Intact tropical peatlands are dense long-term stores of carbon. However, the
future security of these ecosystems is at risk from land conversion and
extensive peatland drainage. This can enhance peat ...oxidation and convert
long-term carbon sinks into significant carbon sources. In Southeast Asia,
the largest land use on peatland is for oil palm plantation agriculture.
Here, we present the first annual estimate of exported fluvial organic carbon
in the drainage waters of four peatland oil palm plantation areas in Sarawak,
Malaysia. Total organic carbon (TOC) fluxes from the plantation second- and
third-order drains were dominated (91 %) by dissolved organic carbon
(DOC) and ranged from 34.4 ± 9.7 C m−2 yr−1 to 57.7 %,
16.3 g C m−2 yr−1 (± 95 % confidence interval). These
fluxes represent a single-year survey which was strongly influenced by an El
Ninõ event and therefore lower discharge than usual was observed. The
magnitude of the flux was found to be influenced by water table depth, with
higher TOC fluxes observed from more deeply drained sites. Radiocarbon dating
on the DOC component indicated the presence of old (pre-1950s) carbon in all
samples collected, with DOC at the most deeply drained site having a mean age
of 735 years. Overall, our estimates suggest fluvial TOC contributes
∼ 5 % of total carbon losses from oil palm plantations on peat.
Maintenance of high and stable water tables in oil palm plantations appears
to be key to minimising TOC losses. This reinforces the importance of
considering all carbon loss pathways, rather than just CO2 emissions
from the peat surface, in studies of tropical peatland land conversion.
Objective:Previous research has demonstrated that the amygdala is enlarged in children with autism spectrum disorder (ASD). However, the precise onset of this enlargement during infancy, how it ...relates to later diagnostic behaviors, whether the timing of enlargement in infancy is specific to the amygdala, and whether it is specific to ASD (or present in other neurodevelopmental disorders, such as fragile X syndrome) are all unknown.Methods:Longitudinal MRIs were acquired at 6–24 months of age in 29 infants with fragile X syndrome, 58 infants at high likelihood for ASD who were later diagnosed with ASD, 212 high-likelihood infants not diagnosed with ASD, and 109 control infants (1,099 total scans).Results:Infants who developed ASD had typically sized amygdala volumes at 6 months, but exhibited significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen’s d=0.56) compared with all other groups. Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the infants were diagnosed with ASD. Infants with fragile X syndrome had a persistent and significantly enlarged caudate volume at all ages between 6 and 24 months (d=2.12), compared with all other groups, which was significantly associated with greater repetitive behaviors.Conclusions:This is the first MRI study comparing fragile X syndrome and ASD in infancy, demonstrating strikingly different patterns of brain and behavior development. Fragile X syndrome–related changes were present from 6 months of age, whereas ASD-related changes unfolded over the first 2 years of life, starting with no detectable group differences at 6 months. Increased amygdala growth rate between 6 and 12 months occurs prior to social deficits and well before diagnosis. This gradual onset of brain and behavior changes in ASD, but not fragile X syndrome, suggests an age- and disorder-specific pattern of cascading brain changes preceding autism diagnosis.
Objective
CD28 and inducible T cell costimulator (ICOS) appear to have nonredundant roles in T cell activation and adaptive immunity. We undertook this study to characterize in vitro and in vivo the ...therapeutic potential of acazicolcept (ALPN‐101), an Fc fusion protein of a human variant ICOS ligand (ICOSL) domain designed to inhibit both CD28 and ICOS costimulation, in inflammatory arthritis.
Methods
Acazicolcept was compared in vitro with inhibitors of either the CD28 or ICOS pathways (abatacept and belatacept CTLA‐4Ig, prezalumab anti‐ICOSL monoclonal antibody) in receptor binding and signaling assays, and in a collagen‐induced arthritis (CIA) model. Acazicolcept was also compared in cytokine and gene expression assays of peripheral blood mononuclear cells (PBMCs) from healthy donors or rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients stimulated with artificial antigen‐presenting cells (APCs) expressing CD28 and ICOS ligands*.
Results
Acazicolcept bound CD28 and ICOS, prevented ligand binding, and inhibited human T cell functional interactions, matching or exceeding the activity of CD28 or ICOS costimulatory single‐pathway inhibitors tested individually or in combination. Acazicolcept administration significantly reduced disease in the CIA model and more potently than abatacept. Acazicolcept also inhibited proinflammatory cytokine production from stimulated PBMCs in cocultures with artificial APCs and demonstrated unique effects on gene expression distinct from those induced by abatacept, prezalumab, or a combination of both.
Conclusion
Both CD28 and ICOS signaling play critical roles in inflammatory arthritis. Therapeutic agents such as acazicolcept that coinhibit both ICOS and CD28 signaling may mitigate inflammation and/or disease progression in RA and PsA more effectively than inhibitors of either pathway alone.
Lower respiratory tract infections are frequently treated with antibiotics, despite a viral cause in many cases. It remains unknown whether low procalcitonin concentrations can identify patients with ...lower respiratory tract infection who are unlikely to benefit from antibiotics. We aimed to compare the efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections in patients with low procalcitonin.
