Search

Abstract Freshwaters play an essential role in providing ecosystem services worldwide, however, the water quality of different water bodies is strongly influenced by human activities such as urbanization, industry and agriculture. In this study, water and biofilm samples were collected from the main channel of the Danube River upstream and downstream of a metropolitan, from a regulated side arm within an urbanized area, and from two differently separated oxbow lakes located in nature conservation areas. The taxonomic diversity of bacterial communities was revealed by 16S rRNA gene-based amplicon sequencing using Illumina MiSeq platform. The results showed that all samples were dominated by phyla Pseudomonadota, Actinobacteriota and Bacteroidota. The bacterial community structures, however, clearly differentiated according to planktonic and epilithic or epiphytic habitats, as well as by riverine body types (main channel, side arm, oxbow lakes). The taxonomic diversity of biofilm communities was higher than that of planktonic ones in all studied habitats. Human impacts were mainly reflected in the slowly changing biofilm composition compared to the planktonic ones. Genera with pollution tolerance and/or degradation potential, such as Acinetobacter, Pseudomonas and Shewanella were mainly detected in biofilm communities of the highly urbanized section of the river side arm.

Abstract The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.

Abstract Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.

Abstract Background Procedural sedation and analgesia (PSA) is a technique of administering sedatives to induce a state that allows the patient to tolerate painful procedures while maintaining cardiorespiratory function, a condition that is frequently desired prehospital. Non-physician prehospital clinicians often have a limited scope of practice when it comes to providing analgesia and sedation; sometimes resulting in a crew request for back-up from physician-staffed prehospital services.“. This is also the case if sedation is desirable. Advanced practice providers (APPs), who are legally authorized and trained to carry out this procedure, may be a solution when the physician-staffed service is not available or will not be available in time. Methods The aim of this study is to gain insight in the circumstances in which an APP, working at the Dutch ambulance service “RAV Brabant MWN” from January 2019 to December 2022, uses propofol for PSA or to provide sedation. With this a retrospective observational document study we describe the characteristics of patients and ambulance runs and evaluates the interventions in terms of safety. Results During the study period, the APPs administered propofol 157 times for 135 PSA and in 22 cases for providing sedation. The most common indication was musculoskeletal trauma such as fracture care or the reduction of joint dislocation. In 91% of the situations where propofol was used, the predetermined goal e.g. alignment of fractured extremity, repositioning of luxated joint or providing sedation the goal was achieved. There were 12 cases in which one or more adverse events were documented and all were successfully resolved by the APP. There were no cases of laryngospam, airway obstruction, nor anaphylaxis. None of the adverse events led to unexpected hospitalization or death. Conclusion During the study period, the APPs performed 135 PSAs and provided 22 sedations. The success rate of predetermined goals was higher than that stated in the literature. Although there were a number of side effects, their incidences were lower than those reported in the literature, and these were resolved by the APP during the episode of care. Applying a PSA by an APP at the EMS “RAV Brabant MWN” appears to be safe with a high success rate.

Abstract Background For most acute conditions, the phase prior to emergency department (ED) arrival is largely unexplored. However, this prehospital phase has proven an important part of the acute care chain (ACC) for specific time-sensitive conditions, such as stroke and myocardial infarction. For patients with undifferentiated complaints, exploration of the prehospital phase of the ACC may also offer a window of opportunity for improvement of care. This study aims to explore the ACC of ED patients with undifferentiated complaints, with specific emphasis on time in ACC and patient experience. Methods This Dutch prospective observational study, included all adult (≥ 18 years) ED patients with undifferentiated complaints over a 4-week period. We investigated the patients’ journey through the ACC, focusing on time in ACC and patient experience. Additionally, a multivariable linear regression analysis was employed to identify factors independently associated with time in ACC. Results Among the 286 ED patients with undifferentiated complaints, the median symptom duration prior to ED visit was 6 days (IQR 2–10), during which 58.6% of patients had contact with a healthcare provider before referral. General Practitioners (GPs) referred 80.4% of the patients, with the predominant patient journey (51.7%) involving GP referral followed by self-transportation to the ED. The median time in ACC was 5.5 (IQR 4.0-8.4) hours of which 40% was spent before the ED visit. GP referral and referral to pulmonology were associated with a longer time in ACC, while referral during evenings was associated with a shorter time in ACC. Patients scored both quality and duration of the provided care an 8/10. Conclusion Dutch ED patients with undifferentiated complaints consulted a healthcare provider in over half of the cases before their ED visit. The median time in ACC is 5.5 h of which 40% is spent in the prehospital phase. Those referred by a GP and to pulmonology had a longer, and those in the evening a shorter time in ACC. The acute care journey starts hours before patients arrive at the ED and 6 days of complaints precede this journey. This timeframe could serve as a window of opportunity to optimise care.

