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Background: Comparative data on clinical presentation, laboratory characteristics, treatment, and outcome of neurosyphilis (NS) in people living with HIV (PLWH) and NS patients without HIV are scarce.Methods: Nationwide, population-based, prospective cohort study on all adults with NS diagnosed between 2015 and 2021 at departments of infectious diseases in Denmark.Results: We identified 108 patients with NS, which equals a yearly incidence of 0.3/100,000 adults. The median age was 49 years, 85 (79%) were male, 43 (40%) were men having sex with men and 20 (22%) were PLWH. Ninety-five (88%) had early NS, 37 (34%) had ocular or ocular and otogenic NS, and 27 (25%) had symptomatic meningitis. Most common symptoms were visual disturbance (44%), skin rash (40%), fatigue (26%) and chancre (17%). Median CSF leukocyte count was 27 × 106 cells/L. PLWH less often had neurological deficits (p = 0.02). Unfavorable outcome was observed in 23 (21%) at discharge of whom 0 were PLWH (p = 0.01). Among the 88 NS patients without HIV a CSF leukocyte count of ≥ 30 × 106 cells/L was associated with unfavorable outcome (OR = 3.3 (95% confidence interval: 1.1-10.4)).Conclusions: PLWH with NS have better outcomes than NS patients without HIV infection. Background: Comparative data on clinical presentation, laboratory characteristics, treatment, and outcome of neurosyphilis (NS) in people living with HIV (PLWH) and NS patients without HIV are scarce.Methods: Nationwide, population-based, prospective cohort study on all adults with NS diagnosed between 2015 and 2021 at departments of infectious diseases in Denmark.Results: We identified 108 patients with NS, which equals a yearly incidence of 0.3/100,000 adults. The median age was 49 years, 85 (79%) were male, 43 (40%) were men having sex with men and 20 (22%) were PLWH. Ninety-five (88%) had early NS, 37 (34%) had ocular or ocular and otogenic NS, and 27 (25%) had symptomatic meningitis. Most common symptoms were visual disturbance (44%), skin rash (40%), fatigue (26%) and chancre (17%). Median CSF leukocyte count was 27 × 106 cells/L. PLWH less often had neurological deficits (p = 0.02). Unfavorable outcome was observed in 23 (21%) at discharge of whom 0 were PLWH (p = 0.01). Among the 88 NS patients without HIV a CSF leukocyte count of ≥ 30 × 106 cells/L was associated with unfavorable outcome (OR = 3.3 (95% confidence interval: 1.1-10.4)).Conclusions: PLWH with NS have better outcomes than NS patients without HIV infection.

Background: Staphylococcus aureus is an uncommon cause of community-acquired bacterial meningitis. We aimed to describe patients with this disease. Methods: We evaluated clinical characteristics and outcome of adults with community-acquired S. aureus meningitis from prospective nationwide cohort studies from Denmark (2015-2020) and the Netherlands (2006-2021). Whole genome sequencing of S. aureus isolates was performed to evaluate the potential association between clonal complex and clinical characteristics. Results: We evaluated 111 episodes of community-acquired S. aureus meningitis: 65 from Denmark and 46 from the Netherlands. The median age was 66 years (interquartile range [IQR] 50-74) and 43 of 111 patients were female (39%). Concomitant infectious foci were found in 95 of 107 patients (89%), most commonly endocarditis (53 of 109 [49%]) and spondylodiscitis (43 of 109 [39%]). The triad of neck stiffness, altered mental status (Glasgow Coma Scale score

PurposeThe ENFORCE cohort is a national Danish prospective cohort of adults who received a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as part of the Danish National SARS-CoV-2 vaccination programme. It was designed to investigate the long-term effectiveness, safety and durability of SARS-CoV-2 vaccines used in Denmark.ParticipantsA total of 6943 adults scheduled to receive a SARS-CoV-2 vaccine in the Danish COVID-19 vaccination programme were enrolled in the study prior to their first vaccination. Participants will be followed for a total of 2 years with five predetermined follow-up visits and additional visits in relation to any booster vaccination. Serology measurements are performed after each study visit. T-cell immunity is evaluated at each study visit for a subgroup of 699 participants. Safety information is collected from participants at visits following each vaccination. Data on hospital admissions, diagnoses, deaths and SARS-CoV-2 PCR results are collected from national registries throughout the study period. The median age of participants was 64 years (IQR 53–75), 56.6% were women and 23% were individuals with an increased risk of a serious course of COVID-19. A total of 340 (4.9%) participants tested positive for SARS-CoV-2 spike IgG at baseline.Findings to dateResults have been published on risk factors for humoral hyporesponsiveness and non-durable response to SARS-CoV-2 vaccination, the risk of breakthrough infections at different levels of SARS-CoV-2 spike IgG by viral variant and on the antibody neutralising capacity against different SARS-CoV-2 variants following primary and booster vaccinations.Future plansThe ENFORCE cohort will continuously generate studies investigating immunological response, effectiveness, safety and durability of the SARS-CoV-2 vaccines.Trial registration numberNCT04760132.

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.

Posterpræsentation

Purpose: Acute bacterial meningitis (ABM) is a severe disease with an overall poor outcome. Neurofilament (NFL) has shown to be a promising biomarker of neuroaxonal injury in various neurological disorders but has not been investigated in ABM. The aims of this study were (i) to obtain a temporal profile of NFL, neuron-specific enolase (NSE) and S100B in serum during ABM, and (ii) to evaluate their use as biomarkers of severity (Glasgow coma score) and prognosis (Glasgow Outcome Score, GOS and death) in severe ABM. Methods: Fifteen adults with severe community-acquired ABM who were admitted to the intensive care unit (ICU) and fulfilled the inclusion criteria were included. Lumbar puncture and blood tests were performed on admission, and blood tests were performed three times daily during the ICU stay. GOS was obtained day 30. Results: Serum NFL was significantly elevated in ABM patients compared to healthy controls, both at admission and throughout the observation period (p

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Background: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients, but is not thoroughly tested in this population. Furthermore, a pneumococcal vaccine dose effect has never been investigated, though observed in healthy adults. To assess whether a double dose of 13-valent pneumococcal conjugate vaccine (PCV13) and of 23-valent pneumococcal polysaccharide vaccine (PPV23) increases the immunogenicity of prime-boost vaccination in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs), a phase 3, randomized, non-blinded trial was conducted. Methods: KTRs and WLPs were in parallel groups assigned either normal or double dosage of both vaccines 12 weeks apart. A ′protective response′ was an average geometric mean concentration ≥ 1 mg/L based on 12 vaccine shared serotype-specific IgG antibodies. Furthermore, number of antibodies with ≥ 2-fold rises and individual serotype-specific antibody concentrations were evaluated. Follow-up was 48 weeks. Results: Seventy-four KTRs and 65 WLPs were enrolled. In WLPs, double dosage resulted in a significantly higher proportion of participants with a ′protective response′ (66.7%), 5 weeks after PPV23, compared to normal dosage (35.5%), p = 0.015. KTRs exhibited no dose effect. After PPV23, all four groups had increased their number of serotypes with ≥ 2-fold rises (p ≤ 0.05 for both WLPs groups; p ≤ 0.01 for both KTRs groups). Vaccines were safe, well tolerated and still immunogenic at week 48. Conclusions: Data suggests that double dosage of pneumococcal vaccines used according to the prime-boost strategy might be recommendable for WLPs. Furthermore, our data supports PPV23́s additive effect to PCV13 in KTRs and WLPs. (EudraCT: 2016–004123-23)