We conducted a randomised, placebo-controlled, double-blind, non-inferiority trial at five health centres in the USA. Adults aged 18 years or older with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 h to 28 days were eligible for enrolment. Participants with a procalcitonin concentration of 0·25 ng/mL or less were randomly assigned (1:1), in blocks of four with stratification by site, to receive over-encapsulated oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). Participants, non-study clinical providers, investigators, and study coordinators were masked to treatment allocation. The primary outcome was efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 in the intention-to-treat population. The non-inferiority margin was –12·5%. Solicited adverse events (abdominal pain, vomiting, diarrhoea, allergic reaction, or yeast infections) were recorded as a secondary outcome. This trial is registered with ClinicalTrials.gov, NCT03341273.
Between Dec 8, 2017, and March 9, 2020, 691 patients were assessed for eligibility and 499 were enrolled and randomly assigned to receive azithromycin (n=249) or placebo (n=250). Clinical improvement at day 5 was observed in 148 (63%, 95% CI 54 to 71) of 238 participants with full data in the placebo group and 155 (69%, 61 to 77) of 227 participants with full data in the azithromycin group in the intention-to-treat analysis (between-group difference –6%, 95% CI –15 to 2). The 95% CI for the difference did not meet the non-inferiority margin. Solicited adverse events and the severity of solicited adverse events were not significantly different between groups at day 5, except for increased abdominal pain associated with azithromycin (47 23%, 95% CI 18 to 29 of 204 participants) compared with placebo (35 16%, 12 to 21 of 221; between-group difference –7% 95% CI –15 to 0; p=0·066).
Placebo was not non-inferior to azithromycin in terms of clinical improvement at day 5 in adults with lower respiratory tract infection and a low procalcitonin concentration. After accounting for both the rates of clinical improvement and solicited adverse events at day 5, it is unclear whether antibiotics are indicated for patients with lower respiratory tract infection and a low procalcitonin concentration.
National Institute of Allergy and Infectious Diseases, bioMérieux.
Commentaries on the target article offer diverse perspectives on integrative experiment design. Our responses engage three themes: (1) Disputes of our characterization of the problem, (2) skepticism ...toward our proposed solution, and (3) endorsement of the solution, with accompanying discussions of its implementation in existing work and its potential for other domains. Collectively, the commentaries enhance our confidence in the promise and viability of integrative experiment design, while highlighting important considerations about how it is used.
Most known synthetic toll-like receptor 4 (TLR4) agonists are carbohydrate-based lipid-A mimetics containing several fatty acyl chains, including a labile 3-O-acyl chain linked to the C-3 position of ...the non-reducing sugar known to undergo cleavage impacting stability and resulting in loss of activity. To overcome this inherent instability, we rationally designed a new class of chemically more stable synthetic TLR4 ligands that elicit robust innate and adaptive immune responses. This new class utilized a diamino allose phosphate (DAP) scaffold containing a nonhydrolyzable 3-amide bond instead of the classical 3-ester. Accordingly, the DAPs have significantly improved thermostability in aqueous formulations and potency relative to other known natural and synthetic TLR4 ligands. Furthermore, the DAP analogues function as potent vaccine adjuvants to enhance influenza-specific antibodies in mice and provide protection against lethal influenza virus challenges. This novel set of TLR4 ligands show promise as next-generation vaccine adjuvants and stand-alone immunomodulators.
Immunocompromised individuals are not optimally protected by COVID-19 vaccines and potentially require additional preventive interventions to mitigate the risk of severe COVID-19. We aimed to ...characterise and describe the risk of severe COVID-19 across immunocompromised groups as the pandemic began to transition to an endemic phase.
COVID-19-related hospitalisations, intensive care unit (ICU) admissions, and deaths (01/01/2022-31/12/2022) were compared among different groups of immunocompromised individuals
the general population, using a retrospective cohort design and electronic health data from a random 25% sample of the English population aged ≥12 years (Registration number: ISRCTN53375662).
Overall, immunocompromised individuals accounted for 3.9% of the study population, but 22% (4585/20,910) of COVID-19 hospitalisations, 28% (125/440) of COVID-19 ICU admissions, and 24% (1145/4810) of COVID-19 deaths in 2022. Restricting to those vaccinated with ≥3 doses of COVID-19 vaccine (∼84% of immunocompromised and 51% of the general population), all immunocompromised groups remained at increased risk of severe COVID-19 outcomes, with adjusted incidence rate ratios (aIRR) for hospitalisation ranging from 1.3 to 13.1. At highest risk for COVID-19 hospitalisation were individuals with: solid organ transplant (aIRR 13.1, 95% confidence interval 95% CI 11.2-15.3), moderate to severe primary immunodeficiency (aIRR 9.7, 95% CI 6.3-14.9), stem cell transplant (aIRR 11.0, 95% CI 6.8-17.6), and recent treatment for haematological malignancy (aIRR 10.6, 95% CI 9.5-11.9). Results were similar for COVID-19 ICU admissions and deaths.
Immunocompromised individuals continue to be impacted disproportionately by COVID-19 and have an urgent need for additional preventive measures beyond current vaccination programmes. These data can help determine the immunocompromised groups for which targeted prevention strategies may have the highest impact.
