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Background. BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods. In 2008–2013, we randomized LW neonates to \"early BCG-Denmark\" (intervention group; n = 2083) or \"control\" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results. Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47–1.04) and a 34% reduction (0.66; .44–1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35–.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46–.83) within the neonatal period and 16% (0.84; .71–1.00) by age 12 months. Conclusion. Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. Clinical Trials Registration. NCT00625482.

To investigate healthcare resource utilization (HRU) and associated costs by depression severity and year of diagnosis among patients with treatment-resistant depression (TRD) in Denmark. Including all adult patients with a first-time hospital contact for major depressive disorder (MDD) in 1996-2015, TRD patients were defined at the second shift in depression treatment (antidepressant medicine or electroconvulsive therapy) and matched 1:2 with non-TRD patients. The risk of utilization and amount of HRU and associated costs including medicine expenses 12 months after the TRD-defining date were reported, comparing TRD patients with non-TRD MDD patients. Identifying 25,321 TRD-patients matched with 50,638 non-TRD patients, the risk of psychiatric hospitalization following TRD diagnosis was 138.4% (95%-confidence interval: 128.3-149.0) higher for TRD patients than for non-TRD MDD patients. The number of hospital bed days and emergency department (ED) visits were also higher among TRD patients, with no significant difference for somatic HRU. Among patients who incurred healthcare costs, the associated HRU costs for TRD patients were 101.9% (97.5-106.4) higher overall, and 55.2% (50.9-59.6) higher for psychiatric services than those of non-TRD patients. The relative differences in costs for TRD-patients vs non-TRD patients were greater for patients with mild depression and tended to increase over the study period (1996-2015), particularly for acute hospitalizations and ED visits. TRD was associated with increased psychiatric-related HRU. Particularly the difference in acute hospitalizations and ED visits between TRD and non-TRD patients increased over the study period.

Background Early diagnosis of alcohol-related liver disease (ALD) can improve survival if it leads to alcohol abstention or very light consumption. It is possible to screen for liver fibrosis, an asymptomatic condition of ALD that can lead to cirrhosis, by an easy and non-invasive approach called transient elastography. It has not yet been established whether screening for liver fibrosis reduces alcohol consumption among individuals with alcohol use disorders compared to standard treatment. In addition, it is important to address whether receiving a screening result indicating no ALD could lead to increased alcohol consumption (the certificate-of-health effect). This paper describes a study protocol aiming to evaluate alcohol drinking outcomes after screening for liver fibrosis among individuals receiving community-based treatment for alcohol use disorder. Methods The study follows a randomized, controlled trial design (RCT) with concealed allocation in a 2:1 ratio to the intervention group or the control group. Blinded outcome assessments will be conducted for both parallel groups. A total of 408 participants will be randomized to receive both transient elastography and blood tests (intervention group, n  = 272) or standard of care consisting of a blood test (control group, n  = 136). Participants are adults receiving outpatient treatment for alcohol use disorder at three specialized centres in Denmark with no known liver disease. The primary outcome is abstinence or light consumption (≤ 10 units/week, 1 unit = 12 g alcohol) throughout the last 30 days, evaluated 6 months after randomization using the validated timeline follow-back method, supplemented by review of electronic health records. Secondary outcomes include quality of life and motivation to reduce alcohol intake. Qualitative studies will explore emotional impacts of screening on participants’ and health professionals’ barriers to the implementation of screening. Discussion This study has the potential to offer important insights into the effect of screening for liver fibrosis on alcohol consumption among individuals who are attending treatment for alcohol use disorder. Furthermore, the study will provide insights into user and health professionals’ experiences related to screening. Findings may have implications for the implementation of non-invasive screening for chronic liver disease in individuals receiving alcohol use disorder treatment. Trial registration ClinicalTrials.gov NCT05855031. Registered on the 20th of April 2023.

ObjectivesTo investigate healthcare resource utilization (HRU) and associated costs by depression severity and year of diagnosis among patients with treatment-resistant depression (TRD) in Denmark.MethodsIncluding all adult patients with a first-time hospital contact for major depressive disorder (MDD) in 1996-2015, TRD patients were defined at the second shift in depression treatment (antidepressant medicine or electroconvulsive therapy) and matched 1:2 with non-TRD patients. The risk of utilization and amount of HRU and associated costs including medicine expenses 12 months after the TRD-defining date were reported, comparing TRD patients with non-TRD MDD patients.ResultsIdentifying 25,321 TRD-patients matched with 50,638 non-TRD patients, the risk of psychiatric hospitalization following TRD diagnosis was 138.4% (95%-confidence interval: 128.3-149.0) higher for TRD patients than for non-TRD MDD patients. The number of hospital bed days and emergency department (ED) visits were also higher among TRD patients, with no significant difference for somatic HRU. Among patients who incurred healthcare costs, the associated HRU costs for TRD patients were 101.9% (97.5-106.4) higher overall, and 55.2% (50.9-59.6) higher for psychiatric services than those of non-TRD patients. The relative differences in costs for TRD-patients vs non-TRD patients were greater for patients with mild depression and tended to increase over the study period (1996-2015), particularly for acute hospitalizations and ED visits.LimitationsTRD was defined by prescription patterns besides ECT treatments.ConclusionTRD was associated with increased psychiatric-related HRU. Particularly the difference in acute hospitalizations and ED visits between TRD and non-TRD patients increased over the study period.

