Immunisation with the BCG and DTPw vaccines induces different programs of trained immunity in mice

In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes.     

Treatment Satisfaction of Men and Partners Following Switch from On‐Demand Phosphodiesterase Type 5 Inhibitor Therapy to Tadalafil 5 mg Once Daily

IntroductionTreatment satisfaction of men receiving phosphodiesterase 5 inhibitors (PDE5) for erectile dysfunction (ED) and their partners is essential to successful long‐term therapy.AimThis study aims to assess treatment satisfaction, in men with a partial response to on‐demand (PRN) PDE5 and their female partners, following tadalafil 5 mg once daily or placebo.MethodsThe study was randomized, double‐blind, parallel, and placebo‐controlled in men primarily with mild to moderate ED. Treatment satisfaction was assessed following a 4‐week maximum dose PRN lead‐in, 4‐week nondrug washout, and treatment through 12 weeks. Men were ≥18 years old with ED for ≥3 months and International Index of Erectile Function Erectile Function score of ≥17 and <26 at screening and <26 following PRN lead‐in.Main Outcome MeasuresTreatment satisfaction was assessed using the Treatment Satisfaction Scale (TSS) for patients and partners. TSS domain scores range from 0 to 100, with higher values indicating greater satisfaction. Statistical comparisons were made using analysis of covariance.ResultsTreatment satisfaction was significantly greater with tadalafil once daily vs. placebo across all TSS domains for both patients and their partners (all P < 0.001). For patients, mean scores for the TSS domains Confidence to Complete Sexual Activity and Satisfaction with Orgasm ranged from 53.7 to 57.8 after the PRN lead‐in and 26.7 to 31.9 following the nondrug washout. Following randomized treatment, scores for tadalafil and placebo were 55.4 and 32.6, respectively, for Confidence to Complete Sexual Activity and 57.5 and 37.9, respectively, for Satisfaction with Orgasm. Results were comparable for other TSS domains and between men and their partners.ConclusionsTreatment satisfaction was comparable for tadalafil 5 mg once daily and PRN PDE5 for both patients and female partners, suggesting that tadalafil once daily is a viable therapy option for men with ED who had a partial response to PRN PDE5 therapy. Burns PR, Rosen RC, Dunn M, Baygani SK, and Perelman MA. Treatment satisfaction of men and partners following switch from on‐demand phosphodiesterase type 5 inhibitor therapy to tadalafil 5 mg once daily. J Sex Med 2015;12:720–727.     

Validating the danger of vehicular protective devices and bowel injury

IntroductionProtective devices such as seat belts and airbags have improved the safety of motor vehicle occupants, but limited data suggest they may be associated with increased blunt bowel (small bowel or colon) injuries (BI). Unfortunately, this risk is unquantified.MethodsWe analyzed the National Trauma Data Bank (2017-2019) using ICD-10 codes to identify adult motor vehicle occupants with BI who underwent surgical repair. We used logistic regression modeling to compare the risk of undergoing surgical repair for BI after using a protective device.ResultsOf 2,848,592 injured patients, 475,546 (16.7%) were motor vehicle occupants. Only 1.2% (n = 5627/475,546) of patients underwent a bowel repair or resection. Using a seat belt only was associated with an adjusted OR of 2.09 (95% CI 1.91, 2.28) for undergoing a bowel repair/resection when adjusting for Injury Severity Score (ISS) and age. Airbag deployment without a seat belt had an adjusted OR of 1.46 (95% CI 1.31, 1.62), while both devices combined conferred an OR of 3.27 (95% CI 3.02, 3.54). However, using a seat belt was protective against death with an OR of 0.50 (95% CI 0.48, 0.53), adjusted for age, sex, Charlson Comorbidity Score, and ISS.ConclusionSeat belts and airbags are essential public health safety interventions and protect against death in motor vehicle-associated injuries. However, patients involved in MVCs with airbag deployment or while wearing a seat belt are at an increased risk of bowel injury requiring surgery compared to unrestrained patients, despite these events being relatively uncommon.     

