Respiratory syncytial virus prophylaxis in cystic fibrosis: the Canadian registry of palivizumab data (2005–2016)

Respiratory syncytial virus (RSV) may cause severe illness in cystic fibrosis (CF) children, but recommendations vary on prophylaxis. CARESS is a prospective registry of children who received palivizumab in 32 Canadian sites from 2005 to 2016. Demographic data were collected at enrollment and respiratory illness-related events recorded monthly. We reviewed respiratory illness hospitalization (RIH) and RSV hospitalization (RSVH) in CF children aged <?24 months versus those prophylaxed for standard indications (SI; prematurity, chronic lung disease [CLD] and congenital heart disease [CHD]), and complex medical disorders (CM). Of 23,228 children analyzed, 19,452 (83.8%) were SI, 3349 (14.4%) were CM, and 427 (1.8%) were CF. CF children were more likely to be Caucasian, heavier at birth and enrollment, and less likely to have a sibling or live in crowded conditions. CF children were similar to the other groups in daycare attendance, history of atopy, and exposure to smoking. RIH incidences were 4.3% (premature), 13.8% CLD, 11.5% CHD, 11.7% CM, and 6.8% CF. RSVH incidence in CF children was similar to that in the SI and CM groups: 1.1, 1.5, and 2.0% groups respectively. Cox regression analyses showed that compared to CF children, the HRs for RSVH in SI (HR 2.0 95% CI 0.5–8.3, p?=?0.3) and CM (HR 2.4, 95% CI 0.6–9.8, p?=?0.2) did not differ. CF children are equally at risk for RSVH relative to those prophylaxed for other indications. Pending robust evidence from prospective trials, palivizumab could perhaps be considered in the interim, for young CF patients born early during the RSV season with evidence of serious lung disease.     

Activity and Capacity Profile of Transplant Physicians and Centers in Australia and New Zealand

We conducted a study to analyze and report on indicators of hematopoietic cell transplant (HCT) physician time use and HCT center output measures. HCT centers in Australia and New Zealand (A&NZ) were invited to provide demographic and time use details for physicians participating in HCT patient care (HCT physicians). Resource details for adult and pediatric centers were included. From a total of 46 centers that were invited to participate, completed data were received from 37 centers (80%) representing 185 HCT physicians, with a median age of 48 (range, 33 to 72), of whom 31% were women. Just over half of HCT physicians cited prior work experience in large overseas HCT centers (97, 52%) and over one-third (79, 43%) possessed postgraduate qualifications other than specialist training. Total annual mean HCTs per HCT physician full-time equivalent (FTE) were 14.2 for centers performing both allogeneic and autologous HCT, 6.6 for autologous only centers, and 10.6 for all centers. For all HCT physicians surveyed the mean proportion of time spent on HCT related tasks was 31.7%. In A&NZ, for centers that perform both allografts and autografts, there was a mean of 4.0 allogeneic HCT annually per HCT bed, compared with 2.6 for the United States and 7.1 allogeneic HCT annually per HCT physician FTE (United States, 6.3). Projections of the A&NZ HCT physician workforce indicated that the numbers of HCT physicians are likely to stay within the region of 170 to 190 for the next 10 years, whereas HCT activity will likely continue to climb steadily. Healthcare and government authorities should be prepared to enable and support greater HCT activity in A&NZ in the future.     

Consequences,conditions and caveats: a qualitative exploration of the influence of undergraduate health professions students at distributed clinical training sites

Background

Traditionally, the clinical training of health professionals has been located in central academic hospitals. This is changing. As academic institutions explore ways to produce a health workforce that meets the needs of both the health system and the communities it serves, the placement of students in these communities is becoming increasingly common. While there is a growing literature on the student experience at such distributed sites, we know less about how the presence of students influences the site itself. We therefore set out to elicit insights from key role-players at a number of distributed health service-based training sites about the contribution that students make and the influence their presence has on that site.

Methods

This interpretivist study analysed qualitative data generated during twenty-four semi-structured interviews with facility managers, clinical supervisors and other clinicians working at eight distributed sites. A sampling grid was used to select sites that proportionally represented location, level of care and mix of health professions students. Transcribed data were subjected to thematic analysis. Following an iterative process, initial analyses and code lists were discussed and compared between team members after which the data were coded systematically across the entire data set.

