Species’ distributions are likely to be affected by a combination of environmental drivers. We used a data set of 11 million species occurrence records over the period 1970–2010 to assess changes in ...the frequency of occurrence of 673 macro‐moth species in Great Britain. Groups of species with different predicted sensitivities showed divergent trends, which we interpret in the context of land‐use and climatic changes. A diversity of responses was revealed: 260 moth species declined significantly, whereas 160 increased significantly. Overall, frequencies of occurrence declined, mirroring trends in less species‐rich, yet more intensively studied taxa. Geographically widespread species, which were predicted to be more sensitive to land use than to climate change, declined significantly in southern Britain, where the cover of urban and arable land has increased. Moths associated with low nitrogen and open environments (based on their larval host plant characteristics) declined most strongly, which is also consistent with a land‐use change explanation. Some moths that reach their northern (leading edge) range limit in southern Britain increased, whereas species restricted to northern Britain (trailing edge) declined significantly, consistent with a climate change explanation. Not all species of a given type behaved similarly, suggesting that complex interactions between species’ attributes and different combinations of environmental drivers determine frequency of occurrence changes. Synthesis and applications. Our findings are consistent with large‐scale responses to climatic and land‐use changes, with some species increasing and others decreasing. We suggest that land‐use change (e.g. habitat loss, nitrogen deposition) and climate change are both major drivers of moth biodiversity change, acting independently and in combination. Importantly, the diverse responses revealed in this species‐rich taxon show that multifaceted conservation strategies are needed to minimize negative biodiversity impacts of multiple environmental changes. We suggest that habitat protection, management and ecological restoration can mitigate combined impacts of land‐use change and climate change by providing environments that are suitable for existing populations and also enable species to shift their ranges.
Obstructive sleep apnoea (OSA) involves repeated breathing pauses during sleep due to upper airway obstruction. It causes excessive daytime sleepiness and has other health impacts. Continuous ...positive airway pressure (CPAP) therapy is effective first line treatment for moderate to severe OSA. Unfortunately, many patients have difficulty tolerating CPAP and pressure intolerance is probably an important contributing factor. Mandibular advancement devices (MAD) are an alternative to CPAP. They are worn in the mouth during sleep to reduce airway obstruction. There is some evidence that, when used in combination with CPAP, MADs improve airway anatomy enough to reduce the CPAP pressure required to treat OSA and that this combination therapy could improve CPAP adherence.
Consecutive patients starting on CPAP for moderate to severe OSA will be recruited at a regional NHS sleep service. Patients with high CPAP pressure requirements after initial titration, who satisfy all entry criteria and consent to participate, will undertake a 2-arm randomised crossover trial. The arms will be (i) standalone CPAP and (ii) CPAP + MAD therapy. Each arm will last 12 weeks, including 2 weeks acclimatisation. CPAP machines will be auto-titrating and with facility for data download, so the impact of MAD on CPAP pressure requirements and CPAP adherence can be easily measured. The primary outcome will be CPAP adherence. Secondary outcomes will include measures of OSA severity, patient-reported outcome measures including subjective daytime sleepiness, quality of life, and treatment preference at the trial exit and health service use. Cost-effectiveness analyses will be undertaken.
If the intervention is shown to be effective and cost-effective in improving adherence in this standard CPAP-eligible OSA patient population it would be relatively straightforward to introduce into existing OSA treatment pathways, within the wider NHS and more widely. Both MAD and CPAP are already used by sleep services so their combination would require only minor adjustments to existing clinical pathways. It would be straightforward to disseminate the results of the study through regional, national, and international respiratory meetings. The health economics analysis would provide cost-effectiveness data to inform service planning and clinical guidelines through policy briefing papers, including those by NICE and SIGN.
PAPMAT was registered with ISRCTN prior to recruitment beginning (ISRCTN Registry 2021): https://www.isrctn.com/ISRCTN33966032 . Registered on 17th November 2021.
Macrocyclic host molecules bound to electrode surfaces enable the complexation of catalytically active guests for molecular heterogeneous catalysis. We present a surface-anchored host–guest complex ...with the ability to electrochemically oxidize ammonia in both organic and aqueous solutions. With an adamantyl motif as the binding group on the backbone of the molecular catalyst Ru(bpy-NMe2)(tpada)(Cl)(PF6) (1) (where bpy-NMe2 is 4,4′-bis(dimethylamino)-2,2′-bipyridyl and tpada is 4′-(adamantan-1-yl)-2,2’:6′,2″-terpyridine), high binding constants with β-cyclodextrin were observed in solution (in DMSO-d 6:D2O (7:3), K 11 = 492 ± 21 M–1). The strong binding affinities were also transferred to a mesoporous ITO (mITO) surface functionalized with a phosphonated derivative of β-cyclodextrin. The newly designed catalyst (1) was compared to the previously reported naphthyl-substituted catalyst Ru(bpy-NMe2)(tpnp)(Cl)(PF6) (2) (where tpnp is 4′-(naphthalene-2-yl)-2,2’:6′,2″-terpyridine) for its stability during catalysis. Despite the insulating nature of the adamantyl substituent serving as the binding group, the stronger binding of this unit to the host-functionalized electrode and the resulting shorter distance between the catalytic active center and the surface led to better performance and higher stability. Both guests are able to oxidize ammonia in both organic and aqueous solutions, and the host-anchored electrode can be refunctionalized multiple times (>3) following the loss of the catalytic activity, without a reduction in performance. Guest 1 exhibits significantly higher stability in comparison to guest 2 toward basic conditions, which often constitutes a challenge for anchored molecular systems. Ammonia oxidation in water led to the selective formation of NO3 – with Faradaic efficiencies of up to 100%.
