Cardiopulmonary exercise test to detect cardiac dysfunction from pulmonary vascular disease.

BACKGROUND: Cardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease. METHODS: We reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O2·pulseAT/O2·pulserest with RHC-determined SVAT/SVrest. We evaluated the sensitivity and specificity of O2·pulseAT/O2·pulserest to detect SVAT/SVrest below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRVpeak) with SVAT/SVrest. RESULTS: From July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O2·pulse and SV at rest and at AT. O2·pulseAT/O2·pulserest correlated highly with SVAT/SVrest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001), whereas TRVpeak did not (r = -0.09, 95% CI -0.47, 0.33; p = 0.69). The AUROC to detect SVAT/SVrest below the LLN was significantly higher for O2·pulseAT/O2·pulserest (0.92, SE 0.04; p = 0.0002) than for TRVpeak (0.69, SE 0.10; p = 0.12). O2·pulseAT/O2·pulserest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SVAT/SVrest. CONCLUSIONS: CPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O2·pulseAT/O2·pulserest may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism.

Data-driven MRI analysis reveals fitness-related functional change in default mode network and cognition following an exercise intervention.

Previous research has indicated that cardiorespiratory fitness (CRF) is structurally and functionally neuroprotective in older adults. However, questions remain regarding the mechanistic role of CRF on cognitive and brain health. The purposes of this study were to investigate if higher pre-intervention CRF was associated with greater change in functional brain connectivity during an exercise intervention and to determine if the magnitude of change in connectivity was related to better post-intervention cognitive performance. The sample included low-active older adults (n = 139) who completed a 6-month exercise intervention and underwent neuropsychological testing, functional neuroimaging, and CRF testing before and after the intervention. A data-driven multi-voxel pattern analysis was performed on resting-state MRI scans to determine changes in whole-brain patterns of connectivity from pre- to post-intervention as a function of pre-intervention CRF. Results revealed a positive correlation between pre-intervention CRF and changes in functional connectivity in the precentral gyrus. Using the precentral gyrus as a seed, analyses indicated that CRF-related connectivity changes within the precentral gyrus were derived from increased correlation strength within clusters located in the Dorsal Attention Network (DAN) and increased anti-correlation strength within clusters located in the Default Mode Network (DMN). Exploratory analysis demonstrated that connectivity change between the precentral gyrus seed and DMN clusters were associated with improved post-intervention performance on perceptual speed tasks. These findings suggest that in a sample of low-active and mostly lower-fit older adults, even subtle individual differences in CRF may influence the relationship between functional connectivity and aspects of cognition following a 6-month exercise intervention.

Genome editing in the mouse brain with minimally immunogenic Cas9 RNPs.

Transient delivery of CRISPR-Cas9 ribonucleoproteins (RNPs) into the central nervous system (CNS) for therapeutic genome editing could avoid limitations of viral vector-based delivery including cargo capacity, immunogenicity, and cost. Here, we tested the ability of cell-penetrant Cas9 RNPs to edit the mouse striatum when introduced using a convection-enhanced delivery system. These transient Cas9 RNPs showed comparable editing of neurons and reduced adaptive immune responses relative to one formulation of Cas9 delivered using AAV serotype 9. The production of ultra-low endotoxin Cas9 protein manufactured at scale further improved innate immunity. We conclude that injection-based delivery of minimally immunogenic CRISPR genome editing RNPs into the CNS provides a valuable alternative to virus-mediated genome editing.

Cardiopulmonary exercise testing during follow-up after acute pulmonary embolism.

