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Background Older adults and immunocompromised individulas are often excluded from vaccine trials. Aim We hypothesised that during the coronavirus disease 2019 (COVID-19) pandemic, the proportion of trials excluding these patients decreased. Methods Using the US Food and Drug Administration and and European Medicines Agency search engines, we identified all vaccines approved against pneumococcal disease, influenza (quadrivalent vaccines), and COVID-19 from 2011 to 2021. Study protocols were screened for direct and indirect age exclusion criteria and exclusion of immunocompromised individuals. In addition, we reviewed the studies with no explicit exclusion criteria and investigated the actual inclusion of those individuals. Results We identified 2024 trial records; 1702 were excluded (e.g., use of other vaccine or risk group); and 322 studies were eligible for our review. Among the pneumococcal and influenza vaccine trials (n = 193), 81 (42%) had an explicit direct age exclusion, and 150 (78%) had an indirect age-related exclusion. In total, 163 trials (84%) trials were likely to exclude older adults. Among the COVID-19 vaccine trials (n = 129), 33 (26%) had direct age exclusion and 82 (64%) had indirect age exclusion; in total, 85 (66%) trials were likely to exclude older adults. Therefore was a 18% decrease in the proportion of trials with age-related exclusion between 2011 and 2021 (only influenza and pneumococcal vaccine trials) and 2020–2021 (only COVID-19 vaccine trials) (p = 0.014). In a sub-analysis assessing observational and randomised trials, the decrease was 25% and 9%, respectively. Immunocompromised individuals were included in 87 (45%) of the pneumococcal and influenza vaccine trials compared with 54 (42%) of the COVID-19 vaccine trials (p = 0.058). Conclusions During the COVID-19 pandemic, we found a decrease in the exclusion of older adults from vaccine trials but no significant change in the inclusion of immunocompromised individulas.

Objective: Cardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high-risk TS and reduce screening in TS participants with low cardiovascular risk.Design, patients, participants and measurements: As part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re-examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFβ), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease.Results: TS participants had lower TGFβ1 and TGFβ2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFβ1 were correlated with the aortic diameter at several measuring positions. During follow-up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFβ1 and TGFβ2 levels in TS.Conclusion: TGFβ and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants. Background: The combined effectiveness of remdesivir and dexamethasone in subgroups of hospitalised patients with COVID-19 is poorly investigated. Methods: In this nationwide retrospective cohort study, we included 3826 patients with COVID-19 hospitalised between February 2020 and April 2021. The primary outcomes were use of invasive mechanical ventilation and 30-day mortality, comparing a cohort treated with remdesivir and dexamethasone with a previous cohort treated without remdesivir and dexamethasone. We used inverse probability of treatment weighting logistic regression to assess associations with progression to invasive mechanical ventilation and 30-day mortality between the two cohorts. The analyses were conducted overall and by subgroups based on patient characteristics. Results: Odds ratio for progression to invasive mechanical ventilation and 30-day mortality in individuals treated with remdesivir and dexamethasone compared to treatment with standard of care alone was 0.46 (95% confidence interval, 0.37–0.57) and 0.47 (95% confidence interval, 0.39–0.56), respectively. The reduced risk of mortality was observed in elderly patients, overweight patients and in patients requiring supplemental oxygen at admission, regardless of sex, comorbidities and symptom duration. Conclusions: Patients treated with remdesivir and dexamethasone had significantly improved outcomes compared to patients treated with standard of care alone. These effects were observed in most patient subgroups.

Utility of dipstick analysis must be investigated in patients admitted to the emergency department. The aim of this study was to evaluate if urine dipstick analysis can be used to detect significant bacteriuria. The cross-sectional study was performed in the Emergency Department of Copenhagen University Hospital - Herlev Hospital, Denmark.We recorded urine dipstick analysis of 500 adult patients admitted to the Emergency Department. Dipstick results were compared with urinary culture.Sensitivity for leukocyte esterase (LE) was 80.9%, but specificity was 58%. The sensitivity of nitrite was 46.5%, and specificity was 90%. The positive predictive value (PPV) and negative predictive value (NPV) of LE for women were 54.5% and 75.9%; for men, 50.0% and 91.6%. PPV and NPV for nitrite in women were 85.9% and 66.8%; for men, 62.9% and 88.7%. Positive LE and positive nitrite had a PPV of 90.2% for women and 70.4% for men. Negative LE and negative nitrite had an NPV of 80.9% for women and 93.3% for men.No single parameter or combination of parameters on the urine dipstick analysis can be used reliably to predict positive urine culture in women. The most accurate predictor of negative urine culture in men is the combination of negative nitrites and negative LE. To minimize unnecessary use of antibiotics, treatment can be delayed in female patients with positive urine dipstick until urine culture results are available.none.not relevant.