Background: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients and candidates. The long-term durability of the antibody (AB) response is unknown. The same applies to a dose-dependent immune response. Methods: We studied the durability of the vaccine response after 18 months in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs). Both groups received either a normal dose (ND) or a double dose (DD) of the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine. The average pneumococcal AB geometric mean concentration (GMC) was evaluated. A level ≥ 1 mg/L was considered protective against invasive pneumococcal disease (IPD). Results: Sixty WLPs and 70 KTRs were included. The proportion of participants protected declined from 52% to 33% in WLPs and from 29% to 16% in KTRs, with the previously significant dose-effect in WLPs no longer present (40% DD vs. 27% ND; p = 0.273). Average pneumococcal AB GMCs remained significantly above baseline levels (all groups p ≤ 0.001). Drug-induced immunosuppression diminished the vaccine dose-effect. Conclusions: At follow-up, the pneumococcal prime-boost vaccination still provided significantly elevated average pneumococcal AB GMCs in both populations. Though the proportion of participants protected against IPD in WLP-DD and WLP-ND were statistically comparable, a DD may still be recommended for WLPs (EudraCT: 2016-004123-23).

Background:The COVID-19 pandemic has changed various spheres of healthcare. The general practitioners (GPs) have widely replaced face-to-face consultations with telephone or video consultation (VC) to reduce the risk of COVID-19 transmission. Using video consultations for health service deliveries is an entirely new way of practicing for many GPs. Yet, this transition process has largely been carried out with no formal guidelines, which may have caused implementation barriers. This study presents a rapid-cycle co-production approach to develop a guide to assist VC implementation in general practice.Objective:The aim of this paper was to describe the developmental phases of the guide and to summarize the evaluation made by general practice users.Methods:The development of a guide for VC in general practice was structured as a stepped process based on co-production and prototyping processes. We used an iterative framework based on rapid qualitative analyses and interdisciplinary collaboration. Thus, the guide was developed in small, repeated cycles of development, implementation, evaluation, and adaptation with a continuous exchange between research and practice. The data collection process was structured in three main phases. First, we made a literature review and qualitative prestudies. Second, we facilitated co-production with stakeholders through four workshops with GPs, a group interview with patient representatives, and individual revisions by general practitioners. Third, nationwide testing was conducted in five general practice clinics and was followed by an evaluation of the guide through interviews with GPs.Results:A rapid-cycle co-production approach was used to explore the needs in general practice in connection with the implementation of VC and to develop useful, relevant, and easily understandable guiding materials. Our findings suggest that a guide for VC should include advice and recommendations regarding the organization of VC, the technical setup, the appropriate target groups, patients’ use of VC, the performance of VC, and the arrangement of booking.Conclusions:The combination of co-production, prototyping, small iterations, and rapid data analysis is a suitable approach when contextually rich, hands-on guide materials are urgently needed. Moreover, this method could provide an efficient way of developing relevant guide materials for general practice to aid the implementation of new technology beyond pandemic times. However, their potential can only be realized if the generated materials are adopted and sustained in practice. Hence, such a developmental approach should involve a plan for the continued engagement of stakeholders. Background: The COVID-19 pandemic has changed various spheres of health care. General practitioners (GPs) have widely replaced face-to-face consultations with telephone or video consultations (VCs) to reduce the risk of COVID-19 transmission. Using VCs for health service delivery is an entirely new way of practicing for many GPs. However, this transition process has largely been conducted with no formal guidelines, which may have caused implementation barriers. This study presents a rapid cycle coproduction approach for developing a guide to assist VC implementation in general practice. Objective: The aim of this paper is to describe the developmental phases of the VC guide to assist general practices in implementing VCs and summarize the evaluation made by general practice users. Methods: The development of a guide for VC in general practice was structured as a stepped process based on the coproduction and prototyping processes. We used an iterative framework based on rapid qualitative analyses and interdisciplinary collaborations. Thus, the guide was developed in small, repeated cycles of development, implementation, evaluation, and adaptation, with a continuous exchange between research and practice. The data collection process was structured in 3 main phases. First, we conducted a literature review, recorded observations, and held informal and semistructured interviews. Second, we facilitated coproduction with stakeholders through 4 workshops with GPs, a group interview with patient representatives, and individual revisions by GPs. Third, nationwide testing was conducted in 5 general practice clinics and was followed by an evaluation of the guide through interviews with GPs. Results: A rapid cycle coproduction approach was used to explore the needs of general practice in connection with the implementation of VC and to develop useful, relevant, and easily understandable guiding materials. Our findings suggest that a guide for VCs should include advice and recommendations regarding the organization of VCs, the technical setup, the appropriate target groups, patients' use of VCs, the performance of VCs, and the arrangements for booking a VC. Conclusions: The combination of coproduction, prototyping, small iterations, and rapid data analysis is a suitable approach when contextually rich, hands-on guide materials are urgently needed. Moreover, this method could provide an efficient way of developing relevant guide materials for general practice to aid the implementation of new technology beyond the pandemic period.

Central nervous system (CNS) infections are rare diseases that are associated with considerable morbidity and mortality. Increased knowledge based on contemporary data is a prerequisite for improved management and prevention of these serious conditions. Yet, population-based databases of patients hospitalized with CNS infections remain scarce. The Danish Study Group of Infections of the Brain (DASGIB) has prospectively registered information on all adults ≥18 years of age admitted with CNS infections at departments of infectious diseases in Denmark since 2015. The main variables collected are baseline demographics, blood and cerebrospinal fluid tests, imaging results, and outcome using the Glasgow Outcome Scale score. To investigate important aspects for each type of CNS infections, additional variables are included specifically for bacterial meningitis, viral meningitis, encephalitis, brain abscess, neurosyphilis, and Lyme neuroborreliosis. From 2015 to 2020, a total of 3579 cases of CNS infections have been recorded in the DASGIB database. Using the unique civil registration number assigned to all Danish residents, the database can be unambiguously linked with nationwide healthcare registries at the individual level. This enables researchers to conduct detailed population-based and longitudinal observational studies of risk and prognosis of CNS infections and to compare them with matched population cohorts. The database is well-suited for epidemiological research and the DASGIB network forms a solid infrastructure for future national and international collaborations.