BACKGROUND: Cardiopulmonary exercise testing (CPET) may provide prognostically valuable information during follow-up after pulmonary embolism (PE). Our objective was to investigate the association of patterns and degree of exercise limitation, as assessed by CPET, with clinical, echocardiographic and laboratory abnormalities and quality of life (QoL) after PE. METHODS: In a prospective cohort study of unselected consecutive all-comers with PE, survivors of the index acute event underwent 3- and 12-month follow-ups, including CPET. We defined cardiopulmonary limitation as ventilatory inefficiency or insufficient cardiocirculatory reserve. Deconditioning was defined as peak O2 uptake (V'O2 ) <80% with no other abnormality. RESULTS: Overall, 396 patients were included. At 3 months, prevalence of cardiopulmonary limitation and deconditioning was 50.1% (34.7% mild/moderate; 15.4% severe) and 12.1%, respectively; at 12 months, it was 44.8% (29.1% mild/moderate; 15.7% severe) and 14.9%, respectively. Cardiopulmonary limitation and its severity were associated with age (OR per decade 2.05, 95% CI 1.65-2.55), history of chronic lung disease (OR 2.72, 95% CI 1.06-6.97), smoking (OR 5.87, 95% CI 2.44-14.15) and intermediate- or high-risk acute PE (OR 4.36, 95% CI 1.92-9.94). Severe cardiopulmonary limitation at 3 months was associated with the prospectively defined, combined clinical-haemodynamic end-point of "post-PE impairment" (OR 6.40, 95% CI 2.35-18.45) and with poor disease-specific and generic health-related QoL. CONCLUSIONS: Abnormal exercise capacity of cardiopulmonary origin is frequent after PE, being associated with clinical and haemodynamic impairment as well as long-term QoL reduction. CPET can be considered for selected patients with persisting symptoms after acute PE to identify candidates for closer follow-up and possible therapeutic interventions.

Synthetic Fibrin-Derived Bß15-42 Peptide Delays Thrombus Resolution in a Mouse Model.

[Figure: see text].

First stellar photons for an integrated optics discrete beam combiner at the William Herschel Telescope.

We present the first on-sky results of a four-telescope integrated optics discrete beam combiner (DBC) tested at the 4.2 m William Herschel Telescope. The device consists of a four-input pupil remapper followed by a DBC and a 23-output reformatter. The whole device was written monolithically in a single alumino-borosilicate substrate using ultrafast laser inscription. The device was operated at astronomical H-band (1.6 µm), and a deformable mirror along with a microlens array was used to inject stellar photons into the device. We report the measured visibility amplitudes and closure phases obtained on Vega and Altair that are retrieved using the calibrated transfer matrix of the device. While the coherence function can be reconstructed, the on-sky results show significant dispersion from the expected values. Based on the analysis of comparable simulations, we find that such dispersion is largely caused by the limited signal-to-noise ratio of our observations. This constitutes a first step toward an improved validation of the DBC as a possible beam combination scheme for long-baseline interferometry.

Light aerobic exercise modulates executive function and cortical excitability.

Single bouts of aerobic exercise can modulate cortical excitability and executive cognitive function, but less is known about the effect of light-intensity exercise, an intensity of exercise more achievable for certain clinical populations. Fourteen healthy adults (aged 22 to 30) completed the following study procedures twice (≥7 days apart) before and after 30 min of either light aerobic exercise (cycling) or seated rest: neurocognitive battery (multitasking performance, inhibitory control and spatial working memory), paired-pulse TMS measures of cortical excitability. Significant improvements in response times during multitasking performance and increases in intracortical facilitation (ICF) were seen following light aerobic exercise. Light aerobic exercise can modulate cortical excitability and some executive function tasks. Populations with deficits in multitasking ability may benefit from this intervention.

Development and Implementation of Multiplex TaqMan Array Cards for Specimen Testing at Child Health and Mortality Prevention Surveillance Site Laboratories.

Child Health and Mortality Prevention Surveillance (CHAMPS) laboratories are employing a variety of laboratory methods to identify infectious agents contributing to deaths of children <5 years old and stillbirths in sub-Saharan Africa and South Asia. In support of this long-term objective, our team developed TaqMan Array Cards (TACs) for testing postmortem specimens (blood, cerebrospinal fluid, lung tissue, respiratory tract swabs, and rectal swabs) for >100 real-time polymerase chain reaction (PCR) targets in total (30-45 per card depending on configuration). Multipathogen panels were configured by syndrome and customized to include pathogens of significance in young children within the regions where CHAMPS is conducted, including bacteria (57 targets covering 30 genera), viruses (48 targets covering 40 viruses), parasites (8 targets covering 8 organisms), and fungi (3 targets covering 3 organisms). The development and application of multiplex real-time PCR reactions to the TAC microfluidic platform increased the number of targets in each panel while maintaining assay efficiency and replicates for heightened sensitivity. These advances represent a substantial improvement in the utility of this technology for infectious disease diagnostics and surveillance. We optimized all aspects of the CHAMPS molecular laboratory testing workflow including nucleic acid extraction, quality assurance, and data management to ensure comprehensive molecular testing of specimens and high-quality data. Here we describe the development and implementation of multiplex TACs and associated laboratory protocols for specimen processing, testing, and data management at CHAMPS site laboratories.