Background There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone. Methods Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI). Results The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38–.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29–.46). Conclusions Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May., Treatment of moderate to severe coronavirus disease 2019 (COVID-19) with remdesivir and dexamethasone was associated with a lower risk of mechanical ventilation and a significant better overall 30-day survival as compared to standard care alone.

Background Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having in vitro antiviral properties. This may improve outcomes in patients hospitalised for COVID-19. Methods Placebo-controlled double-blind randomised multicentre trial. Patients ≥18 years, admitted to hospital for≤48 h (not intensive care) with a positive SARS-CoV-2 RT-PCR test, were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14). Results After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on February 1, 2021. A total of 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median of 9.0 DAOH14 (IQR, 3–11) versus. 9.0 DAOH14 (IQR, 7–10) in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for 1 patient in the intervention group versus. 2 patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for 9 patients in the intervention group versus. 6 patients receiving placebo (p=0.57). Conclusions The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19., There are no beneficial or harmful effects from the combined intervention of hydroxychloroquine and azithromycin for hospitalised patients with confirmed coronavirus disease 2019 (COVID-19).

Mortality due to COVID-19 is higher among elderly patients with comorbidities. Even so, prognostication in COVID-19 remains limited.We assessed 90-day mortality stratified by comorbidities, routine biochemical markers and oxygen need in a consecutive single-centre cohort from 2 March to 2 June 2020.We included 263 hospitalised patients with laboratory-confirmed COVID-19. On admission, fitness for intensive care was determined in 254 patients including 98 (39%) with a do-not-resuscitate order. Ninety-day overall mortality was 29%, whereas intensive care unit (ICU) mortality was 35% (14/40). Alcohol abuse, liver disease and elevated urea were strongly associated with mortality in univariable analyses. In a mutually adjusted multivariable analysis, we found an independent incremental increase in 90-day mortality with each increasing age by decade (hazard ratio (HR) = 1.5; 95% confidence interval (CI): 1.2-1.9), Charlson Comorbidity Index (CCI) score (HR = 1.2; 95% CI: 1.0-1.4), number of abnormal blood tests (HR = 1.2; 95% CI: 1.1-1.3) and l/min. of supplemental oxygen (HR = 1.1; 95% CI: 1.1-1.2).The overall mortality was similar to that of other hospitalised patients, whereas the ICU mortality was lower than expected. On admission, each additional age by decade, CCI score, number of abnormal blood tests and magnitude of supplemental oxygen were independently associated with increased mortality.none.not relevant.

Infection with Mycobacterium chimaera has globally been linked to cardiac surgery using cardiopulmonary bypass devices with contaminated heater-cooler units (HCU). This is a case report of M. chimaera infection linked to HCU in Denmark in which we show, how difficult the diagnosis can be. A 67-year-old man had an aortic graft and valvular replacement using HCU. Post-operatively he developed progressing symptoms of intermittent fever, malaise and endocarditis with septic embolic events, and despite extensive diagnostic work-up, he remained undiagnosed for 16 months following surgery.

The nephrotoxic potential of aminoglycosides is primarily correlated to the duration of therapy. However, there are discrepancies between previous studies regarding the effect of short course treatment. The aim of this study was to compare renal function, renal recovery and mortality in a large cohort of patients with bacteraemia, who were empirically treated with regimens with and without a short course (≤ 3 days) of once daily dosing of gentamicin. This was a retrospective propensity score-matched cohort study based on all patients with bacteraemia in a Danish hospital in the period 2010-2013. We included 702 patients who received gentamicin, and 702 who did not receive gentamicin. To determine the impact of gentamicin on renal function, we used a modified version of the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for acute kidney injury (AKI), and the resulting data were analyzed by logistic regression. We used Cox regression analysis to compare the adjusted mortality rates between the two groups. According to the KDIGO criteria, we found no significant difference in the occurrence of AKI between the two groups (odds ratio (OR) 0.90 (95% CI 0.68-1.20)). We found that recovery of renal function was similar in the two groups, OR 1.00 (95% CI 0.63-1.60). The hazard ratio for 90-day all-cause mortality was 1.02 (95% CI 0.84-1.25). Short-course empirical gentamicin treatment of patients with bacteraemia was not associated with an increased incidence of AKI nor all-cause mortality in this study, and we observed similar reversibility of renal function.

