Prophylactic treatment with PEGylated bovine IFNλ3 effectively bridges the gap in vaccine-induced immunity against FMD in cattle.

Foot-and-mouth disease (FMD) is a vesicular disease of cloven-hoofed animals with devastating economic implications. The current FMD vaccine, routinely used in enzootic countries, requires at least 7 days to induce protection. However, FMD vaccination is typically not recommended for use in non-enzootic areas, underscoring the need to develop new fast-acting therapies for FMD control during outbreaks. Interferons (IFNs) are among the immune system's first line of defense against viral infections. Bovine type III IFN delivered by a replication defective adenovirus (Ad) vector has effectively blocked FMD in cattle. However, the limited duration of protection-usually only 1-3 days post-treatment (dpt)-diminishes its utility as a field therapeutic. Here, we test whether polyethylene glycosylation (PEGylation) of recombinant bovine IFNλ3 (PEGboIFNλ3) can extend the duration of IFN-induced prevention of FMDV infection in both vaccinated and unvaccinated cattle. We treated groups of heifers with PEGboIFNλ3 alone or in combination with an adenovirus-based FMD O1Manisa vaccine (Adt-O1M) at either 3 or 5 days prior to challenge with homologous wild type FMDV. We found that pre-treatment with PEGboIFNλ3 was highly effective at preventing clinical FMD when administered at either time point, with or without co-administration of Adt-O1M vaccine. PEGboIFNλ3 protein was detectable systemically for >10 days and antiviral activity for 4 days following administration. Furthermore, in combination with Adt-O1M vaccine, we observed a strong induction of FMDV-specific IFNγ+ T cell response, demonstrating its adjuvanticity when co-administered with a vaccine. Our results demonstrate the promise of this modified IFN as a pre-exposure prophylactic therapy for use in emergency outbreak scenarios.

High Cardiorespiratory Optimal Point Values Are Related to Cardiovascular Mortality in Men Aged 46 to 70 Years: a Prospective Cohort Study

Abstract Background: Several hemodynamic and respiratory variables measured during cardiopulmonary exercise testing (CPX) have been shown to predict survival. One such measure is the cardiorespiratory optimal point (COP) that reflects the best possible circulation-respiration interaction, but there are still limited data on its relationship with adverse outcomes. Objective: To assess the association between COP and cardiovascular mortality in men aged 46 to 70 years. Methods: A sample of 2201 men who had anthropometric, clinical, and COP data obtained during cycling CPX between 1995 and 2022 was extracted from the CLINIMEX Exercise cohort. COP was identified as the minimal minute-to-minute VE/VO2 during CPX. Vital data were censored on October 31, 2022 for ICD-10-identified cardiovascular deaths. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs). Results: The mean ± standard deviation age was 57 ± 6 years and the median COP value was 24 (interquartile range = 21.2 to 27.4). During a mean follow-up of 4688 ± 2416 days, 129 (5.6%) patients died from cardiovascular causes. The death rates for low (< 28), high (28 to 30), and very high (> 30) categories of COP were 3.2%, 9.6%, and 18.7%, respectively. Following adjustment for age, history of myocardial infarction, diagnosis of coronary artery disease, and diabetes mellitus, the HR (95% CI) for cardiovascular mortality comparing very high versus low COP was 2.76 (1.87 to 4.07; p < 0.001). Conclusions: Our data indicate that, for a general population-based sample of men, COP > 30 represents a considerably higher risk for cardiovascular death. Information on COP could assist cardiovascular risk assessment in men.

A Highly Effective African Swine Fever Virus Vaccine Elicits a Memory T Cell Response in Vaccinated Swine.