Results

The clustering and categorising of codes led to the generation of three over-arching themes: influence on the facility (culturally and materially); on patient care and community (contribution to service; improved patient outcomes); and on supervisors (enriched work experience, attitude towards teaching role). A subsequent stratified analysis of emergent events identified some consequences of taking clinical training to distributed sites. These consequences occurred when certain conditions were present. Further critical reflection pointed to a set of caveats that modulated the nature of these conditions, emphasising the complexity inherent in this context.

Conclusions

The move towards training health professions students at distributed sites potentially offers many affordances for the facilities where the training takes places, for those responsible for student supervision, and for the patients and communities that these facilities serve. In establishing and maintaining relationships with the facilities, academic institutions will need to be mindful of the conditions and caveats that can influence these affordances.

     

Droplet fragmentation: 3D imaging of a previously unidentified pore-scale process during multiphase flow in porous media

Using X-ray computed microtomography, we have visualized and quantified the in situ structure of a trapped nonwetting phase (oil) in a highly heterogeneous carbonate rock after injecting a wetting phase (brine) at low and high capillary numbers. We imaged the process of capillary desaturation in 3D and demonstrated its impacts on the trapped nonwetting phase cluster size distribution. We have identified a previously unidentified pore-scale event during capillary desaturation. This pore-scale event, described as droplet fragmentation of the nonwetting phase, occurs in larger pores. It increases volumetric production of the nonwetting phase after capillary trapping and enlarges the fluid−fluid interface, which can enhance mass transfer between the phases. Droplet fragmentation therefore has implications for a range of multiphase flow processes in natural and engineered porous media with complex heterogeneous pore spaces.Multiphase fluid displacement processes in porous media are important for a broad range of natural and engineering applications such as transport of nonaqueous phase liquid contaminants in aquifers, oil and gas production from hydrocarbon reservoirs, subsurface CO₂ storage, or gas transport in fuel cells. Herein, capillary trapping is a fundamental mechanism that causes immobilization of a portion of the resident nonwetting phase when it is displaced by an invading wetting phase. As a result, production of the nonwetting phase is always less than 100%.The pore-scale physics of capillary trapping are broadly understood, as the underlying mechanisms such as piston-like displacement, snap-off and film development have been observed in physical micromodel experiments and quantitative theories have been established for them (1–4). The conventional view considers such pore-scale processes to occur between multiple pores, i.e., they are interpore processes and the pores are defined as volumes connected by narrower pore throats. By contrast, intrapore processes, as presented in this paper, are not well established in the literature. During drainage (i.e., where a nonwetting phase displaces the wetting phase), the wetting phase can establish films in the corners of the pores, which results in its continuous production and hence low residual saturations of the wetting phase. During imbibition (i.e., where the wetting phase displaces a nonwetting phase), swelling of the corner wetting films causes snap-off of the nonwetting phase, which results in capillary trapping of the nonwetting phase. The trapped nonwetting phase exists as disconnected ganglia within the pore network. Numerical pore network models have been developed to include these pore-level mechanisms with the aim of predicting the macroscopic flow properties of porous materials such as the structure of the phase distributions, residual saturation, relative permeability functions, and capillary pressure curves. Some of these models, referred to as quasi-static models, assume that fluid flow is only governed by capillary forces (5–8), and hence are limited in capturing the dynamics of fluid displacements that occur under the action of both capillary and viscous forces. In another class of pore network models, referred to as dynamic models (9–11), capillary and viscous forces are considered simultaneously. Such models are more applicable in modeling the dynamics of pore-scale events controlled by both capillary and viscous forces.The saturation distribution of two immiscible fluid phases in a porous medium is influenced by the wettability of the system, i.e., the distribution of surfaces that are preferentially water wet or preferentially wetting to a nonaqueous phase such as oil (12). It is known that a trapped nonwetting phase can be remobilized and recovered when the wetting phase is injected at capillary numbers N_c that exceed a critical level. N_c is a dimensionless ratio quantifying the relative importance of viscous to capillary forces, i.e., N_c = vµ/σ where v is the apparent velocity, µ is the viscosity of the invading phase, and σ is the interfacial tension (13). For homogeneous sandstones, remobilization typically occurs at N_c of the order of 10⁻⁵, an effect known as capillary desaturation (14).Recent advances in X-ray computed microtomography (µCT) methods have enabled the visualization and quantitative analysis of the static distribution of fluid phases, fluid rock interactions, and the structure of wetting and nonwetting phases in porous materials (8, 15). A particular focus has been on capillary trapping (16–20). Using synchrotron X-ray μCT facilities, it has also become possible to visualize dynamic pore-scale mechanisms, including snap-off and Haines jumps (21). Most of these imaging studies have focused on relatively homogeneous pore systems such as bead packs (22), sand packs (22–26), and sandstones (8, 18, 21, 23), but less attention has been paid to carbonate rocks. However, more than 50% of the world’s remaining oil reserves are located in carbonate reservoirs (27), and carbonate aquifers supply water wholly or partially to one quarter of the global population (28). Carbonates rocks can have complex multiscale pore structures, which render the application of X-ray µCT more challenging because of the need to select a representative sample that is small enough to achieve high resolutions on µCT images but that also captures the essential heterogeneities of the pore structure (29, 30).In this contribution, we use X-ray µCT to quantify the structure and distribution of a nonwetting phase (oil) after drainage and after its displacement by a wetting phase (brine) at low and high capillary numbers in a heterogeneous carbonate with multiple pore scales. Using image analysis, we demonstrate the effect of capillary desaturation on the cluster size distribution of the trapped oil phase. We identify a previously unidentified pore-scale event, which we refer to as droplet fragmentation. Droplet fragmentation is responsible for further production of the oil phase beyond capillary trapping. This fragmentation process occurs mainly in larger pores. It results in the production of additional oil from these large pores, contributes to a change in the structure of residual oil, and increases the oil−brine surface area. As a consequence, the trapped phase may subsequently be more difficult to mobilize after droplet fragmentation has occurred but mass transfer between the phases can increase.     