In this review, we discuss Staphylococcus aureus bac-teraemia (SAB), which is a frequent and severe condition associated with high morbidity and mortality. Despite these facts, high-quality data on diagnostic approach, treatment and management of SAB remain scarce. Consequently, evidence-based guidelines concerning antibiotic therapy including the optimal choice of antibiotic drug, route of administration and treatment duration are not available. Thus, controlled clinical trials are urgently needed to increase evidence and to potentially improve the outcome for patients with SAB.

To the Editor: We report the result of a 6-year follow-up study among 522 HIV-positive patients showing a positive predictive value (PPV) of 7% (two out of 28) and a negative predictive value (NPV) of 100% (478 out of 478) for developing active tuberculosis (TB) using the QuantiFERON-TB Gold In-Tube test (QFT-IT). Denmark is a low TB incidence country with an annual incidence rate of six cases per 100 000 persons and a HIV prevalence of 70 cases per 100 000 persons [1]. Among HIV-positive patients registered in the Danish HIV Cohort, comprising all known HIV-positive individuals in Denmark, the incidence rate of TB was as high as 8.2 cases per 1000 person-years [2]. The rate was highest before and within the first 6 months of antiretroviral treatment (ART) and among patients with known TB risk factors. HIV is a well-known risk factor for developing active TB, increasing the risk >20-fold compared to HIV-uninfected individuals [3–5]. In Eastern Europe the risk of death in HIV patients co-infected with TB is especially high [6]. Isoniazid preventive treatment (IPT) has shown to be effective in preventing reactivation of TB in HIV positive individuals [7–9], and the treatment has been recommended by the World Health Organization and the US Centers for Disease Control and Prevention [10]. In order to prevent further spread of the disease and prevent infection, IPT of HIV-positive individuals is now recommended in high-burden regions, independently of tuberculin skin test or interferon-gamma release assay results [10]. In Denmark, screening and treatment of latent TB infection is only recommended in individuals with recent TB exposure and candidates of tumour necrosis factor (TNF)-α inhibitor treatment, but no specific guidelines exist for HIV-positive individuals. The …

Preparing populations for health threats, including threats from new or re-emerging infectious diseases is recognised as an important public health priority. The development, production and application of emergency vaccinations are the important measures against such threats. Vaccines are cost-effective tools to prevent disease, and emergency vaccines may be the only means to prevent a true disaster for global society in the event of a new pandemic with potential to cause morbidity and mortality comparable to the Spanish flu, the polio epidemics in the 1950s, or the SARS outbreak in 2003 if its spread had not been contained in time. Given the early recognition of a new threat, and given the advances of biotechnology, vaccinology and information systems, it is not an unrealistic goal to have promising prototype vaccine candidates available in a short time span following the identification of a new infectious agent; this is based on the assumption that the emerging infection is followed by natural immunity. However, major bottlenecks for the deployment of emergency vaccine are lack of established systems for fast-track regulatory approval of such candidates and limited international vaccine production capacity. In the present discussion paper, we propose mechanisms to facilitate development of emergency vaccines in Europe by focusing on public–private scientific partnerships, fast-track approval of emergency vaccine by regulatory agencies and proposing incentives for emergency vaccine production in private vaccine companies.

Background. New, simple, and better-performing diagnostic tools are needed for the diagnosis of tuberculosis (TB). Much effort has been invested in developing an antibody-based test for TB, but to date, no such test has performed with sufficient sensitivity and specificity. A key question remaining is the extent to which the disappointing performance of current tests is associated with a high background prevalence of latent TB. Methods. We compared Mycobacterium tuberculosis-specific ESAT-6 and CFP-10 antibody responses in a total of 565 human serum samples from M. tuberculosis-uninfected donors and donors with latent infection, as well as samples from patients with active TB. Our study included samples from 4 countries, representing environments with low, intermediate, and high TB incidences. Results. We demonstrated significant increases in antibody levels in latently infected contacts, compared with M. tuberculosis-uninfected individuals, and in patients with active TB disease, compared with latently infected contacts. Furthermore, we found a striking increase in the magnitude of the antibody responses in samples obtained from infected Ethiopian individuals (with and without disease), compared with Danish and Brazilian infected individuals; this was presumably the result of higher exposure levels. Conclusions. Our study confirms the presence of ESAT-6 and CFP-10 antibodies in patients with TB, and we demonstrate that significant antibody responses are not restricted to active TB disease but can reflect latent infection, particularly in areas with high levels of exposure to M. tuberculosis. This finding is important for the understanding of the poor discriminatory power of current serodiagnostic tests in regions of endemicity, and it may have major implications on the future development of serologic tests.