ObjectiveTo test the hypothesis that enterovirus meningitis (EM) is a frequent and self-limiting condition, the epidemiology of EM in adults was examined.MethodsUsing a prospective, nationwide, population-based database, all adults with EM confirmed by PCR of the CSF from 2015 to 2019 were included. Unfavorable outcome was defined as Glasgow Outcome Scale scores of 1–4 at discharge. Modified Poisson regression was used to compute adjusted relative risks (RRs).ResultsA total of 419 cases of EM in 418 adults (46% female, median age 31 years [interquartile range (IQR) 27–35]) yielded an incidence of 1.80/100,000/year. Admission diagnoses included CNS infection 247/397 (62%), other neurologic conditions 89/397 (22%), and cerebrovascular diseases 33/397 (8%). Genotype was available for 271 cases, of which echovirus 30 accounted for 155 (57%). Patients presented with headache 412/415 (99%), history of fever 303/372 (81%), photophobia 292/379 (77%), and neck stiffness 159/407 (39%). Fever (≥38.0°C) was observed in 192/399 (48%) at admission. The median CSF leukocyte count was 130 106/L (range 0–2,100) with polymorphonuclear predominance (>50%) in 110/396 (28%). Cranial imaging preceded lumbar puncture in 127/417 (30%) and was associated with non-CNS infection admission diagnoses and delayed lumbar puncture (median 4.8 hours [IQR 3.4–7.9] vs 1.5 [IQR 0.8–2.8], p < 0.001). Unfavorable outcome occurred in 99/419 (24%) at discharge; more often in female patients (RR 2.30 [1.58–3.33]) and less frequent in echovirus 30 (RR 0.67 [0.46–1.00]) in adjusted analyses. Outcome remained unfavorable in 22/379 (6%) after 6 months.ConclusionsEM is common among young, healthy adults. Although the long-term prognosis remains reassuring, a substantial proportion have moderate disability at discharge, especially female patients.

BACKGROUND The COVID-19 pandemic has changed various spheres of health care. General practitioners (GPs) have widely replaced face-to-face consultations with telephone or video consultations (VCs) to reduce the risk of COVID-19 transmission. Using VCs for health service delivery is an entirely new way of practicing for many GPs. However, this transition process has largely been conducted with no formal guidelines, which may have caused implementation barriers. This study presents a rapid cycle coproduction approach for developing a guide to assist VC implementation in general practice. OBJECTIVE The aim of this paper is to describe the developmental phases of the VC guide to assist general practices in implementing VCs and summarize the evaluation made by general practice users. METHODS The development of a guide for VC in general practice was structured as a stepped process based on the coproduction and prototyping processes. We used an iterative framework based on rapid qualitative analyses and interdisciplinary collaborations. Thus, the guide was developed in small, repeated cycles of development, implementation, evaluation, and adaptation, with a continuous exchange between research and practice. The data collection process was structured in 3 main phases. First, we conducted a literature review, recorded observations, and held informal and semistructured interviews. Second, we facilitated coproduction with stakeholders through 4 workshops with GPs, a group interview with patient representatives, and individual revisions by GPs. Third, nationwide testing was conducted in 5 general practice clinics and was followed by an evaluation of the guide through interviews with GPs. RESULTS A rapid cycle coproduction approach was used to explore the needs of general practice in connection with the implementation of VC and to develop useful, relevant, and easily understandable guiding materials. Our findings suggest that a guide for VCs should include advice and recommendations regarding the organization of VCs, the technical setup, the appropriate target groups, patients’ use of VCs, the performance of VCs, and the arrangements for booking a VC. CONCLUSIONS The combination of coproduction, prototyping, small iterations, and rapid data analysis is a suitable approach when contextually rich, hands-on guide materials are urgently needed. Moreover, this method could provide an efficient way of developing relevant guide materials for general practice to aid the implementation of new technology beyond the pandemic period.

Background Knowledge of the epidemiology and clinical characteristics of varicella zoster virus (VZV) encephalitis remains limited. Methods Nationwide prospective cohort study of adults treated for microbiologically confirmed VZV encephalitis at Danish departments of infectious diseases from 2015 to 2019. Modified Poisson regression analysis was used to compute adjusted relative risks (RRs) of unfavorable outcome. Results We identified 92 adults (49% female) with VZV encephalitis, yielding an incidence of 5.3/1 000 000 per year (95% CI, 4.2–6.6). Median age was 75 years (IQR, 67–83) and immunocompromising conditions were frequent (39%). Predominant symptoms were confusion (76%), headache (56%), nausea (45%), gait disturbance (42%), and personality changes (41%). Cranial imaging showed cerebral vasculitis (including infarction and hemorrhage) in 14 (16%) patients and encephalitic abnormalities in 11 (13%) with predilection for the brainstem and deep brain structures. Intravenous acyclovir treatment was initiated a median (IQR) of 13.4 hours (5.2–46.3) since admission, while cranial imaging and lumbar puncture were performed after 6.3 hours (2.5–31.0) and 18.5 hours (4.9–42.0). In-hospital, 1-month, and 3-month mortalities were 4%, 9%, and 11%, respectively. Unfavorable outcome (Glasgow Outcome Score of 1–4) was found in 69% at discharge, with age (adjusted RR [aRR], 1.02; 95% CI, 1.01–1.03), vasculitis (aRR, 1.38; 95% CI, 1.02–1.86), and Glasgow Coma Scale (GCS) Conclusions VZV encephalitis occurs primarily in elderly or immunocompromised patients with a higher incidence than previously estimated. The diagnosis is often delayed; risk factors for unfavorable outcome are age, cerebral vasculitis, and GCS

Annual influenza vaccination is recommended for all people living with HIV (PLWH), and so is pneumococcal vaccination at least once. This is due to higher incidence rates for both infections among PLWH, compared to HIV negative, even in the later highly active antiretroviral therapy era. To clarify the uptake of and attitude toward both vaccines among PLWH in Denmark, a survey on self-reported vaccine uptake was performed during 2017. Analyses identifying factors associated with vaccine uptake in the latest season for 203 participants were performed. Both influenza and pneumococcal vaccination uptake are low among PLWH in Denmark, 31.0% and 4.4%, respectively. Previous vaccination against influenza had the highest impact on influenza vaccine uptake, and lack of immunization guidance lowers the likelihood. Interventions to improve vaccination coverage are needed, such as increased awareness about guidelines and physician education.

