not have an increased risk of developing psychiatric diseases that required hospital care or treatment with prescription medication. The increased receipt of psychiatric medication among patients with Lyme neuroborreliosis within the first year after diagnosis, but not thereafter, suggests that most symptoms associated with the diagnosis subside within a short period.

To provide better care for patients suspected of having a tick-transmitted infection, the Clinic for Tick-borne Diseases at Rigshospitalet, Copenhagen, Denmark was established. The aim of this prospective cohort study was to evaluate diagnostic outcome and to characterize demographics and clinical presentations of patients referred between the 1st of September 2017 to 31st of August 2019. A diagnosis of Lyme borreliosis was based on medical history, symptoms, serology and cerebrospinal fluid analysis. The patients were classified as definite Lyme borreliosis, possible Lyme borreliosis or post-treatment Lyme disease syndrome. Antibiotic treatment of Lyme borreliosis manifestations was initiated in accordance with the national guidelines. Patients not fulfilling the criteria of Lyme borreliosis were further investigated and discussed with an interdisciplinary team consisting of specialists from relevant specialties, according to individual clinical presentation and symptoms. Clinical information and demographics were registered and managed in a database. A total of 215 patients were included in the study period. Median age was 51 years (range 17-83 years), and 56 % were female. Definite Lyme borreliosis was diagnosed in 45 patients, of which 20 patients had erythema migrans, 14 patients had definite Lyme neuroborreliosis, six had acrodermatitis chronica atrophicans, four had multiple erythema migrans and one had Lyme carditis. Furthermore, 12 patients were classified as possible Lyme borreliosis and 12 patients as post-treatment Lyme disease syndrome. A total of 146 patients (68 %) did not fulfil the diagnostic criteria of Lyme borreliosis. Half of these patients (73 patients, 34 %) were diagnosed with an alternative diagnosis including inflammatory diseases, cancer diseases and two patients with a tick-associated disease other than Lyme borreliosis. A total of 73 patients (34 %) were discharged without sign of somatic disease. Lyme borreliosis patients had a shorter duration of symptoms prior to the first hospital encounter compared to patients discharged without a specific diagnosis (p<0.001). When comparing symptoms at presentation, patients discharged without a specific diagnosis suffered more often from general fatigue and cognitive dysfunction. In conclusion, 66 % of all referred patients were given a specific diagnosis after ended outpatient course. A total of 32 % was diagnosed with either definite Lyme borreliosis, possible Lyme borreliosis or post-treatment Lyme disease syndrome; 34 % was diagnosed with a non-tick-associated diagnosis. Our findings underscore the complexity in diagnosing Lyme borreliosis and the importance of ruling out other diseases through careful examination., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Lyme neuroborreliosis (LNB) has recently been added to the list of diseases under the European Union epidemiological surveillance in order to obtain updated information on incidence. The goal of this study was to identify temporal (yearly) variation, high risk geographical regions and risk groups, and seasonal variation for LNB in Denmark. This cohort-study investigated Danish patients (n = 2791) diagnosed with LNB (defined as a positive Borrelia burgdorferi sensu lato (s.l.) intrathecal antibody test) between 1996-2015. We calculated incidence and incidence ratios of LNB by comparing 4-yr groups of calendar-years, area of residency, sex and age, income and education groups, and the number of new LNB cases per month. The incidence of LNB was 2.2 per 100,000 individuals and year in 1996-1999, 2.7 in 2004-2007 and 1.1 per 100,000 individuals in 2012-2015. Yearly variations in LNB incidence were similar for most calendar-year groups. LNB incidence was highest in Eastern Denmark and among males and individuals who were 0-14 yrs old, who had a yearly income of >449,000 DKK, and who had a Master's degree or higher education. The number of LNB cases was highest from July to November (p < 0.001). In conclusion, based on Danish nationwide data of patients with positive B. burgdorferi s.l. intrathecal antibody index (1996-2015) the incidence of LNB was found to increase until 2004-2007 but thereafter to decline. European surveillance studies of Lyme borreliosis should be encouraged to monitor the incidence trend., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background: Lyme neuroborreliosis (LNB), caused by the tick-borne spirochetes of the Borrelia burgdorferi sensu lato species complex, has been suggested to be associated with a range of neurological disorders. In a nationwide, population-based cohort study, we examined the associations between LNB and dementia, Alzheimer's disease, Parkinson's disease, motor neuron disease, epilepsy, and Guillain-Barré syndrome., Methods: We used national registers to identify all Danish residents diagnosed during 1986-2016 with LNB (n = 2067), created a gender- and age-matched comparison cohort from the general population (n = 20 670), and calculated risk estimates and hazard ratios., Results: We observed no long-term increased risks of dementia, Alzheimer's disease, Parkinson's disease, motor neuron diseases, or epilepsy. However, within the first year, 8 (0.4%) of the LNB patients developed epilepsy, compared with 20 (0.1%) of the comparison cohort (difference, 0.3%; 95% confidence interval, .02-.6%). In the LNB group, 11 (0.5%) patients were diagnosed with Guillain-Barré syndrome within the first year after LNB diagnosis, compared with 0 (0.0%) in the comparison cohort. After the first year, the risk of Guillain-Barré was not increased., Conclusions: LNB patients did not have increased long-term risks of dementia, Alzheimer's disease, Parkinson's disease, motor neuron diseases, epilepsy, or Guillain-Barré. Although the absolute risk is low, LNB patients might have an increased short-term risk of epilepsy and Guillain-Barré syndrome., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)