Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial.

BACKGROUND: The first licensed malaria vaccine, RTS,S/AS01E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. METHODS: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01E regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291. FINDINGS: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01E regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1-1·6 infections (95% CI union 0·6-2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0·0053). INTERPRETATION: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. FUNDING: GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research.

BECC438b TLR4 agonist supports unique immune response profiles from nasal and muscular DTaP pertussis vaccines in murine challenge models.

The protection afforded by acellular pertussis vaccines wanes over time, and there is a need to develop improved vaccine formulations. Options to improve the vaccines involve the utilization of different adjuvants and administration via different routes. While intramuscular (IM) vaccination provides a robust systemic immune response, intranasal (IN) vaccination theoretically induces a localized immune response within the nasal cavity. In the case of a Bordetella pertussis infection, IN vaccination results in an immune response that is similar to natural infection, which provides the longest duration of protection. Current acellular formulations utilize an alum adjuvant, and antibody levels wane over time. To overcome the current limitations with the acellular vaccine, we incorporated a novel TLR4 agonist, BECC438b, into both IM and IN acellular formulations to determine its ability to protect against infection in a murine airway challenge model. Following immunization and challenge, we observed that DTaP + BECC438b reduced bacterial burden within the lung and trachea for both administration routes when compared with mock-vaccinated and challenged (MVC) mice. Interestingly, IN administration of DTaP + BECC438b induced a Th1-polarized immune response, while IM vaccination polarized toward a Th2 immune response. RNA sequencing analysis of the lung demonstrated that DTaP + BECC438b activates biological pathways similar to natural infection. Additionally, IN administration of DTaP + BECC438b activated the expression of genes involved in a multitude of pathways associated with the immune system. Overall, these data suggest that BECC438b adjuvant and the IN vaccination route can impact efficacy and responses of pertussis vaccines in pre-clinical mouse models.

Baseline malaria infection status and RTS,S/AS01E malaria vaccine efficacy.

Background: The only licensed malaria vaccine, RTS,S/AS01 E , confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy (VE). Methods: 1,500 children aged 5-17 months were randomized to receive four different RTS,S/AS01 E regimens or a rabies control vaccine in a phase 2b clinical trial in Ghana and Kenya. We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods in over 36K participant specimens. We performed a post hoc analysis of VE based on malaria infection status at first vaccination and force of infection. Results: We observed significant and comparable VE (25-43%, 95% CI union 9-53%) against first new infection for all four RTS,S/AS01 E regimens across both follow-up periods (12 and 20 months). Each RTS,S/AS01 E regimen significantly reduced the number of new infections in the 20-month follow-up period (control mean 4.1 vs. RTS,S/AS01 E mean 2.6-3.0). VE against first new infection was significantly higher in participants who were malaria-infected (68%; 95% CI, 50 to 80%) versus uninfected (37%; 95% CI, 23 to 48%) at the first vaccination (P=0.0053) and in participants experiencing greater force of infection between dose 1 and 3 (P=0.059). Conclusions: All tested dosing regimens blocked some infections to a similar degree. Improved VE in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. ( ClinicalTrials.gov number, NCT03276962 ).

Cheyne-stokes respiration in children with heart failure.

Cheyne-Stokes respiration (CSA-CSR) is a form of central sleep apnea characterized by alternating periods of hyperventilation and central apneas or hypopneas. CSA-CSR develops following a cardiac insult resulting in a compensatory increase in sympathetic activity, which in susceptible patients causes hyperventilation and destabilizes respiratory control. The physiological changes that occur in CSA-CSR include hyperventilation, a reduced blood gas buffering capacity, and circulatory delay. In adults, 25% to 50% of patients with heart failure are reported to have CSA-CSR. The development of CSA-CSR in this group of patients is considered a poor prognostic sign. The prevalence, progression, and treatment outcomes of CSA-CSR in children remain unclear with only 11 children being described in the literature. The lack of data is possibly not due to the paucity of children with severe heart failure and CSA-CSR but because they may be under-recognized, compounded by the absence of routine polysomnographic assessment of children with moderate to severe heart failure. Building on much broader experience in the diagnosis and management of CSA-CSR in adult sleep medicine and our limited experience in a pediatric quaternary center, this paper will discuss the prevalence of CSA-CSR, its' treatment options, outcomes in children, and the potential future direction for research in this understudied area of pediatric sleep medicine.

Multiplexed CRISPR-based microfluidic platform for clinical testing of respiratory viruses and identification of SARS-CoV-2 variants.