Clinical and immunological studies in humans show that the live attenuated (BCG) vaccine has beneficial non-specific effects, increasing resistance against diseases other than tuberculosis. The underlying mechanisms are currently being explored. The pig exhibits considerable physiological similarity to humans in anatomy and physiology, suggesting that similar responses to BCG could be expected. Studies of the non-specific effects of BCG in pigs are scarce. We investigated the feasibility of using pigs as a large animal model to investigate the non-specific immunological effects of BCG. In a series of experiments, we randomized newborn or young piglets from conventional farms to receiving BCG or placebo and investigated the persistence of live BCG bacteria in various tissues, the immunogenicity of BCG in blood and stimulation assays, and the acute phase protein and clinical responses to heterologous infectious challenge with influenza A virus or . The BCG vaccine was generally well tolerated. In contrast to humans, no skin reaction in the form of abscesses, ulcers, or scars was observed. Live BCG was recovered from draining lymph nodes in 2/13 animals 20 weeks after vaccination. Specific responses of IFN-γ to antigen-specific re-stimulation with mycobacterial antigen were increased but not TNF-responses to TLR2 or TLR4 agonists. A few genes were differentially expressed in blood after vaccination, including the antiviral genes and , although the effect disappeared after correction for multiple testing. Clinical symptoms after heterologous bacterial or viral respiratory infections did not differ, nor did virus copies in nasopharyngeal samples after the challenge. However, the acute phase protein response was significantly reduced in BCG-vaccinated animals after influenza challenge but not after challenge. BCG was safe in pigs, inducing specific immunological responses, but our model did not corroborate the innate immunological responsiveness to BCG seen in humans. The dose of BCG or the bacterial and viral challenges may have been sub-optimal. Even so, the acute phase protein response to influenza infection was significantly reduced in BCG-vaccinated animals.

Vaccines may have non-specific effects, affecting resistance to heterologous pathogens. Veterinary vaccines have seldom been investigated for their non-specific effects. However, recent observational studies suggest that an inactivated paratuberculosis vaccine reduced all-cause mortality in goats and cattle. We tested if vaccination with a killed mycobacterial vaccine may have heterologous effects in swine (Sus domesticus), specifically on the pathogenic and clinical effects of a heterologous challenge with Actinobacillus pleuropneumoniae in young pigs. Newborn piglets were randomized to vaccination s.c. with the inactivated paratuberculosis vaccine Gudair (Zoetis Inc.) ( = 17) or no vaccine ( = 16). At 4-5 weeks after vaccination, all piglets were challenged intra-nasally with a high (Gudair: = 8; control: = 8) or a low (Gudair: = 9; control: = 8) dose of the gram-negative bacterium A. pleuropneumoniae causing acute porcine pleuropneumonia. The effect and severity of pathogen challenge was evaluated by measuring acute phase proteins C-reactive protein, haptoglobin and Porcine α1-acid glycoprotein, and by gross pathology 1 day post challenge. Specific and non-specific cytokine responses to vaccination were evaluated in whole blood before bacterial challenge. The vaccine was immunogenic in the pigs as evidenced by increased IFN-γ responses to purified protein derivative of Mycobacterium paratuberculosis. However, Gudair vaccine did not affect IL-6 responses. The gross pathology of the lungs as well as the acute phase protein responses after the high A. pleuropneumoniae dose challenge was slightly increased in the vaccinated animals compared with controls, whereas this was not seen in the animals receiving the low-dose bacterial challenge. The inactivated paratuberculosis vaccine exacerbated the pathological and inflammatory effects of an experimental A. pleuropneumoniae infection in young pigs.