Overview and Development of the Child Health and Mortality Prevention Surveillance Determination of Cause of Death (DeCoDe) Process and DeCoDe Diagnosis Standards.

Mortality surveillance and cause of death data are instrumental in improving health, identifying diseases and conditions that cause a high burden of preventable deaths, and allocating resources to prevent these deaths. The Child Health and Mortality Prevention Surveillance (CHAMPS) network uses a standardized process to define, assign, and code causes of stillbirth and child death (<5 years of age) across the CHAMPS network. A Determination of Cause of Death (DeCoDe) panel composed of experts from a local CHAMPS site analyzes all available individual information, including laboratory, histopathology, abstracted clinical records, and verbal autopsy findings for each case and, if applicable, also for the mother. Using this information, the site panel ascertains the underlying cause (event that precipitated the fatal sequence of events) and other antecedent, immediate, and maternal causes of death in accordance with the International Classification of Diseases, Tenth Revision and the World Health Organization death certificate. Development and use of the CHAMPS diagnosis standards-a framework of required evidence to support cause of death determination-assures a homogenized procedure leading to a more consistent interpretation of complex data across the CHAMPS network. This and other standardizations ensures future comparability with other sources of mortality data produced externally to this project. Early lessons learned from implementation of DeCoDe in 5 CHAMPS sites in sub-Saharan Africa and Bangladesh have been incorporated into the DeCoDe process, and the implementation of DeCoDe has the potential to spur health systems improvements and local public health action.

Mortality Surveillance Methods to Identify and Characterize Deaths in Child Health and Mortality Prevention Surveillance Network Sites.

Despite reductions over the past 2 decades, childhood mortality remains high in low- and middle-income countries in sub-Saharan Africa and South Asia. In these settings, children often die at home, without contact with the health system, and are neither accounted for, nor attributed with a cause of death. In addition, when cause of death determinations occur, they often use nonspecific methods. Consequently, findings from models currently utilized to build national and global estimates of causes of death are associated with substantial uncertainty. Higher-quality data would enable stakeholders to effectively target interventions for the leading causes of childhood mortality, a critical component to achieving the Sustainable Development Goals by eliminating preventable perinatal and childhood deaths. The Child Health and Mortality Prevention Surveillance (CHAMPS) Network tracks the causes of under-5 mortality and stillbirths at sites in sub-Saharan Africa and South Asia through comprehensive mortality surveillance, utilizing minimally invasive tissue sampling (MITS), postmortem laboratory and pathology testing, verbal autopsy, and clinical and demographic data. CHAMPS sites have established facility- and community-based mortality notification systems, which aim to report potentially eligible deaths, defined as under-5 deaths and stillbirths within a defined catchment area, within 24-36 hours so that MITS can be conducted quickly after death. Where MITS has been conducted, a final cause of death is determined by an expert review panel. Data on cause of death will be provided to local, national, and global stakeholders to inform strategies to reduce perinatal and childhood mortality in sub-Saharan Africa and South Asia.

Perfusion Scintigraphy in Diagnosis and Management of Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of acute pulmonary embolism (PE). Because the treatment of CTEPH is markedly different from that of other types of pulmonary hypertension, lung ventilation-perfusion (V/Q) scintigraphy is recommended for the workup of patients with unexplained pulmonary hypertension. Lung V/Q scintigraphy is superior to CT pulmonary angiography for detecting CTEPH. Perfusion defect findings of CTEPH can be different from those of acute PE. Familiarity with the patterns of perfusion defects seen during the initial workup of CTEPH and the expected posttreatment changes seen at follow-up imaging is essential for accurate interpretation of V/Q scintigraphy findings. ©RSNA, 2019.

Multisystem afflictions in former National Football League players.