The coronavirus disease 2019 (COVID-19) pandemic has demonstrated a clear need for high-throughput, multiplexed and sensitive assays for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses and their emerging variants. Here, we present a cost-effective virus and variant detection platform, called microfluidic Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (mCARMEN), which combines CRISPR-based diagnostics and microfluidics with a streamlined workflow for clinical use. We developed the mCARMEN respiratory virus panel to test for up to 21 viruses, including SARS-CoV-2, other coronaviruses and both influenza strains, and demonstrated its diagnostic-grade performance on 525 patient specimens in an academic setting and 166 specimens in a clinical setting. We further developed an mCARMEN panel to enable the identification of 6 SARS-CoV-2 variant lineages, including Delta and Omicron, and evaluated it on 2,088 patient specimens with near-perfect concordance to sequencing-based variant classification. Lastly, we implemented a combined Cas13 and Cas12 approach that enables quantitative measurement of SARS-CoV-2 and influenza A viral copies in samples. The mCARMEN platform enables high-throughput surveillance of multiple viruses and variants simultaneously, enabling rapid detection of SARS-CoV-2 variants.

Transmission from vaccinated individuals in a large SARS-CoV-2 Delta variant outbreak.

An outbreak of over 1,000 COVID-19 cases in Provincetown, Massachusetts (MA), in July 2021-the first large outbreak mostly in vaccinated individuals in the US-prompted a comprehensive public health response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals. To address these questions, we combined viral genomic and epidemiological data from 467 individuals, including 40% of outbreak-associated cases. The Delta variant accounted for 99% of cases in this dataset; it was introduced from at least 40 sources, but 83% of cases derived from a single source, likely through transmission across multiple settings over a short time rather than a single event. Genomic and epidemiological data supported multiple transmissions of Delta from and between fully vaccinated individuals. However, despite its magnitude, the outbreak had limited onward impact in MA and the US overall, likely due to high vaccination rates and a robust public health response.

Somatic, psychological and economic benefits of regular physical activity beginning in childhood.

Physical activity is a natural part of a healthy life-style, which should be nurtured from early childhood. Regular physical activity mitigates against the global problems of overweight and obesity, hypertension, anxiety and depression. It lowers the morbidity and mortality from cardiovascular disease and provides hope for sustainable economics to support an ageing population into their retirement. This is preventative health economics that can be achieved with integrated support from families, communities, health-care professionals and governments at all levels. At present, children lack the support of those responsible for them at a societal level to adequately protect them from the physical and emotional consequences of reduced physical activity.

Evidence of transmission from fully vaccinated individuals in a large outbreak of the SARS-CoV-2 Delta variant in Provincetown, Massachusetts.

Multiple summer events, including large indoor gatherings, in Provincetown, Massachusetts (MA), in July 2021 contributed to an outbreak of over one thousand COVID-19 cases among residents and visitors. Most cases were fully vaccinated, many of whom were also symptomatic, prompting a comprehensive public health response, motivating changes to national masking recommendations, and raising questions about infection and transmission among vaccinated individuals. To characterize the outbreak and the viral population underlying it, we combined genomic and epidemiological data from 467 individuals, including 40% of known outbreak-associated cases. The Delta variant accounted for 99% of sequenced outbreak-associated cases. Phylogenetic analysis suggests over 40 sources of Delta in the dataset, with one responsible for a single cluster containing 83% of outbreak-associated genomes. This cluster was likely not the result of extensive spread at a single site, but rather transmission from a common source across multiple settings over a short time. Genomic and epidemiological data combined provide strong support for 25 transmission events from, including many between, fully vaccinated individuals; genomic data alone provides evidence for an additional 64. Together, genomic epidemiology provides a high-resolution picture of the Provincetown outbreak, revealing multiple cases of transmission of Delta from fully vaccinated individuals. However, despite its magnitude, the outbreak was restricted in its onward impact in MA and the US, likely due to high vaccination rates and a robust public health response.

Acid is a potential interferent in fluorescent sensing of chemical warfare agent vapors.

A common feature of fluorescent sensing materials for detecting chemical warfare agents (CWAs) and simulants is the presence of nitrogen-based groups designed to nucleophilically displace a phosphorus atom substituent, with the reaction causing a measurable fluorescence change. However, such groups are also basic and so sensitive to acid. In this study we show it is critical to disentangle the response of a candidate sensing material to acid and CWA simulant. We report that pyridyl-containing sensing materials designed to react with a CWA gave a strong and rapid increase in fluorescence when exposed to Sarin, which is known to contain hydrofluoric acid. However, when tested against acid-free diethylchlorophosphate and di-iso-propylfluorophosphate, simulants typically used for evaluating novel G-series CWA sensors, there was no change in the fluorescence. In contrast, simulants that had been stored or tested under a standard laboratory conditions all led to strong changes in fluorescence, due to acid impurities. Thus the results provide strong evidence that care needs to be taken when interpreting the results of fluorescence-based solid-state sensing studies of G-series CWAs and their simulants. There are also implications for the application of these pyridyl-based fluorescence and other nucleophilic/basic sensing systems to real-world CWA detection.