Seasonal fluxes of carbonyl sulfide in a midlatitude forest

Carbonyl sulfide (OCS), the most abundant sulfur gas in the atmosphere, has a summer minimum associated with uptake by vegetation and soils, closely correlated with CO₂. We report the first direct measurements to our knowledge of the ecosystem flux of OCS throughout an annual cycle, at a mixed temperate forest. The forest took up OCS during most of the growing season with an overall uptake of 1.36 ± 0.01 mol OCS per ha (43.5 ± 0.5 g S per ha, 95% confidence intervals) for the year. Daytime fluxes accounted for 72% of total uptake. Both soils and incompletely closed stomata in the canopy contributed to nighttime fluxes. Unexpected net OCS emission occurred during the warmest weeks in summer. Many requirements necessary to use fluxes of OCS as a simple estimate of photosynthesis were not met because OCS fluxes did not have a constant relationship with photosynthesis throughout an entire day or over the entire year. However, OCS fluxes provide a direct measure of ecosystem-scale stomatal conductance and mesophyll function, without relying on measures of soil evaporation or leaf temperature, and reveal previously unseen heterogeneity of forest canopy processes. Observations of OCS flux provide powerful, independent means to test and refine land surface and carbon cycle models at the ecosystem scale.Carbonyl sulfide (OCS) is the most abundant sulfur gas in the atmosphere (1), and biogeochemical cycling of OCS affects both the stratosphere and the troposphere. The tropospheric OCS mixing ratio is between 300 and 550 parts per trillion (ppt) (1) (10⁻¹² mol OCS per mol dry air), decreasing sharply with altitude in the stratosphere (2). In times of low volcanic activity, the sulfur budget and aerosol loading of the stratosphere are largely controlled by transport and photooxidation of OCS from the troposphere (3). The processes regulating emission and uptake of OCS are thus important factors in determining how changes in climate and land cover may affect the stratospheric sulfate layer.Oceans are the dominant source of atmospheric OCS (4), with smaller emissions from anthropogenic and terrestrial sources, such as wetlands and anoxic soils (e.g., refs. 5 and 6) and oxic soils during times of heat or drought stress (e.g., refs. 7 and 8). The terrestrial biosphere is the largest sink for OCS (1, 4, 9, 10) with uptake by both oxic soils (e.g., ref. 11) and vegetation (e.g., ref. 9). Once OCS molecules pass through the stomata of leaves, the uptake rate of OCS is controlled by reaction with carbonic anhydrase (CA) within the mesophyll, to produce H₂S and CO₂. CA is the same enzyme that hydrolyzes carbon dioxide (CO₂) in the first chemical step of photosynthesis (12).Studies considering the large-scale atmospheric variability of OCS have linked OCS fluxes and the photosynthetic uptake of CO₂ for regional and global scales (1, 4, 13). Leaf-scale studies have confirmed the OCS link to photosynthesis (14, 15). Initial OCS ecosystem flux estimations were made using flask sampling followed by analysis via gas chromatography–mass spectrometry (GC-MS) (13, 16), but these studies did not have sufficient resolution to examine daily or hourly controls on the OCS flux. Laser spectrometers have been developed (17, 18) to enable direct, in situ measurement of OCS fluxes by eddy covariance, and measurements of OCS ecosystem fluxes have been reported, for periods of up to a few weeks, above arid forests (19) and an agricultural field (8, 20).Net carbon exchange in terrestrial ecosystems [net ecosystem exchange (NEE)] can be measured by eddy flux methods. NEE may be regarded as the sum of two gross fluxes: gross ecosystem productivity (GEP) and ecosystem respiration (R_eco). GEP is the light-dependent part of NEE, estimated by subtracting daytime ecosystem respiration (R_eco), computed by extrapolation of the temperature dependence of nighttime NEE (NEE – R_eco = GEP) (e.g., refs. 21–24). At night, NEE includes all autotrophic and heterotrophic respiration processes. During the day, GEP approximates the carboxylation rate minus photorespiration at the ecosystem scale (25). Extrapolation of nighttime R_eco introduces major uncertainty in the interpretation of GEP, which could be reduced, and the ecological significance of GEP increased, by developing independent methods of measuring rates of photosynthetic processes. As shown below, fluxes of OCS give more direct information on one of the major controls on GEP, stomatal conductance, rather than GEP itself, providing a powerful means for testing and improving ecosystem models and for scaling up leaf-level processes to the whole ecosystem.Here we describe the factors controlling the hourly, daily, seasonal, and total fluxes of OCS in a forest ecosystem, using a year (2011) of high-frequency, direct measurements at Harvard Forest, MA. We report the seasonal cycle, the response to environmental conditions, and the total deposition flux of OCS throughout the year 2011. We compare these fluxes to corresponding measurements of CO₂ flux and to simulations using the Simple Biosphere model (SiB3).     