Abstract Background Providing individualised healthcare in line with patient wishes is a particular challenge for emergency healthcare professionals. Documentation of patient wishes (DPW), e.g. as advance directives, can guide clinicians in making end-of-life decisions that respect the patient’s wishes and autonomy. However, patient centered decisions are hindered by limited availability of DPWs in emergency settings. Objective This systematic review aims to congregate present data on recorded rates for DPW existence and availability in the emergency department (ED) as well as contributing factors for these rates. Methods We searched MEDLINE, Google Scholar, Embase and Web of Science databases in September 2023. Publications providing primary quantitative data on DPW in the ED were assessed. Publications referring only to a subset of ED patients (other than geriatric) and investigating DPW issued after admission were excluded. Results A total of 22 studies from 1996 to 2021 were included in the analysis. Most were from the US (n = 12), followed by Australia (n = 4), Canada (n = 2), South Korea, Germany, the United Kingdom and Switzerland (n = 1 each). In the general adult population presenting to the ED, 19.9–27.8% of patients reported having some form of DPW, but only in 6.8% or less it was available on presentation. In the geriatric population, DPW rates (2.6–79%) as well as their availability (1.1–48.8%) varied widely. The following variables were identified as positive predictors of having DPW, among others: higher age, poorer overall health, as well as sociodemographic factors, such as female gender, having children, being in a relationship, higher level of education or a recent previous presentation to hospital. Conclusions Existence and availability of a recorded DPW among ED patients was low in general and even in geriatric populations mostly well below 50%. While we were able to gather data on prevalence and predictors, this was limited by heterogeneous data. We believe further research is needed to explore the quality of DPW and measures to increase both rates of existence and availability of DPW in the ED.

E tanulmány célja a magyarországi klímasérülékenység területi különbségeinek feltárása. Ehhez három komponenst vizsgáltunk meg: a lakosság, mezőgazdaság és a tóparti turizmus klímasérülékenységét. Kutatásunkhoz a CIVAS modellt adaptáltuk, ami a sérülékenységet a klímaváltozás összetevőinek való kitettség, a változással szembeni környezeti, társadalmi és gazdasági érzékenység, valamint a változásokhoz való alkalmazkodási képesség összesített hatásaiként defniálja. A tanulmány klímakitettséget ábrázoló indikátorai egybevágnak a közelmúlt trendjeivel. A felhasznált forgatókönyvek az ország egész területére további intenzív hőmérsékletnövekedést vetítenek előre. Ezzel szemben a csapadék változása a közelmúltban és a jövőben is jóval differenciáltabb mintázatot mutat: az ország keleti, északkeleti harmadában számottevő csökkenéssel, az ország nyugati, délnyugati részében akár növekedéssel is lehet számolni. A hőmérséklet- és csapadékváltozás trendjeinek megfelelően az aszálykitettség várható változása is jelentős térbeli differenciát mutat, az Alföld közepének kiemelkedő kitettségével. Az érzékenység és az adaptációs képesség indikátorai felhasználásával fnomítottuk a klímasérülékenység egyes komponensek szerinti területi mintázatát. A három komponens vizsgált szerint erősen klímasérülékeny területek jelentős átfedést mutatnak. Kiemelendő a Dél- és Közép-Alföld sérülékenysége, valamint a nagyfokú érzékenység és a gyenge alkalmazkodóképesség miatt az Északi-középhegység egyes településcsoportjainak klímasérülékenysége. Külön kiemelendő a Balaton környezete, ahol a lakossági és mezőgazdasági klímasérülékenység mellett a tóparti turizmusból eredő klímasérülékenység is kockázatot jelent.