Daily stream samples reveal highly complex pesticide occurrence and potential toxicity to aquatic life.

Transient, acutely toxic concentrations of pesticides in streams can go undetected by fixed-interval sampling programs. Here we compare temporal patterns in occurrence of current-use pesticides in daily composite samples to those in weekly composite and weekly discrete samples of surface water from 14 small stream sites. Samples were collected over 10-14 weeks at 7 stream sites in each of the Midwestern and Southeastern United States. Samples were analyzed for over 200 pesticides and degradates by direct aqueous injection liquid chromatography with tandem mass spectrometry. Nearly 2 and 3 times as many unique pesticides were detected in daily samples as in weekly composite and weekly discrete samples, respectively. Based on exceedances of acute-invertebrate benchmarks (AIB) and(or) a Pesticide Toxicity Index (PTI) >1, potential acute-invertebrate toxicity was predicted at 11 of 14 sites from the results for daily composite samples, but was predicted for only 3 sites from weekly composites and for no sites from weekly discrete samples. Insecticides were responsible for most of the potential invertebrate toxicity, occurred transiently, and frequently were missed by the weekly discrete and composite samples. The number of days with benthic-invertebrate PTI ≥0.1 in daily composite samples was inversely related to Ephemeroptera, Plecoptera, and Trichoptera (EPT) richness at the sites. The results of the study indicate that short-term, potentially toxic peaks in pesticides frequently are missed by weekly discrete sampling, and that such peaks may contribute to degradation of invertebrate community condition in small streams. Weekly composite samples underestimated maximum concentrations and potential acute-invertebrate toxicity, but to a lesser degree than weekly discrete samples, and provided a reasonable approximation of the 90th percentile total concentrations of herbicides, insecticides, and fungicides, suggesting that weekly composite sampling may be a compromise between assessment needs and cost.

Challenges in Fluorescence Detection of Chemical Warfare Agent Vapors Using Solid-State Films.

Organophosphorus (OP)-based nerve agents are extremely toxic and potent acetylcholinesterase inhibitors and recent attacks involving nerve agents highlight the need for fast detection and intervention. Fluorescence-based detection, where the sensing material undergoes a chemical reaction with the agent causing a measurable change in the luminescence, is one method for sensing and identifying nerve agents. Most studies use the simulants diethylchlorophosphate and di-iso-propylfluorophosphate to evaluate the performance of sensors due to their reduced toxicity relative to OP nerve agents. While detection of nerve agent simulants in solution is relatively widely reported, there are fewer reports on vapor detection using solid-state sensors. Herein, progress in organic semiconductor sensing materials developed for solid-state detection of OP-based nerve agent vapors is reviewed. The effect of acid impurities arising from the hydrolysis of simulants and nerve agents on the efficacy and selectivity of the reported sensing materials is also discussed. Indeed, in some cases it is unclear whether it is the simulant that is detected or the acid hydrolysis products. Finally, it is highlighted that while analyte diffusion into the sensing film is critical in the design of fast, responsive sensing systems, it is an area that is currently not well studied.

Novel 3D geometry and models of the lower regions of large trees for use in carbon accounting of primary forests.

There is high uncertainty in the contribution of land-use change to anthropogenic climate change, especially pertaining to below-ground carbon loss resulting from conversion of primary-to-secondary forest. Soil organic carbon (SOC) and coarse roots are concentrated close to tree trunks, a region usually unmeasured during soil carbon sampling. Soil carbon estimates and their variation with land-use change have not been correspondingly adjusted. Our aim was to deduce allometric equations that will allow improvement of SOC estimates and tree trunk carbon estimates, for primary forest stands that include large trees in rugged terrain. Terrestrial digital photography, photogrammetry and GIS software were used to produce 3D models of the buttresses, roots and humus mounds of large trees in primary forests dominated by Eucalyptus regnans in Tasmania. Models of 29, in situ eucalypts were made and analysed. 3D models of example eucalypt roots, logging debris, rainforest tree species, fallen trees, branches, root and trunk slices, and soil profiles were also derived. Measurements in 2D, from earlier work, of three buttress 'logs' were added to the data set. The 3D models had high spatial resolution. The modelling allowed checking and correction of field measurements. Tree anatomical detail was formulated, such as buttress shape, humus volume, root volume in the under-sampled zone and trunk hollow area. The allometric relationships developed link diameter at breast height and ground slope, to SOC and tree trunk carbon, the latter including a correction for senescence. These formulae can be applied to stand-level carbon accounting. The formulae allow the typically measured, inter-tree SOC to be corrected for not sampling near large trees. The 3D models developed are irreplaceable, being for increasingly rare, large trees, and they could be useful to other scientific endeavours.