Genetic susceptibility towards clinical tuberculosis has been proposed in several population studies. We investigated whether polymorphisms in the candidate genes encoding solute carrier 11a1 protein (SLC11A1 formerly NRAMP1), mannose-binding lectin (MBL2) and Vitamin D receptor (VDR) were associated with tuberculosis in an East-African setting. Four hundred and forty-three culture positive pulmonary tuberculosis patients and 426 controls from Mwanza district in the northern part of Tanzania were prospectively included. Polymorphisms in the candidate genes were detected by different PCR-based techniques. A significant association between pulmonary tuberculosis and a microsatellite marker in the 5′(CA) n locus in the SLC11A1 gene compared with controls (38% versus 30% odds ratio 1.45, 95% CI: 1.06–1.9, P = 0.014) was observed. The association was apparent only in HIV negative tuberculosis patients. No association with tuberculosis was seen with 3 other SLC11A1 loci investigated, which previously have been associated with tuberculosis in other populations or with MBL2 and VDR polymorphisms. The tuberculosis associated microsatellite marker was situated on different SLC11A1 haplotypes. In this cohort a microsatellite marker in the 5′(CA) n locus situated in the SLC11A1 gene was associated with tuberculosis. The observed association was seen only in HIV negative patients suggesting that this genetic susceptibility for tuberculosis may be surpassed by co-infections.

The locus coeruleus is the largest cluster of noradrenaline-producing neurons in the brain and has been involved in regulating attention. The neurotransmitter system contributes to the initiation and maintenance of forebrain activity as well as modulation of the collection and processing of sensory information. This makes locus coeruleus a target of interest in the study of possible structural changes in the brains of subjects with chronic schizophrenia. Uniform sampling and optical disectors were used for estimation of total neuron numbers and the rotator principle for estimation of mean cell volume. This study estimated the bilateral total number of pigmented neurons in the locus coeruleus of schizophrenic and control subjects and found no difference between the two; schizophrenic subjects have 37,400 (coefficient of variation = CV = SD/mean = 0.28), control subjects have 35,500 (CV = 0.19), p = 0.64. The average volume of the cell perikaryon of pigmented neurons was measured in both groups and showed a significant larger cell volume in the locus coeruleus of schizophrenic compared to control subjects; mean locus coeruleus cell volume was 58,400 μm3 (CV = 0.31) in schizophrenic subjects, which is 55% larger than the 37,600 μm3 (CV = 0.33) found in control subjects, a difference of 20,800 μm3 (p = 0.009). The fixation time was significantly longer for the schizophrenic brains with an average of 169 months compared to 88 months for the control brains. No relation was found between total numbers or geometric mean volume of the pigmented cells and fixation time.

Mannose-binding lectin (MBL) mediates protection against infections by using the complement system, but certain microorganisms may increase infectivity by exploiting this host defense system. Thus, it has been speculated whether genetically determined low MBL levels may confer partial protection against certain intracellular microorganisms, such as Mycobacterium tuberculosis. We investigated MBL alleles in 109 culture-positive human immunodeficiency virus-uninfected patients with tuberculosis living in Denmark and 250 white control subjects. Patients and control subjects were divided into 3 different groups defined by undetectable, low, and high serum MBL concentrations, which correlates to deficient, low, and high expressing MBL genotypes. A significantly decreased frequency of patients with the low-expressing MBL genotype was observed in white patients compared to control subjects. The same tendency also was observed in patients of other ethnic origin. It may be hypothesized that heterozygosity for MBL variant alleles, which encodes low serum MBL levels, is associated with protection against clinical tuberculosis.