BACKGROUND: The long-term health consequences of participation in American style football (ASF) are not well understood. METHODS: We conducted a retrospective cohort study of men who had played in the NFL after 1960. Participants were studied using a standardized self-administered questionnaire designed to determine both the exposure history to ASF and the prevalence of chronic pain, sleep apnea, cardiometabolic disease, and neurocognitive impairment. Logistic regression and negative binomial regression models were used to assess associations between age, ethnicity, body-mass index during professional football career, field position, and football career duration with individual and multiple afflictions. RESULTS: In this cohort of former NFL players (n = 3745), approximately one quarter of the eligible former players (27%) reported two or more medical afflictions (chronic pain, cardiometabolic disease, sleep apnea, or neurocognitive impairment). Career duration was significantly associated with an increase in the number of comorbidities. Age, race, and body-mass index were associated with all affliction categories, other than neurocognitive impairment, which was similarly prevalent in middle-aged players and older players. Earlier age when first playing the sport was protective against cardiometabolic affliction. CONCLUSIONS: Former NFL players report significant combinations of cross-system afflictions. Future work will be required to determine mechanistic underpinnings. However, attention to the whole player, rather than specific organ systems seems critical to improve long-term health outcomes in former ASF professional athletes.

Orthodontic referral management systems: Do they make a difference?

AIMS: To assess the performance of the referral management system (RMS) compared to a previous paper-based referral system and to determine whether referrals reflected the patients' malocclusion and met current guidelines. DESIGN: Three-cycle audit. SETTING: Orthodontic Department, Liverpool University Dental Hospital, UK. PARTICIPANTS: Consecutive new orthodontic patient referrals. METHODS: Data were collected prospectively from orthodontic referral letters and new patient clinic proformas (2016-2017). Cycle 1 assessed the original paper-based referral form, Cycle 2 assessed the first RMS online form and Cycle 3 assessed a modified RMS form. RESULTS: Cycles 1, 2 and 3 audited 83, 84 and 81 referrals, respectively. Agreement between the reason for referral and the new patient clinic findings was moderate for Cycles 1 and 3 (Kappa = 0.47 and 0.60, respectively) and fair for Cycle 2 (Kappa = 0.40). In Cycles 1, 2 and 3, the proportion of new patients appropriate for hospital orthodontic care reduced from 52% to 51% and 40%, respectively. None of the three cycles reached the 90% target for compliance with current referral guidelines. CONCLUSIONS: Cycle 3's RMS form gave a truer reflection of the patients' malocclusion but reduced the proportion of appropriate referrals. Further audit is required in this area to investigate the cost-effectiveness and clinical benefits of the RMS.

Fibrinogen and the prediction of residual obstruction manifested after pulmonary embolism treatment.

Residual pulmonary vascular obstruction (RPVO) and chronic thromboembolic pulmonary hypertension (CTEPH) are both long-term complications of acute pulmonary embolism, but it is unknown whether RPVO can be predicted by variants of fibrinogen associated with CTEPH.We used the Akaike information criterion to select the best predictive models for RPVO in two prospectively followed cohorts of acute pulmonary embolism patients, using as candidate variables the extent of the initial obstruction, clinical characteristics and fibrinogen-related data. We measured the selected models' goodness of fit by analysis of deviance and compared models using the Chi-squared test.RPVO occurred in 29 (28.4%) out of 102 subjects in the first cohort and 46 (25.3%) out of 182 subjects in the second. The best-fit predictive model derived in the first cohort (p=0.0002) and validated in the second cohort (p=0.0005) implicated fibrinogen Bß-chain monosialylation in the development of RPVO. When the derivation procedure excluded clinical characteristics, fibrinogen Bß-chain monosialylation remained a predictor of RPVO in the best-fit predictive model (p=0.00003). Excluding fibrinogen characteristics worsened the predictive model (p=0.03).Fibrinogen Bß-chain monosialylation, a common structural attribute of fibrin, helped predict RPVO after acute pulmonary embolism. Fibrin structure may contribute to the risk of developing RPVO.

Feasibility of Aerobic Exercise in the Subacute Phase of Recovery From Traumatic Brain Injury: A Case Series.