BackgroundLarge language models (LLMs) have demonstrated impressive performances in various medical domains, prompting an exploration of their potential utility within the high-demand setting of emergency department (ED) triage. This study evaluated the triage proficiency of different LLMs and ChatGPT, an LLM-based chatbot, compared to professionally trained ED staff and untrained personnel. We further explored whether LLM responses could guide untrained staff in effective triage. ObjectiveThis study aimed to assess the efficacy of LLMs and the associated product ChatGPT in ED triage compared to personnel of varying training status and to investigate if the models’ responses can enhance the triage proficiency of untrained personnel. MethodsA total of 124 anonymized case vignettes were triaged by untrained doctors; different versions of currently available LLMs; ChatGPT; and professionally trained raters, who subsequently agreed on a consensus set according to the Manchester Triage System (MTS). The prototypical vignettes were adapted from cases at a tertiary ED in Germany. The main outcome was the level of agreement between raters’ MTS level assignments, measured via quadratic-weighted Cohen κ. The extent of over- and undertriage was also determined. Notably, instances of ChatGPT were prompted using zero-shot approaches without extensive background information on the MTS. The tested LLMs included raw GPT-4, Llama 3 70B, Gemini 1.5, and Mixtral 8x7b. ResultsGPT-4–based ChatGPT and untrained doctors showed substantial agreement with the consensus triage of professional raters (κ=mean 0.67, SD 0.037 and κ=mean 0.68, SD 0.056, respectively), significantly exceeding the performance of GPT-3.5–based ChatGPT (κ=mean 0.54, SD 0.024; P

As industrial communication continues to evolve to increase flexibility through wireless communication, networked optical wireless communication (OWC), also known as LiFi, has emerged as a promising candidate technology due to its unlicensed spectrum and relatively deterministic propagation. The inherent containment of light improves security, enables dense cellular networks with spatial reuse, and results in reduced sporadic interference while providing high-capacity short range communication links to mobile end devices. This paper outlines the features of the new IEEE Std 802.15.13-2013, suitable for industrial OWC, and presents details of our prototype implementation along with initial experiments. The standard specifies deterministic medium access control (MAC), based on dynamic time division multiple access (TDMA), as well as two physical layers (PHYs) for extended range and robustness, and for spectral efficiency, respectively. Our prototype includes a central coordinator, implemented entirely in software, running on commodity server hardware. It connects to distributed ceiling-mounted optical wireless frontends via a packet-switched network (Ethernet) and is capable of forming them into adaptive virtual cells on a per-user basis. This approach enhances reliability through multiple-input multiple-output (MIMO) transmission and allows for smooth mobility. We implemented the Pulsed Modulation PHY (PM-PHY) on a commercially available field programmable gate array (FPGA) evaluation board. Initial test results indicate that the PM-PHY supports typical distances of up to 6 m between the ceiling and the mobile device. The MAC achieves deterministic latency values below 4 ms.