In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging

Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer’s dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-β] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.The consensus statement on concussions from the Fourth International Conference on Concussion in Sports (Zurich 2012) (1) defines acute mild traumatic brain injury (mTBI) or cerebral concussion as a brain injury with a complex pathophysiological process induced by biomechanical forces. Cerebral concussion causes white matter axonal injury due to axonal shearing and stretching (2), typically resulting in the rapid onset of short-lived impairment of neurological function that resolves spontaneously and largely reflects a functional disturbance rather than a structural injury. As such, no abnormality is seen on standard structural neuroimaging determinations (1).A number of early literature reports described a neurodegenerative disease associated with a history of repetitive TBI in retired professional boxers (3, 4), with a prevalence rate of up to 47% among retired professional boxers aged 50 y and older who boxed for more than 10 y (5). Initially named “punch drunk syndrome” (3) and dementia pugilistica (4), this syndrome is now known as chronic traumatic encephalopathy (CTE) in the current literature (6, 7).Compelling autopsy evidence (6–8) and neurobehavioral determinations (9) of retired professional American football athletes indicate that a subgroup develops neurodegenerative and clinical changes typical of CTE, a progressive syndrome distinctively different from Alzheimer’s disease (AD), which is the most common form of dementia in the elderly (10). The connection between multiple concussions and subconcussive head impacts (2) and CTE is compelling, because history of repetitive concussions is the strongest risk factor for development of CTE in numerous contact sports (e.g., American football, rugby, boxing, ice hockey, soccer, and professional wrestling), in war veterans with a history of blast or blunt force TBI, and in conditions where trauma to the head occurs for various reasons (e.g., falls during seizures, head-banging in autistic children, motor vehicle and domestic accidents, domestic violence and abuse) (6, 8, 11–14). As with most neurodegenerative diseases, clinical diagnosis remains elusive due to the lack of specificity of CTE clinical symptomatology criteria, and histopathological examination of brain at autopsy is the most definitive diagnostic modality (6, 8, 11).The novel imaging approaches leading to the in vivo characterization of CTE brain neuropathology premortem (e.g., PET) are complementary to structural imaging modalities [e.g., diffusion tensor imaging MRI (DTI MRI)] and offer a specific and sensitive strategy to facilitate diagnosis of CTE. Neuronal and glial fibrillar hyperphosphorylated microtubule-associated protein tau deposits composed of paired helical filament (PHF)-tau are the primary brain proteinopathy of CTE based on autopsy determinations, and their 3R/4R tau isoform ratio is similar to that of AD (11). Their topographically predictable pattern of distribution was used as a basis for a severity staging system of CTE neuropathology (7), ranging from mild (neuropathology stages I and II) to advanced (neuropathology stages III and IV) (7) (Tables S1 and S2). In addition, more than 80% of analyzed pathologically confirmed CTE cases also show transactive response (TAR) DNA-binding protein of ∼43 kDa (TDP-43) either as inclusions in sparse neurites in cortex, medial temporal lobe structures, and brainstem in CTE neuropathology stages I–III, as widespread neuronal and glial inclusions in severe CTE cases (neuropathology stage IV), or in CTE cases with motor neuron disease (7, 15) (Tables S1 and S2). CTE cases also can exhibit the presence of other fibrillar protein aggregates. McKee et al. (7) and Omalu et al. (8) reported that in autopsy determinations, less