Real-time multiplexed digital cavity-enhanced spectroscopy.

Cavity-enhanced spectroscopy is a sensitive optical absorption technique but one where the practical applications have been limited to studying small wavelength ranges. This Letter shows that wideband operation can be achieved by combining techniques usually reserved for the communications community with that of cavity-enhanced spectroscopy, producing a multiplexed real-time cavity-enhanced spectrometer. We use multiple collinear laser sources operating asynchronously and simultaneously while being detected on a single photodetector. This is synonymous with radio frequency (RF) cellular systems in which signals are detected on a single antenna but decoded uniquely. Here, we demonstrate results with spectra of methyl salicylate and show parts-per-billion per root hertz sensitivity measured in real-time.

Diffusion capacity of carbon monoxide (DLCO) pre- and post-exercise in children in health and disease.

RATIONALE: A decrease in diffusion capacity for carbon monoxide (DLCO) after exercise has been reported in healthy adults. There is limited information for post-exercise DLCO available in children either in health or in disease. OBJECTIVES: To evaluate (1) reproducibility of DLCO measures in children, (2) differences in DLCO between elite athletic swimmers (AS), stable cystic fibrosis patients (CF), and healthy controls (Con) at rest; and (3) after a maximal treadmill exercise test. METHODS: Participants performed spirometry and DLCO at baseline, a maximal treadmill exercise test and repeated DLCO measures for 2 hr after cessation of exercise. RESULTS: The mean (SD) co-efficient of variation between baseline DLCO tests was 2.49% (1.86%). In girls, the mean baseline DLCO (ml/min/mmHg) was 18.61 (4.15) in CF, 22.32 (4.79) in controls and 27.18 (5.33) in AS. In boys: 23.68 (5.31) in CF, 28.09 (9.95) in controls and 37.75 (9.46) in AS. Baseline DLCO was significantly higher in AS than in CF patients (P < 0.01). In girls post-exercise, the greatest mean decrease in DLCO from baseline was -7.50% to -12.83% and in boys -6.92% to -17.71%. The decline in DLCO was less important in the athletes than the other groups (P < 0.05). CONCLUSIONS: DLCO is highly repeatable in children. AS have an increased DLCO at rest compared to both children with CF and controls. There is a decline from baseline to post-exercise DLCO and while there are disease-specific differences, the general pattern of change in DLCO measures after exercise is similar in children to adults.

Managing snoring and obstructive sleep apnoea in childhood.

Snoring assessment and its differentiation from obstructive sleep apnoea are difficult based upon a parent history and physical examination of the size of the tonsils. Not only is the presence of obstructive sleep apnoea important to diagnose, but confirming its severity is the key determinant in prioritising treatment in a resource-limited setting. This review provides current knowledge on the utility of common diagnostic tests, results of treatment options available and implications of treatment and unrecognised or untreated obstructive sleep apnoea.

Diffusion capacity in children: what happens with exercise?

There is comparatively little data on diffusion capacity in children during exercise. With the advent of improved technology, there is an increasing interest in exercise testing of children in order to predict the evolution of lung disease. In addition to the standard measure of exercise capacity, the VO(2max), interest is evolving in the consequences of alterations in diffusion capacity which may be unmasked with exercise. This review will consider what is known about diffusion capacity with exercise in children with well documented lung disease in the form of cystic fibrosis, healthy controls and swimmers as elite athletes with the largest lung volumes.

Can an athlete have too much ticker? Hypertrophic cardiomyopathy in young athletes.

Sudden cardiac death (SCD) is an uncommon but devastating potential consequence of participation in competitive sport. It is seen in adolescent and young adult athletes. The most common cause of this, hypertrophic cardiomyopathy (HCM), is a genetic disorder responsible for more than a third of cases and is manageable. Screening is undertaken for HCM, using differing strategies in Europe and North America. Screening and early diagnosis have reduced the mortality rate but has come at a significant economic cost. The evidence and relevant arguments for and against screening are presented together with management strategies as reflected by an illustrative case.