Background Coronary pressure indices to assess coronary artery disease are currently underused in patients with aortic stenosis due to many potential physiological effects that might hinder their interpretation. Studies with varying sample sizes have provided us with conflicting results on the effect of transcatheter aortic valve replacement (TAVR) on these indices. The aim of this meta‐analysis was to study immediate and long‐term effects of TAVR on fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs). Methods and Results Lesion‐specific coronary pressure data were extracted from 6 studies, resulting in 147 lesions for immediate change in FFR analysis and 105 for NHPR analysis. To investigate the long‐term changes, 93 lesions for FFR analysis and 68 for NHPR analysis were found. Lesion data were pooled and compared with paired t tests. Immediately after TAVR, FFR decreased significantly (−0.0130±0.0406 SD, P: 0.0002) while NHPR remained stable (0.0003±0.0675, P: 0.9675). Long‐term after TAVR, FFR decreased significantly (−0.0230±0.0747, P: 0.0038) while NHPR increased nonsignificantly (0.0166±0.0699, P: 0.0543). When only borderline NHPR lesions were considered, this increase became significant (0.0249±0.0441, P: 0.0015). Sensitivity analysis confirmed our results in borderline lesions. Conclusions TAVR resulted in small significant, but opposite, changes in FFR and NHPR. Using the standard cut‐offs in patients with severe aortic stenosis, FFR might underestimate the physiological significance of a coronary lesion while NHPRs might overestimate its significance. The described changes only play a clinically relevant role in borderline lesions. Therefore, even in patients with aortic stenosis, an overtly positive or negative physiological assessment can be trusted.

Objectives To estimate the economic burden of informal caregivers not in the labour force (NILF) due to caring for a person with arthritis in Australia, with projections of these costs from 2015 to 2030.Design Static microsimulation modelling using national survey data.Setting Australia nationwide survey.Participants Participants include respondents to the Survey of Disability, Ageing and Carers who are informal carers of a person who has arthritis as their main chronic condition and non-carers.Outcome measures Estimating the economic impact and national aggregated costs of informal carers NILF to care for a person with arthritis and projecting these costs from 2015 to 2030 in 5-year intervals.Results On a per-person basis, when adjusted for age, sex and highest education attained, the difference in average weekly total income between informal carers and non-carers employed in the labour force is $A1051 (95% CI: $A927 to $A1204) in 2015 and projected to increase by up to 22% by 2030. When aggregated, the total national annual loss of income to informal carers NILF is estimated at $A388.2 million (95% CI: $A324.3 to $A461.9 million) in 2015, increasing to $A576.9 million (95% CI: $A489.2 to $A681.8 million) by 2030. The national annual tax revenue lost to the government of the informal carers NILF is estimated at $A99 million (95% CI: $A77.9 to $A126.4 million) in 2015 and is projected to increase 49% by 2030.Conclusion Informal carers NILF are economically worse off than employed non-carers, and the aggregated national annual costs are substantial. The future economic impact of informal carers NILF to care for a person with arthritis in Australia is projected to increase, with the estimated differences in income between informal carers and employed non-carers increasing by 22% from 2015 to 2030.

IMPORTANCE:. Cardiopulmonary resuscitation (CPR) is an exceptional physical situation and may lead to significant psychological, spiritual, and social distress in patients and their next of kin. Furthermore, clinicians might experience distress related to a CPR event. Specialist palliative care (sPC) integration could address these aspects but is not part of routine care. OBJECTIVES:. This study aimed to explore perspectives on sPC integration during and after CPR. A needs assessment for sPC, possible triggers indicating need, and implementation strategies were addressed. DESIGN, SETTING, AND PARTICIPANTS:. A multiprofessional qualitative semistructured focus group study was conducted in a German urban academic teaching hospital. Participants were clinicians (nursing staff, residents, and consultants) working in the emergency department and ICUs (internal medicine and surgical). ANALYSIS:. The focus groups were recorded and subsequently transcribed. Data material was analyzed using the content-structuring content analysis according to Kuckartz. RESULTS:. Seven focus groups with 18 participants in total were conducted online from July to November 2022. Six main categories (two to five subcategories) were identified: understanding (of palliative care and death), general CPR conditions (e.g., team, debriefing, and strains), prognosis (e.g., preexisting situation, use of extracorporeal support), next of kin (e.g., communication, presence during CPR), treatment plan (patient will and decision-making), and implementation of sPC (e.g., timing, trigger factors). CONCLUSIONS:. Perceptions about the need for sPC to support during and after CPR depend on roles, areas of practice, and individual understanding of sPC. Although some participants perceive CPR itself as a trigger for sPC, others define, for example, pre-CPR-existing multimorbidity or complex family dynamics as possible triggers. Suggestions for implementation are multifaceted, especially communication by sPC is emphasized. Specific challenges of extracorporeal CPR need to be explored further. Overall, the focus groups show that the topic is considered relevant, and studies on outcomes are warranted.