African Swine Fever Virus (ASFV) is the causative agent of a highly contagious and lethal vector-borne disease in suids. Recently, a live attenuated virus strain, developed using the currently circulating, virulent Georgia strain (ASFV-G) with a single gene deletion (ASFV-G-ΔI177L), resulted in an effective vaccine. Nevertheless, protective immune response mechanisms induced by this candidate are poorly understood. In this study, Yorkshire crossbred swine intramuscularly vaccinated with 106 50% hemadsorption dose (HAD50) of ASFV-G-ΔI177L or a vehicle control were challenged at 28 days post-inoculation (dpi) with 102 HAD50 of ASFV-G. Analysis of purified peripheral blood mononuclear cells following inoculation and challenge revealed that CD4+, CD8+ and CD4+CD8+ central memory T cells (CD44+CD25-CD27-CD62L+CCR7+, Tcm) decreased significantly by 28 dpi in ASFV-G-ΔI177L-vaccinated swine compared to baseline and time-matched controls. Conversely, CD4+, CD8+ and CD4+CD8+ effector memory T cells (CD44+CD25-CD27-CD62-CCR7-, Tem) increased significantly among ASFV-G-ΔI177L-vaccined swine by 28 dpi compared to baseline and time-matched controls. Additionally, the percentage of natural killer (NK), CD4+ and CD4+CD8+ Tem and CD8+ Tcm and Tem positive for IFNγ increased significantly following inoculation, surpassing that of controls by 28 dpi or earlier. These results suggest that NK and memory T cells play a role in protective immunity and suggest that studying these cell populations may be a surrogate immunity marker in ASF vaccination.

Successful 10-second one-legged stance performance predicts survival in middle-aged and older individuals.

OBJECTIVES: Balance quickly diminishes after the mid-50s increasing the risk for falls and other adverse health outcomes. Our aim was to assess whether the ability to complete a 10- s one-legged stance (10-second OLS) is associated with all-cause mortality and whether it adds relevant prognostic information beyond ordinary demographic, anthropometric and clinical data. METHODS: Anthropometric, clinical and vital status and 10-s OLS data were assessed in 1702 individuals (68% men) aged 51-75 years between 2008 and 2020. Log-rank and Cox modelling were used to compare survival curves and risk of death according to ability (YES) or inability (NO) to complete the 10-s OLS test. RESULTS: Overall, 20.4% of the individuals were classified as NO. During a median follow-up of 7 years, 7.2% died, with 4.6% (YES) and 17.5% (NO) on the 10-s OLS. Survival curves were worse for NO 10-s OLS (log-rank test=85.6; p<0.001). In an adjusted model incorporating age, sex, body mass index and comorbidities, the HR of all-cause mortality was higher (1.84 (95% CI: 1.23 to 2.78) (p<0.001)) for NO individuals. Adding 10-s OLS to a model containing established risk factors was associated with significantly improved mortality risk prediction as measured by differences in -2 log likelihood and integrated discrimination improvement. CONCLUSIONS: Within the limitations of uncontrolled variables such as recent history of falls and physical activity, the ability to successfully complete the 10-s OLS is independently associated with all-cause mortality and adds relevant prognostic information beyond age, sex and several other anthropometric and clinical variables. There is potential benefit to including the 10-s OLS as part of routine physical examination in middle-aged and older adults.

Prediction of Mortality in Coronary Artery Disease: Role of Machine Learning and Maximal Exercise Capacity.

OBJECTIVE: To develop a prediction model for survival of patients with coronary artery disease (CAD) using health conditions beyond cardiovascular risk factors, including maximal exercise capacity, through the application of machine learning (ML) techniques. METHODS: Analysis of data from a retrospective cohort linking clinical, administrative, and vital status databases from 1995 to 2016 was performed. Inclusion criteria were age 18 years or older, diagnosis of CAD, referral to a cardiac rehabilitation program, and available baseline exercise test results. Primary outcome was death from any cause. Feature selection was performed using supervised and unsupervised ML techniques. The final prognostic model used the survival tree (ST) algorithm. RESULTS: From the cohort of 13,362 patients (60±11 years; 2400 [18%] women), 1577 died during a median follow-up of 8 years (interquartile range, 4 to 13 years), with an estimated survival of 67% up to 21 years. Feature selection revealed age and peak metabolic equivalents (METs) as the features with the greatest importance for mortality prediction. Using these 2 features, the ST generated a long-term prediction with a C-index of 0.729 by splitting patients in 8 clusters with different survival probabilities (P<.001). The ST root node was split by peak METs of 6.15 or less or more than 6.15, and each patient's subgroup was further split by age or other peak METs cut points. CONCLUSION: Applying ML techniques, age and maximal exercise capacity accurately predict mortality in patients with CAD and outperform variables commonly used for decision-making in clinical practice. A novel and simple prognostic model was established, and maximal exercise capacity was further suggested to be one of the most powerful predictors of mortality in CAD.