This study was funded by AstraZeneca UK.
Objective: To describe patterns of care for men diagnosed with prostate cancer in Victoria, Australia, between 2008 and 2011.
Design, setting and patients: Men who were diagnosed with prostate cancer ...at 11 public and six private hospitals in Victoria from August 2008 to February 2011, and for whom prostate cancer notifications were received by the Prostate Cancer Registry.
Main outcome measures: Characteristics of men diagnosed with prostate cancer; details of treatment provided within 12 months of diagnosis, according to National Comprehensive Cancer Network risk categories; and characteristics of men who did not receive active treatment within 12 months of diagnosis.
Results: Treatment details were collected for 98.1% of men who were assessed as eligible to participate in the study (2724/2776) and were confirmed by telephone 12 months after diagnosis for 74.4% of them (2027/2724). Most patients (2531/2724 92.9%) were diagnosed with clinically localised disease, of whom 1201 (47.5%) were at intermediate risk of disease progression. Within 12 months of diagnosis, 299 of the 736 patients (40.6%) who had been diagnosed as having disease that was at low risk of progression had received no active treatment, and 72 of 594 patients (12.1%) who had been diagnosed as having disease that was at high risk of progression had received no active treatment. Of those diagnosed as having intermediate risk of disease progression, 54.5% (655/1201) had undergone radical prostatectomy. Those who received no active treatment were more likely than those who received active treatment to be older (odds ratio 95% CI, 2.96 2.01–4.38, 10.94 6.96–17.21 and 32.76 15.84–67.89, respectively, for age 65–74 years, 75–84 years and ≥ 85 years, compared with < 55 years), to have less advanced disease (odds ratio 95% CI, 0.20 0.16–0.26, 0.09 0.06–0.12 and 0.05 0.02–0.90, respectively, for intermediate, high and very high‐risk locally advanced or metastatic disease, compared with low‐risk disease) and to have had their prostate cancer notified by a private hospital (odds ratio 95% CI, 1.35 1.10–1.66, compared with public hospital).
Conclusion: Our data reveal a considerable “stage migration” towards earlier diagnosis of prostate cancer in Victoria and a large increase in the use of radical prostatectomy among men with clinically localised disease.
Abstract Objective To examine the effects of activity-based therapy (ABT) on neurologic function, walking ability, functional independence, metabolic health, and community participation. Design ...Randomized controlled trial with delayed treatment design. Setting Outpatient program in a private, nonprofit rehabilitation hospital. Participants Volunteer sample of adults (N=48; 37 men and 11 women; age, 18–66y) with chronic (≥12mo postinjury), motor-incomplete (ASIA Impairment Scale grade C or D) spinal cord injury (SCI). Interventions A total of 9h/wk of ABT for 24 weeks including developmental sequencing; resistance training; repetitive, patterned motor activity; and task-specific locomotor training. Algorithms were used to guide group allocation, functional electrical stimulation utilization, and locomotor training progression. Main Outcome Measures Neurologic function (International Standards for Neurological Classification of Spinal Cord Injury); walking speed and endurance (10-meter walk test, 6-minute walk test, and Timed Up and Go test); community participation (Spinal Cord Independence Measure, version III, and Reintegration to Normal Living Index); and metabolic function (weight, body mass index, and Quantitative Insulin Sensitivity Check). Results Significant improvements in neurologic function were noted for experimental versus control groups (International Standards for Neurological Classification of Spinal Cord Injury total motor score 5.1±6.3 vs 0.9±5.0; P =.024 and lower extremity motor score 4.2±5.2 vs −0.6±4.2; P =.004). Significant differences between experimental and control groups were observed for 10-meter walk test speed (0.096±0.14m/s vs 0.027±0.10m/s; P =.036) and 6-minute walk test total distance (35.97±48.2m vs 3.0±25.5m; P =.002). Conclusions ABT has the potential to promote neurologic recovery and enhance walking ability in individuals with chronic, motor-incomplete SCI. However, further analysis is needed to determine for whom ABT is going to lead to meaningful clinical benefits.
Potential effectiveness of harvest weed seed control (HWSC) systems depends upon seed shatter of the target weed species at crop maturity, enabling its collection and processing at crop harvest. ...However, seed retention likely is influenced by agroecological and environmental factors. In 2016 and 2017, we assessed seed-shatter phenology in 13 economically important broadleaf weed species in soybean Glycine max (L.) Merr. from crop physiological maturity to 4 wk after physiological maturity at multiple sites spread across 14 states in the southern, northern, and mid-Atlantic United States. Greater proportions of seeds were retained by weeds in southern latitudes and shatter rate increased at northern latitudes. Amaranthus spp. seed shatter was low (0% to 2%), whereas shatter varied widely in common ragweed (Ambrosia artemisiifolia L.) (2% to 90%) over the weeks following soybean physiological maturity. Overall, the broadleaf species studied shattered less than 10% of their seeds by soybean harvest. Our results suggest that some of the broadleaf species with greater seed retention rates in the weeks following soybean physiological maturity may be good candidates for HWSC.
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