than half of all CTE cases and less than one third of “pure” CTE cases show amyloid-β (Aβ) deposits, predominantly as scattered cortical diffuse plaques in low density (Tables S1 and S2). Of note is that subjects with Aβ deposits were significantly older than those without. Moreover, their neuropathology was more severe than that in cases without Aβ deposits and was often combined with α-synuclein deposits (7). As an example, as reported by McKee et al. (7), of 30 CTE cases with at least some cortical Aβ deposits (of 68 confirmed CTE cases), 29 brains were from subjects who died in their seventh decade of life and one from a subject who died in his sixth decade.Subsequent to our preliminary report (16), in this work we use [F-18]FDDNP, an imaging agent for fibrillar insoluble protein aggregates (16–20), and PET imaging with the aim of establishing (i) topographic brain localization of [F-18]FDDNP PET signals indicative of fibrillar neuroaggregates in retired professional American football players with suspected CTE (mTBI group) vs. controls (CTRL); (ii) determination of [F-18]FDDNP PET signal patterns in the mTBI group; (iii) presence of [F-18]FDDNP PET signal as a measure of neuropathology in the brain areas involved in mood disorders related neurocircuits; (iv) correlation of [F-18]FDDNP PET results with neuropathology distributions in confirmed CTE cases; (v) differential patterns of [F-18]FDDNP PET signals, and thus deposition of fibrillar neuroaggregates, in the mTBI group with respect to the AD group; and (vi) preliminary demonstration of differences in [F-18]FDDNP PET signal patterns in mTBI cases with different etiology, i.e., contact-sport–related mTBI in retired professional American football players vs. blast-induced mTBI in war veterans. We further intended to demonstrate that tau (vs. Aβ) specificity of high affinity PET molecular imaging probes may not be a necessary requirement when used in CTE subjects with primary proteinopathy in the form of PHF-tau (8): PET imaging probes potentially sensitive to TDP-43 aggregates and Aβ deposits, which are present in higher densities almost exclusively in older CTE cases with more advanced neuropathology (e.g., stage IV), could better define disease progression based on quantification of differences in regional loads of combined neuropathologies because additional neuropathologies appear in predictable topographical and temporal patterns.     

Defects in Mitochondrial Efficiency and H2O2 Emissions in Obese Women Are Restored to a Lean Phenotype With Aerobic Exercise Training

The notion that mitochondria contribute to obesity-induced insulin resistance is highly debated. Therefore, we determined whether obese (BMI 33 kg/m²), insulin-resistant women with polycystic ovary syndrome had aberrant skeletal muscle mitochondrial physiology compared with lean, insulin-sensitive women (BMI 23 kg/m²). Maximal whole-body and mitochondrial oxygen consumption were not different between obese and lean women. However, obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H₂O₂ (mtH₂O₂) emissions compared with lean women. We further evaluated the impact of 12 weeks of aerobic exercise on obesity-related impairments in insulin sensitivity and mitochondrial energetics in the fasted state and after a high-fat mixed meal. Exercise training reversed obesity-related mitochondrial derangements as evidenced by enhanced mitochondrial bioenergetics efficiency and decreased mtH₂O₂ production. A concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity. mtH₂O₂ emissions were refractory to a high-fat meal at baseline, but after exercise, mtH₂O₂ emissions increased after the meal, which resembles previous findings in lean individuals. We demonstrate that obese women exhibit impaired mitochondrial bioenergetics in the form of decreased efficiency and impaired mtH₂O₂ emissions, while exercise effectively restores mitochondrial physiology toward that of lean, insulin-sensitive individuals.