Recent studies have shown that immune responses against the cell-traversal protein for Plasmodium ookinetes and sporozoites (CelTOS) can inhibit parasite infection. While these studies provide ...important evidence toward the development of vaccines targeting this protein, it remains unknown whether these responses could engage the Plasmodium falciparum CelTOS in vivo Using a newly developed rodent malaria chimeric parasite expressing the P. falciparum CelTOS (PfCelTOS), we evaluated the protective effect of in vivo immune responses elicited by vaccination and assessed the neutralizing capacity of monoclonal antibodies specific against PfCelTOS. Mice immunized with recombinant P. falciparum CelTOS in combination with the glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE) or glucopyranosyl lipid adjuvant-liposome-QS21 (GLA-LSQ) adjuvant system significantly inhibited sporozoite hepatocyte infection. Notably, monoclonal antibodies against PfCelTOS strongly inhibited oocyst development of P. falciparum and Plasmodium berghei expressing PfCelTOS in Anopheles gambiae mosquitoes. Taken together, our results demonstrate that anti-CelTOS responses elicited by vaccination or passive immunization can inhibit sporozoite and ookinete infection and impair vector transmission.
Subclavian and axillary artery injuries are uncommon. In addition to many open vascular repairs, endovascular techniques are used for definitive repair or vascular control of these anatomically ...challenging injuries. The aim of this study was to determine the relative roles of endovascular and open techniques in the management of subclavian and axillary artery injuries comparing hospital outcomes, and long-term limb viability.
A multicenter, retrospective review of patients with subclavian or axillary artery injuries from January 1, 2004, to December 31, 2014, was completed at 11 participating Western Trauma Association institutions. Statistical analysis included χ, t-tests, and Cochran-Armitage trend tests. A p value less than 0.05 was significant.
Two hundred twenty-three patients were included; mean age was 36 years, 84% were men. An increase in computed tomography angiography and decrease in conventional angiography was observed over time (p = 0.018). There were 120 subclavian and 119 axillary artery injuries. Procedure type was associated with injury grade (p < 0.001). Open operations were performed in 135 (61%) patients, including 93% of greater than 50% circumference lacerations and 83% of vessel transections. Endovascular repairs were performed in 38 (17%) patients; most frequently for pseudoaneurysms. Fourteen (6%) patients underwent a hybrid procedure. Use of endovascular versus open procedures did not increase over the duration of the study (p = 0.248). In-hospital mortality rate was 10%. Graft or stent thrombosis occurred in 7% and graft or stent infection occurred in 3% of patients. Mean follow-up was 1.6 ± 2.4 years (n = 150). Limb salvage was achieved in 216 (97%) patients.
The management of subclavian and axillary artery injuries still requires a wide variety of open exposures and procedures, especially for the control of active hemorrhage from more than 50% vessel lacerations and transections. Endovascular repairs were used most often for pseudoaneurysms. Low early complication rates and limb salvage rates of 97% were observed after open and endovascular repairs.
Prognostic/epidemiologic, level IV.
New surgical procedures can expose patients to harm and should be carefully evaluated before widespread use. The InSpace balloon (Stryker, USA) is an innovative surgical device used to treat people ...with rotator cuff tears that cannot be repaired. We aimed to determine the effectiveness of the InSpace balloon for people with irreparable rotator cuff tears.
We conducted a double-blind, group-sequential, adaptive randomised controlled trial in 24 hospitals in the UK, comparing arthroscopic debridement of the subacromial space with biceps tenotomy (debridement only group) with the same procedure but including insertion of the InSpace balloon (debridement with device group). Participants had an irreparable rotator cuff tear, which had not resolved with conservative treatment, and they had symptoms warranting surgery. Eligibility was confirmed intraoperatively before randomly assigning (1:1) participants to a treatment group using a remote computer system. Participants and assessors were masked to group assignment. Masking was achieved by using identical incisions for both procedures, blinding the operation note, and a consistent rehabilitation programme was offered regardless of group allocation. The primary outcome was the Oxford Shoulder Score at 12 months. Pre-trial simulations using data from early and late timepoints informed stopping boundaries for two interim analyses. The primary analysis was on a modified intention-to-treat basis, adjusted for the planned interim analysis. The trial was registered with ISRCTN, ISRCTN17825590.