STUDY OBJECTIVE: This study sought to describe the clinical presentation of normocellular community-acquired bacterial meningitis in adults.METHODS: Using the prospective, nationwide, population-based database of the Danish Study Group of Infections of the Brain, the study identified all adults with normocellular community-acquired bacterial meningitis who were treated at departments of infectious diseases in Denmark from 2015 through 2018. Normocellular community-acquired bacterial meningitis was defined as a cerebrospinal fluid leukocyte count of up to 10×106/L combined with detection of bacteria in the cerebrospinal fluid. Outcome was categorized according to the Glasgow Outcome Scale at discharge.RESULTS: Normocellular cerebrospinal fluid was observed in 12 of 696 (2%) patients with community-acquired bacterial meningitis. The median age was 70 years (range 17 to 92 years), and 8 of 12 (67%) patients were male. All patients had symptoms suggestive of community-acquired bacterial meningitis and pathogens identified by culture (Streptococcus pneumoniae, n=10; Staphylococcus aureus, n=1) or polymerase chain reaction (Neisseria meningitidis; n=1) of the cerebrospinal fluid. Bacteremia was found in 9 of 12 (75%) patients, and 1 of 12 (8%) presented with septic shock. None of the patients had serious underlying immunocompromising conditions. The median times from admission to lumbar puncture and meningitis treatment were 2.5 hours (interquartile range 1.1 to 3.9 hours) and 2.6 hours (interquartile range 0.9 to 22.8 hours). In 3 of 11 (27%) patients, empiric treatment for community-acquired bacterial meningitis was interrupted by a normal cerebrospinal fluid cell count. The overall case-fatality rate was 3 of 12 (25%); meningitis treatment was interrupted in 1 of these patients, and 8 of 12 (67%) had a Glasgow Outcome Scale score of 1 to 4 at discharge.CONCLUSION: Normocellular community-acquired bacterial meningitis is not very common, but it is important to consider and may be associated with a pneumococcal cause.

BACKGROUND: We aimed to describe the use and findings of cranial computerized tomography (CT-head), spine and brain magnetic resonance imaging (MRI-spine/MRI-brain) in Lyme neuroborreliose (LNB).METHODS: Patients with LNB were identified using a nationwide, population-based prospective cohort of all adults treated for neuroinfections at departments of infectious diseases in Denmark from 2015 to 2019. Multivariate logistic regression analyses assessed associations between clinical characteristics and MRI-findings consistent with LNB.RESULTS: We included 368 patients (272 definite LNB and 96 probable LNB), 280 scans were performed in 198 patients. Neuroimaging was associated with older age (59 vs. 57, p = 0.03), suspicion of other diseases (77% vs. 37%, p CONCLUSION: In this Danish cohort including 368 LNB-patients, use of neuroimaging was common and often performed in older comorbid patients without previous tick-bite intended to investigate alternative diagnoses. The results were in general without pathology and neuroimaging cannot exclude LNB or replace lumbar puncture. MRI is of value when investigating alternative neurological diseases and may support suspicion of LNB in cases with meningeal/leptomeningeal/neural enhancement.

BACKGROUND: To characterize level and predictors of influenza and pneumococcal vaccine uptake among Danish kidney transplant recipients (KTR) and kidney transplant waiting list patients (WLP).METHODS: A cross-sectional survey based on self-reported vaccine uptake including WLP and KTR ≤ 1½ years post transplantation. Descriptive statistics and logistic regression analyses identifying factors associated with influenza vaccine uptake in the latest season were performed.RESULTS: A total of 220 participants were included in the study, 54% KTR and 46% WLP. Self-reported influenza vaccine uptake in the latest season was overall 41.8%. Uptake of influenza vaccine on any prior season apart from the latest season was 53.2% and significantly higher among WLP than KTR (P = .007). Pneumococcal vaccine uptake was only 4% overall. The only factor positively associated with influenza vaccine uptake in the latest season was any prior influenza vaccine uptake (OR 5.79, CI95 2.44-13.76) (P < .001). Recommendations given by other persons (non-physician) were negatively associated with receiving the influenza vaccination in the latest season (OR 0.34, CI95 0.13-0.92) (P = .03). Reasons for not being vaccinated were primarily lack of information, perception of own good health, and fear of adverse reactions.CONCLUSIONS: Influenza and pneumococcal vaccine uptakes were suboptimal among Danish WLP and KTR. Increased awareness about guidelines and physicians´ education are warranted.

Background: Compromised cerebral energy metabolism is common in patients with bacterial meningitis. In this study, simultaneous measurements of cerebral oxygen tension and lactate/pyruvate ratio were compared to explore whether disturbed energy metabolism was usually caused by insufficient tissue oxygenation or compromised oxidative metabolism of pyruvate indicating mitochondrial dysfunction. Subject and Methods: Ten consecutive patients with severe streptococcus meningitis were included in this prospective cohort study. Intracranial pressure, brain tissue oxygen tension (PbtO 2 ), and energy metabolism (intracerebral microdialysis) were continuously monitored in nine patients. A cerebral lactate/pyruvate (LP) ratio 30 simultaneously with pyruvate below lower normal level (70 µmol/L) was interpreted as biochemical indication of ischemia, and LP ratio >30 simultaneously with a normal or increased level of pyruvate was interpreted as mitochondrial dysfunction. The biochemical variables were compared with PbtO 2 simultaneously monitored within the same cerebral region. Results: In two cases, the LP ratio was normal during the whole study period and the simultaneously monitored PbtO 2 was 18 ± 6 mm Hg. In six cases, interpreted as mitochondrial dysfunction, the simultaneously monitored PbtO 2 was 20 ± 6 mm Hg and without correlation with the LP ratio. In one patient, exhibiting a pattern interpreted as ischemia, PbtO 2 decreased below 10 mm Hg and a correlation between LP and PbtO 2 was observed. Conclusion: This study demonstrated that compromised cerebral energy metabolism, evidenced by increased LP ratio, was common in patients with severe bacterial meningitis while not related to insufficient tissue oxygenation.