BACKGROUND AND PURPOSE: Aerobic exercise is as important for individuals with traumatic brain injury (TBI) as for the general population; however, the approach to aerobic training may require some adaptation. The objective of the trial program was to examine the feasibility of introducing aerobic physical exercise programs into the subacute phase of multidisciplinary rehabilitation from moderate to severe TBI, which includes computerized cognitive training. CASE DESCRIPTION: Five individuals undergoing inpatient rehabilitation with moderate or severe TBIs who also have concomitant physical injuries. All of these individuals were in the subacute phase of recovery from TBIs. INTERVENTION: An 8-week progressive aerobic physical exercise program. Participants were monitored to ensure that they could both adhere to and tolerate the exercise program. In addition to the physical exercise, individuals were undergoing their standard rehabilitation procedures that included cognitive training. Neuropsychological testing was performed to gain an understanding of each individual's cognitive function. OUTCOMES: Participants adhered to both aerobic exercise and cognitive training. Poor correlations were noted between heart rate reserve and ratings of perceived effort. Two minor adverse events were reported. DISCUSSION: Despite concomitant physical injuries and cognitive impairments, progressive aerobic exercise programs seem feasible and well tolerated in subacute rehabilitation from moderate to severe TBI. Findings highlight the difficulty in measuring exercise intensity in this population.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A235).

Removal of an apex predator initiates a trophic cascade that extends from herbivores to vegetation and the soil nutrient pool.

It is widely assumed that organisms at low trophic levels, particularly microbes and plants, are essential to basic services in ecosystems, such as nutrient cycling. In theory, apex predators' effects on ecosystems could extend to nutrient cycling and the soil nutrient pool by influencing the intensity and spatial organization of herbivory. Here, we take advantage of a long-term manipulation of dingo abundance across Australia's dingo-proof fence in the Strzelecki Desert to investigate the effects that removal of an apex predator has on herbivore abundance, vegetation and the soil nutrient pool. Results showed that kangaroos were more abundant where dingoes were rare, and effects of kangaroo exclusion on vegetation, and total carbon, total nitrogen and available phosphorus in the soil were marked where dingoes were rare, but negligible where dingoes were common. By showing that a trophic cascade resulting from an apex predator's lethal effects on herbivores extends to the soil nutrient pool, we demonstrate a hitherto unappreciated pathway via which predators can influence nutrient dynamics. A key implication of our study is the vast spatial scale across which apex predators' effects on herbivore populations operate and, in turn, effects on the soil nutrient pool and ecosystem productivity could become manifest.

A Community-Based Participatory Research Intervention to Promote Physical Activity Among Rural Children: Theory and Design.

The overall objective of Project SHAPE (Shaping Health using Activity Photovoice and E-Video) was to improve physical activity levels of rural, medically underserved children by designing and implementing a culturally relevant physical activity intervention. This objective was met by using a community-based participatory research approach to design and implement an intervention that would positively affect the psychosocial constructs related to increasing physical activity, which, in turn, would lead to increases in the time spent in daily physical activity. This article describes the unique design of the intervention including its theoretical framework, its interrelated components, and the logistics involved.

The effect of Me2SO overexposure during cryopreservation on HOS TE85 and hMSC viability, growth and quality.

With the cell therapy industry continuing to grow, the ability to preserve clinical grade cells, including mesenchymal stem cells (MSCs), whilst retaining cell viability and function remains critical for the generation of off-the-shelf therapies. Cryopreservation of MSCs, using slow freezing, is an established process at lab scale. However, the cytotoxicity of cryoprotectants, like Me2SO, raises questions about the impact of prolonged cell exposure to cryoprotectant at temperatures >0 °C during processing of large cell batches for allogenic therapies prior to rapid cooling in a controlled rate freezer or in the clinic prior to administration. Here we show that exposure of human bone marrow derived MSCs to Me2SO for ≥1 h before freezing, or after thawing, degrades membrane integrity, short-term cell attachment efficiency and alters cell immunophenotype. After 2 h's exposure to Me2SO at 37 °C post-thaw, membrane integrity dropped to ∼70% and only ∼50% of cells retained the ability to adhere to tissue culture plastic. Furthermore, only 70% of the recovered MSCs retained an immunophenotype consistent with the ISCT minimal criteria after exposure. We also saw a similar loss of membrane integrity and attachment efficiency after exposing osteoblast (HOS TE85) cells to Me2SO before, and after, cryopreservation. Overall, these results show that freezing medium exposure is a critical determinant of product quality as process scale increases. Defining and reporting cell sensitivity to freezing medium exposure, both before and after cryopreservation, enables a fair judgement of how scalable a particular cryopreservation process can be, and consequently whether the therapy has commercial feasibility.