Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a\u27s than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes

Immunological resilience and biodiversity for prevention of allergic diseases and asthma

Increase of allergic conditions has occurred at the same pace with the Great Acceleration, which stands for the rapid growth rate of human activities upon earth from 1950s. Changes of environment and lifestyle along with escalating urbanization are acknowledged as the main underlying causes. Secondary (tertiary) prevention for better disease control has advanced considerably with innovations for oral immunotherapy and effective treatment of inflammation with corticosteroids, calcineurin inhibitors, and biological medications. Patients are less disabled than before. However, primary prevention has remained a dilemma. Factors predicting allergy and asthma risk have proven complex: Risk factors increase the risk, while protective factors counteract them. Interaction of human body with environmental biodiversity with micro-organisms and biogenic compounds as well as the central role of epigenetic adaptation in immune homeostasis have given new insight. Allergic diseases are good indicators of the twisted relation to environment. In various non-communicable diseases, the protective mode of the immune system indicates low-grade inflammation without apparent cause. Giving microbes, pro- and prebiotics, has shown some promise in prevention and treatment. The real-world public health programme in Finland (2008-2018) emphasized nature relatedness and protective factors for immunological resilience, instead of avoidance. The nationwide action mitigated the allergy burden, but in the lack of controls, primary preventive effect remains to be proven. The first results of controlled biodiversity interventions are promising. In the fast urbanizing world, new approaches are called for allergy prevention, which also has a major cost saving potential.Peer reviewe

Host Specialization and Dispersal in Avian Haemosporidians

In order to be able to understand the ecological and evolutionary processes involved in the emergence of infectious diseases, one needs to comprehend how parasites arrive at new geographical areas and how they manage to maintain viable populations and even expand their ranges. We discuss host specificity in avian haemosporidians and how encounter and compatibility filters affect the dispersal of avian haemosporidians, and how these filters affect avian haemosporidian assemblages at different spatial and evolutionary scales. There are at least three important barriers to the dispersal of avian haemosporidians: (i) geographic barriers, (ii) environmental barriers, and (iii) interspecies barriers. In this chapter, we discuss the factors involved in these barriers and their effects on the structure of avian haemosporidian assemblages. Host specificity plays an important role in parasite dispersal, and in the case of avian haemosporidians that are vector-borne parasites, it needs to be evaluated both at the vector and bird host levels. Understanding the effects of these factors on host–vector–parasite dynamics is important to unravel the dispersal and diversification mechanisms of avian haemosporidians. We end this chapter reviewing host specialization in avian haemosporidians of tropical regions, discussing the mechanisms involved in the dispersal and specialization of these parasites and point out important research gaps that need attention

Revised Hammersmith Scale for Spinal Muscular Atrophy: : A SMA specific clinical outcome assessment tool

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.Peer reviewedFinal Published versio

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Towards common ground in the biodiversity–disease debate

The disease ecology community has struggled to come to consensus on whether biodiversity reduces or increases infectious disease risk, a question that directly affects policy decisions for biodiversity conservation and public health. Here, we summarize the primary points of contention regarding biodiversity–disease relationships and suggest that vector-borne, generalist wildlife and zoonotic pathogens are the types of parasites most likely to be affected by changes to biodiversity. One synthesis on this topic revealed a positive correlation between biodiversity and human disease burden across countries, but as biodiversity changed over time within these countries, this correlation became weaker and more variable. Another synthesis—a meta-analysis of generally smaller-scale experimental and field studies—revealed a negative correlation between biodiversity and infectious diseases (a dilution effect) in various host taxa. These results raise the question of whether biodiversity–disease relationships are more negative at smaller spatial scales. If so, biodiversity conservation at the appropriate scales might prevent wildlife and zoonotic diseases from increasing in prevalence or becoming problematic (general proactive approaches). Further, protecting natural areas from human incursion should reduce zoonotic disease spillover. By contrast, for some infectious diseases, managing particular species or habitats and targeted biomedical approaches (targeted reactive approaches) might outperform biodiversity conservation as a tool for disease control. Importantly, biodiversity conservation and management need to be considered alongside other disease management options. These suggested guiding principles should provide common ground that can enhance scientific and policy clarity for those interested in simultaneously improving wildlife and human health

Kidney Function Trajectories and Right Heart Failure Following LVAD Implantation

Background Preoperative kidney dysfunction is a risk factor for right heart failure (RHF) after implantation of a left ventricular assist device (LVAD). However, characteristic kidney function trajectories before and after post‐LVAD RHF are uncertain, so we investigated this. Methods and Results We identified individuals who received primary continuous‐flow LVAD implantation from July 1, 2014 to December 31, 2017 in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) data set. Incident RHF was ascertained using the INTERMACS definition at 1 and 3 months and classified as transient or persistent. Kidney function trajectories before and after RHF onset, and relationships of baseline kidney function with RHF risk at the different time points, were assessed. We identified 8076 LVAD recipients who met inclusion criteria. Incident RHF was present at 1 month in 26.4%. There were 4850 individuals with follow‐up at 3 months, with incident RHF in 4.2%. Kidney function trajectories differed from pre‐LVAD implantation to 1‐month follow‐up by RHF category, with those developing persistent RHF having no improvement in baseline kidney function. For trajectories before the 3‐month RHF ascertainment time, the shape was similar for those with and without RHF, with lower estimated glomerular filtration rate levels among those who developed RHF. Baseline estimated glomerular filtration rate levels below the normal range were associated with higher risk of RHF at 1 and 3 months. Conclusions In LVAD recipients, preimplantation kidney function and subsequent kidney function trajectories differed substantially by RHF at 1 and 3 months postimplantation, even after adjustment for several confounders. This may demonstrate bidirectional associations between kidney function and right ventricular function in LVAD recipients