Between June 1, 2018, and July 30, 2020, we assessed 385 people for eligibility, of which 317 were eligible. 249 (79%) people consented for inclusion in the study. 117 participants were randomly allocated to a treatment group, 61 participants to the debridement only group and 56 to the debridement with device group. A predefined stopping boundary was met at the first interim analysis and recruitment stopped with 117 participants randomised. 43% of participants were female, 57% were male. We obtained primary outcome data for 114 (97%) participants. The mean Oxford Shoulder Score at 12 months was 34·3 (SD 11·1) in the debridement only group and 30·3 (10·9) in the debridement with device group (mean difference adjusted for adaptive design –4·2 95% CI –8·2 to –0·26;p=0·037) favouring control. There was no difference in adverse events between the two groups.
In an efficient, adaptive trial design, our results favoured the debridement only group. We do not recommend the InSpace balloon for the treatment of irreparable rotator cuff tears.
Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health and Care Research partnership
Despite several new therapeutic options for acute myeloid leukemia (AML), disease relapse remains a significant challenge. We have previously demonstrated that augmenting ceramides can counter ...various drug‐resistance mechanisms, leading to enhanced cell death in cancer cells and extended survival in animal models. Using a nanoscale delivery system for ceramide (ceramide nanoliposomes, CNL), we investigated the effect of CNL within a standard of care venetoclax/cytarabine (Ara‐C) regimen. We demonstrate that CNL augmented the efficacy of venetoclax/cytarabine in in vitro, ex vivo, and in vivo models of AML. CNL treatment induced non‐apoptotic cytotoxicity, and augmented cell death induced by Ara‐C and venetoclax. Mechanistically, CNL reduced both venetoclax (Mcl‐1) and cytarabine (Chk1) drug‐resistant signaling pathways. Moreover, venetoclax and Ara‐C augmented the generation of endogenous pro‐death ceramide species, which was intensified with CNL. Taken together, CNL has the potential to be utilized as an adjuvant therapy to improve outcomes, potentially extending survival, in patients with AML.
After centuries of overexploitation and habitat loss, many of the world's sturgeon (Acipenseridae) populations are at the brink of extinction. Although significant resources are invested into the ...conservation and restoration of imperiled sturgeons, the burgeoning commercial culture industry poses an imminent threat to the persistence of many populations. In the past decade, the number and distribution of captive sturgeon facilities has grown exponentially and now encompasses diverse interest groups ranging from hobby aquarists to industrial‐scale commercial facilities. Expansion of sturgeon captive culture has largely fallen outside the purview of existing regulatory frameworks, raising concerns that continued growth of this industry has real potential to jeopardize conservation of global sturgeon populations. Here, we highlight some of the most significant threats commercial culture poses to wild populations, with particular emphasis on how releases can accelerate wild population declines through mechanisms such as hybridization, introgression, competition, and disease transmission. We also note that in some circumstances, commercial captive culture has continued to motivate harvest of wild populations, potentially accelerating species' declines. Given the prevalence and trajectory of sturgeon captive culture programs, we comment on modifications to regulatory frameworks that could improve the ability of captive culture to support wild sturgeon conservation.
•Mass synaptometry method for single synapse multiplexed molecular profiling.•Synapse by Time Of Flight (SynTOF) panel of 34 antibodies for wide application.•Optimized synaptosome preparation and ...CyTOF acquisition parameters.•Proof of principle validation in 4 Lewy body disease and 2 Alzheimer’s disease cases.
Synaptic alterations, especially presynaptic changes, are cardinal features of neurodegenerative diseases and strongly correlate with cognitive decline.
We report “Mass Synaptometry” for the high-dimensional analysis of individual human synaptosomes, enriched nerve terminals from brain. This method was adapted from cytometry by time-of-flight mass spectrometry (CyTOF), which is commonly used for single-cell analysis of immune and blood cells.
Here we overcome challenges for single synapse analysis by optimizing synaptosome preparations, generating a ‘SynTOF panel,’ recalibrating acquisition settings, and applying computational analyses. Through the analysis of 390,000 individual synaptosomes, we also provide proof-of principle validation by characterizing changes in synaptic diversity in Lewy Body Disease (LBD), Alzheimer’s disease and normal brain.
Current imaging methods to study synapses in humans are capable of analyzing a limited number of synapses, and conventional flow cytometric techniques are typically restricted to fewer than 6 parameters. Our method allows for the simultaneous detection of 34 parameters from tens of thousands of individual synapses.
We applied Mass Synaptometry to analyze 34 parameters simultaneously on more than 390,000 synaptosomes from 13 human brain samples. This new approach revealed regional and disease-specific changes in synaptic phenotypes, including validation of this method with the expected changes in the molecular composition of striatal dopaminergic synapses in Lewy body disease and Alzheimer’s disease. Mass synaptometry enables highly parallel molecular profiling of individual synaptic terminals.
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