ObjectiveTo examine predefined risk factors and outcome of seizures in community-acquired bacterial meningitis (CABM).DesignObservational cohort studiesSettingDenmarkParticipantsIn the derivation cohort, we retrospectively included all adults (>15 years of age) with CABM in North Denmark Region from 1998 to 2014 and at Hvidovre and Hillerød hospitals from 2003 to 2014. In the validation cohort, we prospectively included all adults (>18 years of age) with CABM treated at all departments of infectious diseases in Denmark from 2015 to 2017.Primary and secondary outcome measuresIn the derivation cohort, we used modified Poisson regression to compute adjusted relative risks (RRs) with 95% confidence intervals for predefined risk factors for seizures during CABM as well as for risks of death and unfavourable outcome assessed by the Glasgow Outcome Scale score (1-4). Next, results were validated in the validation cohort.ResultsIn the derivation cohort (n=358), risk factors for seizures at any time were pneumococcal aetiology (RR 1.69, 1.01–2.83) and abnormal cranial imaging (RR 2.27, 1.46–3.53), while the impact of age >65 years and immunocompromise was more uncertain. Examining seizures occurring after admission, risk factors were abnormal cranial imaging (RR 2.23, 1.40–3.54) and immunocompromise (RR 1.59, 1.01–2.50). Seizures at any time were associated with increased risks of in-hospital mortality (RR 1.45, 1.01–2.09) and unfavourable outcome at discharge (RR 1.27, 1.02–1.60). In the validation cohort (n=379), pneumococcal aetiology (RR 1.69, 1.10–2.59) and abnormal cranial imaging (RR 1.68, 1.09–2.59) were confirmed as risk factors for seizures at any time. For seizures occurring after admission, only pneumococcal meningitis (RR 1.92, 1.12–3.29) remained significant. Seizures at any time were also associated with in-hospital mortality (RR 3.26, 1.83–5.80) and unfavourable outcome (RR 1.23, 1.00–1.52) in this cohort.ConclusionsPneumococcal aetiology, immunocompromise and abnormal cranial imaging were risk factors for seizures in CABM. Seizures were strongly associated with mortality and unfavourable outcome.

Background: The ability of cerebrospinal fluid (CSF) lactate to distinguish between acute bacterial meningitis (ABM) and aseptic meningitis/encephalitis (AME) is debated. We assessed the diagnostic value of CSF lactate to discriminate between ABM and AME. Methods: We included 176 patients from a prospective adult cohort with neuroinfections. In total, 51 ABM and 125 AME patients with clinically and/or microbiologically diagnosed acute meningitis were examined with CSF-lactate and traditional markers for infection. Receiver operating characteristic (ROC) curves were used to assess diagnostic performance. Results: In CSF, lactate, leukocytes, fraction of neutrophils, protein and glucose ratio, were significantly different between the ABM and AME groups. CSF lactate had the best diagnostic value, with an area under the curve (AUC) of 0.976 (95%CI 0.966–0.997) and using a cut-off of 3.5 mmol/L a sensitivity of 96% and specificity of 85%. Antibiotic treatment before lumbar puncture had no significant effect on the AUC of CSF lactate. Conclusions: Compared to traditional CSF-markers, CSF lactate is more accurate to distinguish between ABM and AME.

BACKGROUND: Cerebral mitochondrial dysfunction is prominent in the pathophysiology of severe bacterial meningitis. In the present study, we hypothesize that the metabolic changes seen after intracisternal lipopolysaccharide (LPS) injection in a piglet model of meningitis is compatible with mitochondrial dysfunction and resembles the metabolic patterns seen in patients with bacterial meningitis.METHODS: Eight pigs received LPS injection in cisterna magna, and four pigs received NaCl in cisterna magna as a control. Biochemical variables related to energy metabolism were monitored by intracerebral microdialysis technique and included interstitial glucose, lactate, pyruvate, glutamate, and glycerol. The intracranial pressure (ICP) and brain tissue oxygen tension (PbtO2) were also monitored along with physiological variables including mean arterial pressure, blood glucose, lactate, and partial pressure of O2 and CO2. Pigs were monitored for 60 min at baseline and 240 min after LPS/NaCl injection.RESULTS: After LPS injection, a significant increase in cerebral lactate/pyruvate ratio (LPR) compared to control group was registered (p = 0.01). This increase was due to a significant increased lactate with stable and normal values of pyruvate. No significant change in PbtO2 or ICP was registered. No changes in physiological variables were observed.CONCLUSIONS: The metabolic changes after intracisternal LPS injection is compatible with disturbance in the oxidative metabolism and partly due to mitochondrial dysfunction with increasing cerebral LPR due to increased lactate and normal pyruvate, PbtO2, and ICP. The metabolic pattern resembles the one observed in patients with bacterial meningitis. Metabolic monitoring in these patients is feasible to monitor for cerebral metabolic derangements otherwise missed by conventional intensive care monitoring.

BACKGROUND: The aim of this study was to evaluate the clinical outcome of patients with severe bacterial meningitis where intracranial pressure (ICP) monitoring has been performed.METHODS: A retrospective observational study including patients admitted 1st(.) January 2005 to 31st(.) December 2014. Thirty nine patients age 18-89 years were included. All the patients received intensive care with mechanical ventilation, ICP monitoring, sedation, antibiotics and corticosteroids according to current guidelines. Clinical outcome was defined as death during hospitalization or survival at hospital discharge.RESULTS: The most common pathogen was Streptococcus pneumoniae (26; 67%). Thirteen patients died (33%) and neurologic impairment was noted in twenty two (84.6%) surviving patients. In S. pneumoniae cases patients with adverse outcome were significantly older (p = 0.0024) and immunosuppressed (p = 0.034). Lower mean-cerebral perfusion pressure (CPP) was found to correlate with adverse outcome (p = 0.005). Cerebrospinal fluid (CSF) was drained in fourteen patients. Increased ICP (>20 mmHg) was observed in twenty four patients. No significant correlation was found between measured ICP and head CT scans with signs of elevated ICP.CONCLUSIONS: Patients with severe meningitis should be admitted to intensive care units and evaluated for ICP monitoring regardless of head CT findings.

Ghaydaa, Shehata/0000-0002-3631-893X; Radic, Ljiljana Betica/0000-0002-8778-106X; Silva-Pinto, Andre/0000-0002-2077-3356; Cascio, Antonio/0000-0002-1992-1796; Bossi, Paolo/0000-0003-0135-0224; Stebel, Roman/0000-0001-6922-4465; Namani, Sadie/0000-0002-2411-8623; Chan, Phillip/0000-0002-4071-4409; Hargreaves, Sally/0000-0003-2974-4348; Artuk, Cumhur/0000-0003-0827-990X; Harxhi, Arjan/0000-0001-8518-7377; Larsen, Lykke/0000-0002-4113-4182; Uysal, Serhat/0000-0002-4294-5999 WOS: 000407582200010 PubMed: 28397100 Risk assessment of central nervous system (CNS) infection patients is of key importance in predicting likely pathogens. However, data are lacking on the epidemiology globally. We performed a multicenter study to understand the burden of community-acquired CNS (CA-CNS) infections between 2012 and 2014. A total of 2583 patients with CA-CNS infections were included from 37 referral centers in 20 countries. Of these, 477 (18.5%) patients survived with sequelae and 227 (8.8%) died, and 1879 (72.7%) patients were discharged with complete cure. The most frequent infecting pathogens in this study were Streptococcus pneumoniae (n = 206, 8%) and Mycobacterium tuberculosis (n = 152, 5.9%). Varicella zoster virus and Listeria were other common pathogens in the elderly. Although staphylococci and Listeria resulted in frequent infections in immunocompromised patients, cryptococci were leading pathogens in human immunodeficiency virus (HIV)-positive individuals. Among the patients with any proven etiology, 96 (8.9%) patients presented with clinical features of a chronic CNS disease. Neurosyphilis, neurobrucellosis, neuroborreliosis, and CNS tuberculosis had a predilection to present chronic courses. Listeria monocytogenes, Staphylococcus aureus, M. tuberculosis, and S. pneumoniae were the most fatal forms, while sequelae were significantly higher for herpes simplex virus type 1 (p < 0.05 for all). Tackling the high burden of CNS infections globally can only be achieved with effective pneumococcal immunization and strategies to eliminate tuberculosis, and more must be done to improve diagnostic capacity.