Women Have Lower Mortality Than Men After Attending a Long-Term Medically Supervised Exercise Program.

PURPOSE: Medically supervised exercise programs (MSEPs) are equally recommended for men and women with cardiovascular disease (CVD). Aware of the lower CVD mortality in women, we hypothesized that among patients attending a MSEP, women would also have better survival. METHODS: Data from men and women, who were enrolled in a MSEP between 1994 and 2018, were retrospectively analyzed. Sessions included aerobic, resistance, flexibility and balance exercises, and cardiopulmonary exercise test was performed. Date and underlying cause of death were obtained. Kaplan-Meier methods and Cox proportional hazards regression were used for survival analysis. RESULTS: A total of 2236 participants (66% men, age range 33-85 yr) attended a median of 52 (18, 172) exercise sessions, and 23% died during 11 (6, 16) yr of follow-up. In both sexes, CVD was the leading cause of death (39%). Overall, women had a more favorable clinical profile and a longer survival compared to men (HR = 0.71: 95% CI, 0.58-0.85; P < .01). When considering those with coronary artery disease and similar clinical profile, although women had a lower percentage of sex- and age-predicted maximal oxygen uptake at baseline than men (58 vs 78%; P < .01), after adjusting for age, women still had a better long-term survival (HR = 0.68: 95% CI, 0.49-0.93; P = .02). CONCLUSION: Survival after attendance to a long-term MSEP was better among women, despite lower baseline cardiorespiratory fitness. Future studies should address whether men and women would similarly benefit when participating in an MSEP.

Comparison of the FRIEND and Wasserman-Hansen Equations in Predicting Outcomes in Heart Failure.

Background Percentage of age-predicted peak oxygen uptake (VO2) achieved (ppVO2) has been widely used to stratify risk in patients with heart failure. However, there are limitations to traditional normal standards. We compared the recently derived FRIEND (Fitness Registry and the Importance of Exercise: A National Data Base) equation to the widely used Wasserman-Hansen (WH) ppVO2 equation to predict outcomes in patients with heart failure. Methods and Results A subgroup of 4055 heart failure patients from the FRIEND registry (mean age 53±15 years) was followed for a mean of 28±16 months. The FRIEND and WH equations along with measured peak VO2 expressed in mL/kg-1 per min-1 were compared for mortality and composite cardiovascular events. ppVO2 was higher for the FRIEND versus the WH equation (66±30% versus 58±25%; P<0.001). The areas under the receiver operating characteristic curves were slightly but significantly higher for the FRIEND equation for mortality (0.74 versus 0.72; P=0.03) and cardiac events (0.70 versus 0.68; P=0.008). Area under the receiver operating characteristic curve for measured peak VO2 was 0.70 (P<0.001) for mortality and 0.73 (P<0.001) for cardiovascular events. For each 1-SD higher ppVO2 for the FRIEND equation, mortality was reduced by 18% (hazard ratio, 0.82; 95% CI, 0.69-0.97; P<0.02); for each 1-SD higher ppVO2 for the WH equation, the mortality was reduced by 17% (hazard ratio, 0.83; 95% CI, 0.71-0.97; P=0.02). The corresponding reductions in risk per 1 SD for cardiovascular events for the FRIEND and WH equations were 23 and 21%, respectively (both P<0.001). Conclusions Peak VO2 expressed as percentage of an age-predicted standard strongly predicts mortality and major cardiovascular events in patients with heart failure. The FRIEND registry equation exhibited test characteristics slightly superior to the commonly used WH equation.