Magnesium intake and primary liver cancer incidence and mortality in the Prostate,Lung, Colorectal and Ovarian Cancer Screening Trial

Epidemiological studies on magnesium intake and primary liver cancer (PLC) are scarce, and no prospective studies have examined the associations of magnesium intake with PLC incidence and mortality. We sought to clarify whether higher magnesium intake from diet and supplements was associated with lower risks of PLC incidence and mortality in the US population. Magnesium intake from diet and supplements was evaluated through a food frequency questionnaire in a cohort of 104,025 participants. Cox regression was employed to calculate hazard ratios for PLC incidence and competing risk regression was employed to calculate subdistribution hazard ratios for PLC mortality. Restricted cubic spline regression was employed to test nonlinearity. We documented 116 PLC cases during 1,193,513.5 person-years of follow-up and 100 PLC deaths during 1,198,021.3 person-years of follow-up. Total (diet + supplements) magnesium intake was found to be inversely associated with risks of PLC incidence (hazard ratio_{tertile 3 vs. 1}: 0.44; 95% confidence interval: 0.24, 0.80; p_trend = 0.0065) and mortality (subdistribution hazard ratio_{tertile 3 vs. 1}: 0.37; 95% confidence interval: 0.19, 0.71; p_trend = 0.0008). Similar results were obtained for dietary magnesium intake. Nonlinear inverse dose–response associations with PLC incidence and mortality were observed for both total and dietary magnesium intakes (all p_nonlinearity < 0.05). In summary, in the US population, a high magnesium intake is associated with decreased risks of PLC incidence and mortality in a nonlinear dose–response manner. These findings support that increasing the consumption of foods rich in magnesium may be beneficial in reducing PLC incidence and mortality.     

Investigating the association of receipt of seasonal influenza vaccine with occurrence of anesthesia/paresthesia and severe headaches,Canada 2012/13–2016/17, the Canadian Vaccine Safety Network

BackgroundConcern about adverse events following immunization is frequently cited by both those who receive or decline vaccines. Neurological adverse events are especially concerning.ObjectivesOur aim was to detect associations between seasonal influenza vaccination and the occurrence of severe anesthesia/paresthesia or severe headaches.MethodsData were analyzed from the Canadian National Vaccine Safety network. Events occuring on days 0–7 were self-reported and prevented daily activity, led to school or work absenteeism, or required medical attention. Controls were the previous year’s vaccinees; events in controls were collected prior to the start of the influenza vaccination program of each year (2012/13 through 2016/17). Multivariable logistic regression was used to determine the association between seasonal influenza vaccination and the occurrence of anesthesia/paresthesia or severe headaches.ResultsThe total sample was 107,565 for investigating anesthesia/paresthesia and 97,420 for investigating severe headaches. Anesthesia/paresthesia was reported by 104/107,565 (0.10%) participants; 63/69,129 (0.09%) vaccinees and 41/38,436 (0.11%) controls (adjusted odds ratio (aOR) = 0.89; 95% CI = 0.60, 1.32). Severe headaches were reported by 1361/97,420 (1.40%) participants; 907/61,463 (1.48%) vaccinees and 454/35,957 (1.26%) controls (aOR = 1.21; 95% CI = 1.08, 1.36). No specific vaccine product was associated with severe headaches.ConclusionsOur study found no association between severe anesthesia/paresthesia and seasonal influenza vaccination. While there was an association with severe headaches as an adverse event following influenza vaccination, the rates of these events are similar to rates reported from clinical trials and are not a cause for additional concern.     

Fibrinogen concentrate and maternal outcomes in severe postpartum hemorrhage: A population-based cohort study with a propensity score-matched analysis

Study objectiveFibrinogen concentrate is used to treat severe postpartum hemorrhage despite limited evidence of its effectiveness in obstetric settings. We aimed to explore the association between its administration and maternal outcomes in women with severe postpartum hemorrhage.Design, setting and patientsThis secondary analysis of the EPIMOMS prospective population-based study, exploring severe maternal morbidity, as defined by national expert consensus (2012–2013, 182,309 deliveries, France), included all women with severe postpartum hemorrhage and transfused with red blood cells during active bleeding.MeasurementsThe primary endpoint was maternal near-miss or death, and the secondary endpoint the total number of red blood cells units transfused.InterventionsWe studied fibrinogen concentrate administration as a binary variable and then by the timing of its administration. We used multivariable analysis and propensity score matching to account for potential indication bias.Main resultsAmong the 730 women with severe postpartum hemorrhage and transfused, 313 (42.9%) received fibrinogen concentrate, and 142 (19.5%) met near-miss criteria or died. The risk of near-miss or death was not significantly lower among the women treated with fibrinogen concentrate than among those not treated, in either the multivariable analysis (adjusted RR = 1.03; 95% CI, 0.72–1.49; P = 0.855) or the propensity score analysis (RR = 0.85; 95% CI, 0.55–1.32; P = 0.477). Among women treated with fibrinogen concentrate, administration more than three hours after red blood cell transfusion started was associated with a higher risk of near-miss or death than administration before or within 30 min after the transfusion began (adjusted RR = 2.07; 95% CI, 1.10–3.89; P = 0.024). Results were similar for the secondary endpoint.ConclusionsThe use of fibrinogen concentrate in severe postpartum hemorrhage needing red blood cell transfusion during active bleeding is not associated with improved maternal outcomes.