It is well described that patients with pulmonary arteriovenous malformations (PAVMs) and Hereditary Hemorrhagic Telangiectasia (HHT) have an increased risk of cerebral abscess (CA). However, as both CA and HHT are rare, the proportion of patients with CA who are diagnosed with HHT has not been previously described. A retrospective study was carried out of all patients treated surgically for CA between January 1995 and September 2014 at the Department of Neurosurgery, Odense University Hospital. The cases were then cross-referenced with the Danish HHT database. Eighty patients aged 5–79 years were included. The incidence of CA was 0.33/100,000/year. Two patients (2.5%) were registered as having HHT. Bacterial pathogens were identified in 70% of all cases, most frequently streptococci species (46.3%). The most common predisposing condition was odontogenic infection (20%), followed by post-operative infection (13.8%) and post-trauma (6.3%). Patients undergoing a full diagnostic program to determine predisposing conditions causing CA increased over the 20-year period from 11.8% to 65.2%. The 3-month and 1-year mortality rates were 7.5% and 11.25%, respectively. There is an overrepresentation of HHT patients in a cohort of patients with CA, and HHT should be investigated as the cause of the CA if no other apparent cause can be identified.

The aim of this book is to exemplify the ways in which social work and research develop in ‘advanced’ welfare states - countries where public spending is relatively high as a proportion of GNP. While such countries have traditionally been associated with Scandinavian countries in particular and North-Western Europe more generally, there are other countries where the public spend on welfare is relatively high. The contributors to this book explore and exemplify ways in which social work and research are distinctive for advanced welfare states. This involves exploring their connection to professional identities, histories and welfare systems, their associations with academic, theoretical and cultural traditions of collaboration between academic and social work practice, and the distinctive links with community, national policy, governmentality and agency, with respect to forms of knowledge discourses and conception of social problems.While the content of this book originate predominantly in work undertaken in Denmark, there are contributors from Belgium Italy and the United Kingdom, thus suggesting that within European social work community there are important elements of common ground.

Background Herpes simplex virus (HSV) encephalitis is associated with adverse clinical outcomes in 50% of patients. The use and impact of adjunctive steroids in improving the prognosis of this devastating disease is unknown. Methods A multicenter international retrospective study of adults (age >15 years) with confirmed HSV encephalitis. An adverse clinical outcome was defined as death or survived with sequelae. Results A total of 438 adults with HSV encephalitis were enrolled. The mean age was 50.58 years (15.94, SD), 226 (51.6%) were female and 59 (13.5%) were immunosuppressed. New onset seizures were seen in 91 (20.8%) patients and the median Glasgow coma scale was 14 (13–15, IQR). A total of 73 (16.6%) patients received adjunctive steroids during their hospitalization. Adjunctive steroids were given more frequently to patients with fever (84.5% vs. 66.7%, P = 0.003), seizures (38.3% vs. 17.3%, P < 0.001), abnormalities on MRI (77.7% vs. 61.8%, P = 0.017), lower mean Glasgow coma scales (10.42 vs. 11.3, P = 0.013) and it was also associated with a longer length of stay (median duration of 23 days vs. 20 days, P = 0.012). Adjunctive steroids were not associated with an impact on adverse clinical outcomes (46.6% vs. 46.9%, P = 0.95). Conclusion Adjunctive steroids in HSV encephalitis are used more commonly in the sicker patients and are not associated with a benefit in clinical outcomes. Disclosures All authors: No reported disclosures.

WOS: 000379252100027, PubMed ID: 27085724, There have been many studies pertaining to the management of herpetic meningoencephalitis (HME), but the majority of them have focussed on virologically unconfirmed cases or included only small sample sizes. We have conducted a multicentre study aimed at providing management strategies for HME. Overall, 501 adult patients with PCR-proven HME were included retrospectively from 35 referral centres in 10 countries; 496 patients were found to be eligible for the analysis. Cerebrospinal fluid (CSF) analysis using a PCR assay yielded herpes simplex virus (HSV)-1 DNA in 351 patients (70.8%), HSV-2 DNA in 83 patients (16.7%) and undefined HSV DNA type in 62 patients (12.5%). A total of 379 patients (76.4%) had at least one of the specified characteristics of encephalitis, and we placed these patients into the encephalitis presentation group. The remaining 117 patients (23.6%) had none of these findings, and these patients were placed in the nonencephalitis presentation group. Abnormalities suggestive of encephalitis were detected in magnetic resonance imaging (MRI) in 83.9% of the patients and in electroencephalography (EEG) in 91.0% of patients in the encephalitis presentation group. In the nonencephalitis presentation group, MRI and EEG data were suggestive of encephalitis in 33.3 and 61.9% of patients, respectively. However, the concomitant use of MRI and EEG indicated encephalitis in 96.3 and 87.5% of the cases with and without encephalitic clinical presentation, respectively. Considering the subtle nature of HME, CSF HSV PCR, EEG and MRI data should be collected for all patients with a central nervous system infection. (C) 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Objectives To monitor epidemiological trends of infectious meningitis (bacterial and viral) and encephalitis in Denmark. Methods Nationwide prospective observational study of all cases of proven community-acquired infectious meningitis and encephalitis in adults treated in all infectious diseases departments in Denmark from 1 January 2015 to 30 June 2016. We included data on symptoms, aetiology, treatment and outcome assessed by the Glasgow Outcome Scale (GOS) 30 days after discharge. GOS 1–4 was categorized as unfavourable outcome. Results During 18 months of observation, we identified 252 cases of viral meningitis (3.6/100 000/year), 214 cases of bacterial meningitis (3.1/100 000/year) and 96 cases of infectious encephalitis (1.4/100 000/year). In bacterial meningitis, Streptococcus pneumoniae was the most frequent infectious agent ( n = 101) followed by Staphylococcus aureus ( n = 24) and β-haemolytic streptococci ( n = 14). Meningococcal meningitis was rare ( n = 11). In encephalitis, herpes simplex virus type 1 was most common ( n = 37) followed by varicella zoster virus ( n = 20), whereas varicella zoster virus ( n = 61) was most common in viral meningitis followed by enterovirus ( n = 50) and herpes simplex virus type 2 ( n = 46). Case fatality and unfavourable outcome occurred in 31/214 (15%) and 96/214 (45%) with bacterial meningitis and in 5/96 (5%) and 55/89 (62%) with encephalitis. For viral meningitis, unfavourable outcome occurred in 41/252 (17%). Conclusions The epidemiology and clinical presentation of the examined central nervous system infections differed considerably and bacterial meningitis was more frequent than previously estimated. Overall prognosis remains poor for bacterial meningitis and encephalitis. Prospective nationwide clinical databases of central nervous system infections may be superior to epidemiological monitoring based on notifications or laboratory systems.