Introduction Nigeria is committed to reducing industrial trans-fatty acids (iTFA) from the food supply, but the potential health gains, costs and cost-effectiveness are unknown.Methods The effect on ischaemic heart disease (IHD) burden, costs and cost-effectiveness of a mandatory iTFA limit (≤2% of all fats) for foods in Nigeria were estimated using Markov cohort models. Data on demographics, IHD epidemiology and trans-fatty acid intake were derived from the 2019 Global Burden of Disease Study. Avoided IHD events and deaths; health-adjusted life years (HALYs) gained; and healthcare, policy implementation and net costs were estimated over 10 years and the population’s lifetime. Incremental cost-effectiveness ratios using net costs and HALYs gained (both discounted at 3%) were used to assess cost-effectiveness.Results Over the first 10 years, a mandatory iTFA limit (assumed to eliminate iTFA intake) was estimated to prevent 9996 (95% uncertainty interval: 8870 to 11 118) IHD deaths and 66 569 (58 862 to 74 083) IHD events, and to save US$90 million (78 to 102) in healthcare costs. The corresponding lifetime estimates were 259 934 (228 736 to 290 191), 479 308 (95% UI 420 472 to 538 177) and 518 (450 to 587). Policy implementation costs were estimated at US$17 million (11 to 23) over the first 10 years, and US$26 million USD (19 to 33) over the population’s lifetime. The intervention was estimated to be cost-saving, and findings were robust across several deterministic sensitivity analyses.Conclusion Our findings support mandating a limit of iTFAs as a cost-saving strategy to reduce the IHD burden in Nigeria.

PurposePrevious studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign.MethodsThis study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections.ResultsAfter booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer.ConclusionOur study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.

BackgroundA positive PET scan at diagnosis was associated with a greater yearly increase in ascending and descending aortic diameter and thoracic aortic volume in patients with giant cell arteritis (GCA). Radiologic and histopathologic vascular abnormalities persist in a subset of treated patients despite clinical remission. The aim of this study was to evaluate the association between vascular FDG uptake during follow-up and the development of thoracic aortic aneurysms.MethodsWe recently performed a prospective cohort study of 106 GCA patients, who underwent FDG PET and CT imaging at diagnosis and CT imaging yearly for a maximum of 10 years. In this post hoc analysis, GCA patients who also have had FDG PET imaging during follow-up were included. PET scans were visually scored (0–3) at 7 vascular areas. PET scans were considered positive in case of FDG uptake ≥grade 2 in any large vessel.ResultsEighty-eight repeat PET scans were performed in 52 out of 106 GCA patients, who were included in the original prospective cohort. Fifty-five (63%) PET scans were done at the time of a relapse and 33 (38%) were done while in remission. Nine out of ten patients with an incident thoracic aortic aneurysm had both a positive PET scan at diagnosis and during follow-up.ConclusionIn addition to the intensity and extent of the initial vascular inflammation, ongoing aortic inflammation may contribute to the development of thoracic aortic aneurysms in GCA. However, this hypothesis should be confirmed in a large prospective trial with repeat PET scans at predefined time points during follow-up.

Abstract Environmental monitoring and long-term research produce detailed understanding, but its collective effort does not add up to ‘the environment’ and therefore may be difficult to relate to. Local knowledge, by contrast, is multifaceted and relational and therefore can help ground and complement scientific knowledge to reach a more complete and holistic understanding of the environment and changes therein. Today’s societies, however, are increasingly fleeting, with mobility potentially undermining the opportunity to generate rich community knowledge. Here we perform a case study of High Arctic Svalbard, a climate change and environmental science hotspot, using a range of community science methods, including a Maptionnaire survey, focus groups, interviews and cognitive mapping. We show that rich local knowledge on Svalbard could indeed be gathered through community science methods, despite a high level of transience of the local population. These insights complement environmental monitoring and enhance its local relevance. Complex understanding of Svalbard’s ecosystems by the transient local community arose because of strong place attachment, enabling environmental knowledge generation during work and play. We conclude that transience does not necessarily prevent the generation of valuable local knowledge that can enrich and provide connection to scientific understanding of the environment.