IntroductionReceiving Bacille Calmette-Guérin (BCG)-Denmark vaccine at birth has been associated with ~40% reductions in all-cause neonatal mortality. We evaluated determinants of BCG skin reaction characteristics by age 2 months and tested the association with subsequent mortality.MethodsProspective observational study amalgamating five trials providing BCG-at-birth that were conducted between 2002 and 2018 in Guinea-Bissau. The reaction status and size were evaluated at home-visits by 2 months of age among 6012 neonates; mortality from 2 to 12 months was assessed at subsequent visits. Reaction determinants were evaluated by binomial regression providing risk ratios (RRs). In Cox-models providing adjusted mortality rate ratios (aMRRs), we assessed the association between (1) having a 2-month reaction (yes/no) and (2) reaction size tertiles and subsequent all-cause mortality risk. A subgroup had their BCG reaction evaluated and were bled at age 4 weeks; their samples underwent in vitro analysis for specific and non-specific cytokine responses.ResultsThe BCG strain was the main determinant for developing a 2-month reaction and the reaction size: the BCG-Russia/BCG-Denmark RR for large-reaction was 0.38 (0.30–0.47) and the BCG-Russia/BCG-Japan RR was 0.61 (0.51–0.72). 5804 infants (96.5%) were reactors by age 2 months; 208 (3.5%) were non-reactors. The 2–12 months mortality risk was 4.8% (10/208) for non-reactors, 2.9% (64/2213) for small reactors, 1.8% (30/1710) for medium reactors and 0.8% (15/1881) for large reactors. The reactor/non-reactor aMRR was 0.49 (0.26–0.95) and there was a linear trend of decreasing mortality with increasing reaction size (p for trend <0.001). BCG reactors had higher 4-week specific and non-specific cytokine responses, responses that were highest among those with large reactions.ConclusionAmong BCG-vaccinated infants, having a BCG skin reaction by age 2 months was associated with markedly better survival, as was the reaction size. Our findings thus support that BCG has substantial effects on all-cause mortality. Emphasising at-birth vaccination with immunogenic BCG strains and revaccinating non-reactors and small reactors could have major public health benefits.Trial registration numbersNCT00146302, NCT00168610, NCT00625482, NCT01989026 and NCT02447536.

Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (T FH cell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting T FH cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust T FH cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of T FH cell differentiation and a promising target for T FH cell–skewing vaccine adjuvants. Sander and colleagues show that antigen-presenting cells detect bacterial RNA from live bacteria via TLR8 and promote T FH cell differentiation and vaccine responses through the induction of a specific cytokine profile.

The BCG vaccine protects non-specifically against other diseases than tuberculosis. Three randomised controlled trials of early BCG in Guinea-Bissau found a 38% reduction in all-cause neonatal mortality. Little is known about the underlying mechanisms. In Guinea-Bissau, prevalent infectious diseases display distinct seasonality. Revisiting the three trials (>6500 infants) comparing early BCG versus no early BCG in low weight infants on all-cause neonatal mortality over 12 consecutive years, we explored the seasonal variation in BCG’s effect on mortality. In a subgroup of participants, adaptive and innate cytokine responses were measured 4 weeks after randomisation. Consistently over the course of the three trials and 12 years, the effect of BCG on all-cause neonatal mortality was particularly beneficial when administered in November to January, coincident with peaking malaria infections. During these months, BCG was also associated with stronger proinflammatory responses to heterologous challenge. Recent studies have suggested a protective effect of BCG against malaria. BCG may also ameliorate immune-compromising fatal effects of placental malaria in the newborn.

After measles vaccine (MV), all-cause mortality is reduced more than can be explained by the prevention of measles, especially in females. We aimed to study the biological mechanisms underlying the observed non-specific and sex-differential effects of MV on mortality. Within a large randomised trial of MV at 4.5 months of age blood samples were obtained before and six weeks after randomisation to early MV or no early MV. We measured concentrations of cytokines and soluble receptors from plasma (interleukin-1 receptor agonist (IL-1Ra), IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, soluble urokinase-type plasminogen activator receptor), and secreted cytokines (interferon-γ, TNF-α, IL-5, IL-10, IL-13, IL-17) after in vitro challenge with innate agonists and recall antigens. We analysed the effect of MV in multiple imputation regression, overall and stratified by sex. The majority of the infants had previously been enrolled in a randomised trial of neonatal vitamin A. Post hoc we explored the potential effect modification by neonatal vitamin A. Overall, MV versus no MV was associated with higher plasma MCP-1 levels, but the effect was only significant among females. Additionally, MV was associated with increased plasma IL-1Ra. MV had significantly positive effects on plasma IL-1Ra and IL-8 levels in females, but not in males. These effects were strongest in vitamin A supplemented infants. Vitamin A shifted the effect of MV in a pro-inflammatory direction. In this explorative study we found indications of sex-differential effects of MV on several of the plasma biomarkers investigated; in particular MV increased levels in females, most strongly in vitamin A recipients. The findings support that sex and micronutrient supplementation should be taken into account when analysing vaccine effects. clinicaltrials.gov number NCT 00168545.