WOS: 000358623200015, PubMed ID: 25779579, Data in the literature regarding the factors that predict unfavorable outcomes in adult herpetic meningoencephalitis (HME) cases are scarce. We conducted a multicenter study in order to provide insights into the predictors of HME outcomes, with special emphasis on the use and timing of antiviral treatment. Samples from 501 patients with molecular confirmation from cerebrospinal fluid were included from 35 referral centers in 10 countries. Four hundred thirty-eight patients were found to be eligible for the analysis. Overall, 232 (52.9%) patients experienced unfavorable outcomes, 44 died, and 188 survived, with sequelae. Age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02 to 1.05), Glasgow Coma Scale score (OR, 0.84; 95% CI, 0.77 to 0.93), and symptomatic periods of 2 to 7 days (OR, 1.80; 95% CI, 1.16 to 2.79) and >7 days (OR, 3.75; 95% CI, 1.72 to 8.15) until the commencement of treatment predicted unfavorable outcomes. The outcome in HME patients is related to a combination of therapeutic and host factors. This study suggests that rapid diagnosis and early administration of antiviral treatment in HME patients are keys to a favorable outcome.

Background: Mortality and morbidity have remained high in bacterial meningitis. Impairment of cerebral energy metabolism probably contributes to unfavorable outcome. Intracerebral microdialysis is routinely used to monitor cerebral energy metabolism, and recent experimental studies indicate that this technique may separate ischemia and non-ischemic mitochondrial dysfunction. The present study is a retrospective interpretation of biochemical data obtained in a series of patients with severe community-acquired meningitis. Methods: Cerebral energy metabolism was monitored in 15 patients with severe community-acquired meningitis utilizing intracerebral microdialysis and bedside biochemical analysis. According to previous studies, cerebral ischemia was defined as lactate/pyruvate (LP) ratio >30 with intracerebral pyruvate level −1. Non-ischemic mitochondrial dysfunction was defined as LP-ratio >30 at a normal or increased interstitial concentration of pyruvate (≥70 μmol L −1). Patients with LP-ratios

The mechanism of positive regulation of cytokine signalling pathways has been well investigated, whereas our knowledge of negative regulation is relatively sparse. Here we review recent literature on important negative regulators: the family of suppressors of cytokine signalling, SOCS, consisting of eight members (SOCS-1 to SOCS-7 and CIS) all sharing a central SH2 domain and a C-terminal SOCS box. Expression of CIS, SOCS-1, SOCS-2 and SOCS-3 is induced by various cytokines, and overexpression studies in various cell lines have demonstrated their inhibitory roles. These family members have been implicated in the negative regulation of several pathways, particularly the JAK/STAT pathway, and since this signalling pathway is responsible for their induction, they form part of a classical negative feedback circuit. To date, at least three different modulating mechanisms have been demonstrated: through the SH2 domain they bind to phosphotyrosines on the target protein, leading to inhibition of signal transduction by N-terminal inactivation of JAK, by blocking access of STAT to the receptor sites, or by SOCS box-targeting bound proteins to proteasomal degradation. In gene modification studies in mice, it has been demonstrated that SOCS-1 plays an important role in IFNgamma-regulation and T-cell differentiation, while SOCS-2 seems necessary for normal growth regulation. SOCS-3(-/-) mice die during embryogenesis for a reason still not fully understood, but insufficient control of fetal erythropoiesis or defects in placental development may be involved. The physiological role for the other family members, as well as their molecular regulation mechanisms, remain to be revealed.

Upon termination of bone matrix synthesis, osteoblasts either undergo apoptosis or differentiate into osteocytes or bone lining cells. In this study, we investigated the role of matrix metalloproteinases (MMPs) and growth factors in the differentiation of osteoblasts into osteocytes and in osteoblast apoptosis. The mouse osteoblast cell line MC3T3-E1 and primary mouse calvarial osteoblasts were either grown on two-dimensional (2-D) collagen-coated surfaces, where they morphologically resemble flattened, cuboidal bone lining cells, or embedded in three-dimensional (3-D) collagen gels, where they resemble dendritic osteocytes constituting a network of cells. When MC3T3-E1 osteoblasts were grown in a 3-D matrix in the presence of an MMP inhibitor (GM6001), the cell number was dose-dependently reduced by approximately 50%, whereas no effect was observed on a 2-D substratum. In contrast, the murine mature osteocyte cell line, MLO-Y4, was unaffected by GM6001 under all culture conditions. According to TUNEL assay, the osteoblast apoptosis was increased 2.5-fold by 10 microm GM6001. To investigate the mechanism by which MMPs mediate the survival of osteoblasts, we examined the effect of GM6001 on MC3T3-E1 osteoblasts in the presence of extracellular matrix components and growth factors, including tenascin, fibronectin, laminin, collagenase-cleaved collagen, gelatin, parathyroid hormone, basic fibroblast growth factor, vascular epidermal growth factor, insulin-like growth factor, interleukin-1, and latent and active transforming growth factor-beta (TGF-beta). Only active TGF-beta, but not latent TGF-beta or other agents tested, restored cell number and apoptosis to control levels. Furthermore, we found that the membrane type MMP, MT1-MMP, which is produced by osteoblasts, could activate latent TGF-beta and that antibodies neutralizing endogenous TGF-beta led to a similar decrease in cell number as GM6001. Whereas inhibitors of other protease families did not induce osteoblast apoptosis, an inhibitor of the p44/42 mitogen-activated protein kinase showed the same but non-synergetic effect as GM6001. These findings suggest that MMP-activated TGF-beta maintains osteoblast survival during trans-differentiation into osteocytes by a p44/42-dependent pathway.