P 1 .16 but carriage of Nramp1 variant alleles at loci INT4 and 5 � (CA)n conferred a significantly increased risk of having microscopy-positive compared with microscopy-negative tuberculosis (65% vs. 35% ( ) and 63% vs. 38% ( ), respectively). The Nramp1 alleles were P p .0004 P p .047 not associated with increased risk for the development of cavities seen on chest radiographs, or with extrapulmonary tuberculosis. These results indicate that variant alleles in the Nramp1 gene are associated with increased mycobacterial replication rather than susceptibility for tuberculosis and may thus confer increased risk of severe disease. Even though susceptibility to tuberculosis (TB) is multifac- torial, only 10% of infected individuals develop clinical TB, and the concordance rates for dizygotic and monozygotic twins are ∼20% and ∼60%, respectively (1). Thus, an underlying genetic predisposition might be anticipated. Several studies have indi- cated that there is an increased risk of TB in carriers of the HLA type DR2 and certain haptoglobin allotypes, as well as in indi- viduals with polymorphisms in the vitamin D receptor (2). The natural resistance-associated macrophage protein 1 (NRAMP1 or "Slc11a1") gene, Nramp1, was primarily iden- tified in mice as the Bcg/Ity/Lsh (bacille Calmette-Guerin (BCG)/Salmonella typhimurium/Leishmania donovani) suscep- tibility gene and later identified genetically as Nramp1 on mouse chromosome 1 (3, 4). Two Nramp1 genotypes in mice have been described as "Bcg s

Vitamin D is essential to immune function, but little is known about the vitamin D status in equatorial populations. A cross-sectional study was conducted among pulmonary tuberculosis (PTB) patients in Mwanza, Tanzania to identify the predictors of their vitamin D status. Data on sociodemography, season, and intake of food, alcohol, tobacco, and soil were collected, anthropometric measurements taken, and serum alpha(1)-antichymotrypsin (ACT), ferritin and soluble transferrin receptor (sTfR), and serum 25-hydroxy-(ergocalciferol+cholecalciferol) [25(OH)D] determined. Of the 655 patients studied, 79.7% (508/637) were culture-positive (PTB+) and 47.2% HIV infected. Mean serum ACT, an acute phase reactant, was 0.73 +/- 0.25 g/L with 69.2% >0.6 g/L. Mean serum 25(OH)D was 86.6 +/- 32.9 nmol/L, with 41.2%

The locus coeruleus is the largest cluster of noradrenaline-producing neurons in the brain and has been involved in regulating attention. The neurotransmitter system contributes to the initiation and maintenance of forebrain activity as well as modulation of the collection and processing of sensory information. This makes locus coeruleus a target of interest in the study of possible structural changes in the brains of subjects with chronic schizophrenia. Uniform sampling and optical disectors were used for estimation of total neuron numbers and the rotator principle for estimation of mean cell volume. This study estimated the bilateral total number of pigmented neurons in the locus coeruleus of schizophrenic and control subjects and found no difference between the two; schizophrenic subjects have 37,400 (coefficient of variation=CV=SD/mean=0.28), control subjects have 35,500 (CV=0.19), p=0.64. The average volume of the cell perikaryon of pigmented neurons was measured in both groups and showed a significant larger cell volume in the locus coeruleus of schizophrenic compared to control subjects; mean locus coeruleus cell volume was 58,400 microm(3) (CV=0.31) in schizophrenic subjects, which is 55% larger than the 37,600 microm(3) (CV=0.33) found in control subjects, a difference of 20,800 microm(3) (p=0.009). The fixation time was significantly longer for the schizophrenic brains with an average of 169 months compared to 88 months for the control brains. No relation was found between total numbers or geometric mean volume of the pigmented cells and fixation time.

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) hunting millions worldwide, is a challenge to work with in the laboratory. Modern molecular biology has provided extremely useful tools which have changed conventional diagnostic procedures in the TB laboratories. Research in molecular epidemiology is currently expanding our knowledge of the natural history of TB. Access to the genome sequence has opened new avenues for research in drug development and new vaccines. However, we are still awaiting the impact of these efforts in the resource-poor TB endemic countries.

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) hunting millions worldwide, is a challenge to work with in the laboratory. Modern molecular biology has provided extremely useful tools which have changed conventional diagnostic procedures in the TB laboratories. Research in molecular epidemiology is currently expanding our knowledge of the natural history of TB. Access to the genome sequence has opened new avenues for research in drug development and new vaccines. However, we are still awaiting the impact of these efforts in the resource-poor TB endemic countries.

In this review, we discuss Staphylococcus aureus bac-teraemia (SAB), which is a frequent and severe condition associated with high morbidity and mortality. Despite these facts, high-quality data on diagnostic approach, treatment and management of SAB remain scarce. Consequently, evidence-based guidelines concerning antibiotic therapy including the optimal choice of antibiotic drug, route of administration and treatment duration are not available. Thus, controlled clinical trials are urgently needed to increase evidence and to potentially improve the outcome for patients with SAB.