Infant presenting with pyloric stenosis and autosomal recessive polycystic kidney disease at 36 weeks' postmenstrual age (PMA).

This case report describes a premature male infant born after a pregnancy complicated by oligohydramnios of unknown aetiology but otherwise unremarkable prenatal scans. He had sudden onset of projectile emesis and severe hypertension in the third week of life, and further investigations revealed both pyloric stenosis and polycystic kidneys, at just 36 weeks' postmenstrual age (PMA). His course thereafter was complicated by severe refractory hypertension requiring multiple antihypertensive agents in order to gain control, although his renal function remained normal. Few case reports have previously described this unusual association, but none have presented with both entities at such an early PMA.

Association between cardiorespiratory fitness, obesity, and incidence of atrial fibrillation.

BACKGROUND: The interaction between cardiorespiratory fitness (CRF) and incidence of atrial fibrillation (AF) and the interaction between obesity and incidence of AF have been explored separately. Therefore, we evaluated the association between CRF, body mass index (BMI), and risk of developing AF in a cohort of middle-aged and older US Veterans. METHODS: Symptom limited exercise tests (ETT) were conducted among 16,397 Veterans (97% male) from January 9,1987 to December 31,2017. No history of AF was evident at the time of the ETTs. CRF was expressed as quartiles of peak metabolic equivalents (METs) achieved within each age decile. Weight status was classified as normal (BMI < 25 kg/m2), overweight (BMI 25-30 kg/m2), obese (BMI 30-35 kg/m2), or severely obese (BMI > 35 kg/m2). Multivariable Cox proportional hazards regression models were used to compare the association between BMI, CRF categories, and incidence of AF. RESULTS: Over a median follow-up of 10.7 years, 2,155 (13.1%) developed AF. Obese and severely obese subjects had 13% and 32% higher risks for incidence of AF, respectively, vs. normal weight subjects. Overweight and obese subjects in the most fit quartile had 50% decline in AF risk compared to the least-fit subjects. Severely obese subjects had marked increases in AF risk (~50-60%) regardless of fitness level. Risk of developing AF increases with higher BMI and lower CRF. CONCLUSION: Improving CRF should be advocated when assessing those at risk for developing AF.

Effect of Beta-Blocker Use on Exercise Heart Rate Gradient and Reclassification of Mortality Risk in Patients Referred for Exercise Testing.

Impairments in heart rate (HR) reserve and HR recovery are associated with mortality, and the combination of these two, termed exercise HR gradient (EHRG), is a better predictor than either alone. However, the confounding effect of beta-blockade on chronotropic impairment to exercise has not been fully explored; the aim of the present study was to evaluate the effect of beta blockade on EHRG. Participants were 2769 Veterans (58.7 ± 11.6 years) who underwent a maximal exercise test for clinical reasons. HR reserve and HR recovery were acquired and divided into quintiles and summed to provide an EHRG score. Net reclassification improvement (NRI) was performed to evaluate the impact of HR reserve, HR recovery and EHRG on all-cause mortality for patients with and without beta-blocker use. During a mean follow up of 10.9 ± 4.1 years, 657 patients died. Among patients without beta-blocker therapy, adding EHRG score to an established model including multiple baseline risk factors and exercise capacity resulted in an NRI of 14.3% (p <0.001). Adding HR recovery instead of EHRG score yielded an NRI of 11.5% (p <0.001), whereas HR reserve had no significant NRI among patients without beta-blocker therapy. In contrast, among participants on beta-blocker therapy, the addition of HR reserve, HR recovery, or EHRG score did not result in any significant reclassification. In conclusion, EHRG was superior to both HR reserve and HR recovery in predicting mortality and provides significant reclassification of risk but only among patients not taking beta-blockers.