The type 1 diabetes mellitus (T1DM) candidate gene SNP IL6-174G/C was genotyped in 253 Danish T1DM families (1129 individuals). TDT analysis demonstrated linkage in the presence of association between the IL6-174C allele and T1DM in the 416 T1DM offspring, P(tdt)=0.04. Gender conditioned TDT analyses revealed that linkage and association with T1DM were present in females exclusively; P(tdt)=6.5 x 10(-4) and P(tdt)=2.4 x 10(-4), respectively. Random transmission of the IL6-174C/G alleles was found in T1DM males, non-T1DM males and non-T1DM females; all P(tdt)>/=0.37. Heterogeneity analyses (T1DM versus non-T1DM females) excluded preferential meiotic segregation in females, P=4.6 x 10(-3), and demonstrated differences in the transmission patterns between female and male T1DM offspring, P=5.1 x 10(-3). The IL6-174 CC genotype was associated with younger age at onset of T1DM in females (P=0.002). The impact of 17beta-estradiol (E(2)) on the IL6-174G/C variants was investigated by reporter studies. The PMA stimulated activity of the T1DM risk IL6-174C variant exceeded that of the T1DM protective IL6-174G variant by approximately 70% in the absence of E(2) (P(c)=0.004), but not with E(2) present (P(c)=0.12). The PMA stimulated activity of the IL6-174G variant was repressed without E(2) present, but was derepressed by addition of E(2), P(c)=0.024. In contrast, the PMA stimulated IL6-174C activity was unaffected by E(2) as were the constitutive activities of the IL6-174G/C variants. In conclusion, higher IL6 promoter activity may confer risk to T1DM in very young females. This excess risk is negated with increasing age, possibly by the increasing E(2) levels in puberty.

The mechanism of positive regulation of cytokine signalling pathways has been well investigated, whereas our knowledge of negative regulation is relatively sparse. Here we review recent literature on important negative regulators: the family of suppressors of cytokine signalling, SOCS, consisting of eight members (SOCS-1 to SOCS-7 and CIS) all sharing a central SH2 domain and a C-terminal SOCS box. Expression of CIS, SOCS-1, SOCS-2 and SOCS-3 is induced by various cytokines, and overexpression studies in various cell lines have demonstrated their inhibitory roles. These family members have been implicated in the negative regulation of several pathways, particularly the JAK/STAT pathway, and since this signalling pathway is responsible for their induction, they form part of a classical negative feedback circuit. To date, at least three different modulating mechanisms have been demonstrated: through the SH2 domain they bind to phosphotyrosines on the target protein, leading to inhibition of signal transduction by N-terminal inactivation of JAK, by blocking access of STAT to the receptor sites, or by SOCS box-targeting bound proteins to proteasomal degradation. In gene modification studies in mice, it has been demonstrated that SOCS-1 plays an important role in IFNgamma-regulation and T-cell differentiation, while SOCS-2 seems necessary for normal growth regulation. SOCS-3(-/-) mice die during embryogenesis for a reason still not fully understood, but insufficient control of fetal erythropoiesis or defects in placental development may be involved. The physiological role for the other family members, as well as their molecular regulation mechanisms, remain to be revealed.

BACKGROUND: Herpetic meningoencephalitis is the most frequent form of sporadic fatal encephalitis in the world and accounts for 10- 20% of all viral encephalitides. There were studies assessing the outcomes particularly by comparing the efficacies of antiviral drugs in the past. To the best of our knowledge, no datum exists in the literature on the mortality indicators of HME patients with definite microbiological diagnosis. Thus, our study makes use of the largest case series ever reported in the literature to provide data for the predictors of unfavorable outcome in HME cases. METHODS: This multicenter study enrolled HME patients from referral participant centers in 10 countries (Croatia, Czech Republic, Denmark, Egypt, France, Iraq, Italy, Lebanon, Slovenia, and Turkey). The study had a retrospective design and included patients hospitalized between 2000 and 2013. Only the adult patients with HME over the age of 15 were enrolled. Dr Lütfi Kirdar Training and Research Hospital’s Review Board in Istanbul approved the study. The inclusion criteria were as follows: 1. Symptoms and/or signs of parenchymatous disease of the brain such as focal neurological signs, seizures, decreased consciousness or disorientation often concomitant with fever and pathological neuroradiology or neurophysiology findings 2. Positive CSF-PCR result for HSV-1 or HSV-2 or both. 3. The unlikely presence of another parenchymatous disease of the brain. Unfavorable Outcome included death and sequelae. RESULTS: In this study, 501 patients with microbiologically confirmed HME were enrolled from 35 referral centers in 10 countries [Turkey (n=144), Denmark (n=127), France (n=64), Slovenia (n=54), Croatia (n=32), Iraq (n=30), Czech Republic (n=23), Italy (n=12), Lebanon (n=8), Egypt (n=7)]. However, 438 patients were found to be eligible for outcome analysis and 63 HME cases were excluded due to missing data. In this study 44 (10 %) patients died and 188 (42.9 %) experienced unfavorable outcome. Hence, 232 (52.9 %) cases experienced unfavorable outcome. The results of multivariate analysis are presented in the table. The interrelation between the elapsed time since the onset of symptoms to anti-viral treatment and unfavorable outcome is presented in the figure. CONCLUSION: Advancing age, lower GCS scores, delayed start of antivirals exceeding one week in particular, and new onset of convulsions seem to increase unfavorable outcome in HME. Thus, it appears that both host and therapeutic parameters contribute to success in these cases. Table. Final model including independent predictors of unfavorable outcome 95% CIs OR [1] Low High p Age (years) 1.04 1.02 1.05 0.000 Glasgow coma scale 0.84 0.77 0.93 0.000 Elapsed time [2] >2 days 7 days 3.75 1.72 8.15 0.001 New onset convulsion [3] 1.61 0.93 2.76 0.088 constant 1.08 0.27 4.43 0.910 [1] OR, odds ratio [2] Elapsed time between unset of symptoms and administration of anti-viral treatment [3] Newly unset convulsion before hospital admission

Background Herpes simplex virus (HSV) encephalitis is associated with adverse clinical outcomes in 50% of patients. The use and impact of adjunctive steroids in improving the prognosis of this devastating disease is unknown. Objectives 1) To describe the use of adjunctive steroids in HSV encephalitis. 2) To explore clinical factors associated with the use of steroids. 3) To assess the impact of steroids on outcomes Methods A multicenter international retrospective study of adults (age> 15 years) with confirmed HSV encephalitis. An adverse clinical outcome was defined as death or survived with sequelae. Results 1) A total of 438 adults with HSV encephalitis proven by HSV PCR were enrolled. The mean age was 50.58 years (15.94, SD), 226 (51.6%) were female and the median Glasgow coma scale was 14 (13-15, IQR). Temporal lobe abnormalities on magnetic resonance imaging (MRI) were seen in 200 /340 (58.8%); 140 (70%) with unilateral findings. 2) A total of 73 (16.6%) patients received adjunctive steroids. Adjunctive steroids were given more frequently to patients with: fever (84.5% vs 66.7%, P=0.003), seizures (38.3% vs 17.3%, P