Abstract Gradual climate cooling and CO2 decline in the Miocene were recently shown not to be associated with major ice volume expansion, challenging a fundamental paradigm in the functioning of the Antarctic cryosphere. Here, we explore Miocene ice-ocean-climate interactions by presenting a multi-proxy reconstruction of subtropical front migration, bottom water temperature and global ice volume change, using dinoflagellate cyst biogeography, benthic foraminiferal clumped isotopes from offshore Tasmania. We report an equatorward frontal migration and strengthening, concurrent with surface and deep ocean cooling but absence of ice volume change in the mid–late-Miocene. To reconcile these counterintuitive findings, we argue based on new ice sheet modelling that the Antarctic ice sheet progressively lowered in height while expanding seawards, to maintain a stable volume. This can be achieved with rigorous intervention in model precipitation regimes on Antarctica and ice-induced ocean cooling and requires rethinking the interactions between ice, ocean and climate.

Future projections of sea-level rise under strong warming scenarios are dominated by mass loss in the marine-grounded sectors of West Antarctica, where thinning shelves as a result of warming oceans can lead to reduced buttressing. This consequently leads to accelerated flow from the upstream grounded ice. However, the relation between warming oceans and increased melt rates under the shelves is very uncertain, especially when interactions with the changing shelf geometry are considered. Here, we compare six widely used, highly parameterised formulations relating sub-shelf melt to thermal forcing. We implemented them in an ice-sheet model, and applied the resulting set-up to an idealised-geometry setting, as well as to the Antarctic ice sheet. In our simulations, the differences in modelled ice-sheet evolution resulting from the choice of parameterisation, as well as the choice of numerical scheme used to apply sub-shelf melt near the grounding line, generally are larger than differences from ice-dynamical processes such as basal sliding, as well as uncertainties from the forcing scenario of the model providing the ocean forcing. This holds for the idealised-geometry experiments as well as for the experiments using a realistic Antarctic topography.

Abstract Background The global increase in mean body mass index has resulted in a substantial increase of non-communicable diseases (NCDs), including in many low- and middle-income countries such as Kenya. This paper assesses four interventions for the prevention and control of overweight and obesity in Kenya to determine their potential health and economic impact and cost effectiveness. Methods We reviewed the literature to identify evidence of effect, determine the intervention costs, disease costs and total healthcare costs. We used a proportional multistate life table model to quantify the potential impacts on health conditions and healthcare costs, modelling the 2019 Kenya population over their remaining lifetime. Considering a health system perspective, two interventions were assessed for cost-effectiveness. In addition, we used the Human Capital Approach to estimate productivity gains. Results Over the lifetime of the 2019 population, impacts were estimated at 203,266 health-adjusted life years (HALYs) (95% uncertainty interval [UI] 163,752 − 249,621) for a 20% tax on sugar-sweetened beverages, 151,718 HALYs (95% UI 55,257 − 250,412) for mandatory kilojoule menu labelling, 3.7 million HALYs (95% UI 2,661,365–4,789,915) for a change in consumption levels related to supermarket food purchase patterns and 13.1 million HALYs (95% UI 11,404,317 − 15,152,341) for a change in national consumption back to the 1975 average levels of energy intake. This translates to 4, 3, 73 and 261 HALYs per 1,000 persons. Lifetime healthcare cost savings were approximately United States Dollar (USD) 0.14 billion (USD 3 per capita), USD 0.08 billion (USD 2 per capita), USD 1.9 billion (USD 38 per capita) and USD 6.2 billion (USD 124 per capita), respectively. Lifetime productivity gains were approximately USD 1.8 billion, USD 1.2 billion, USD 28 billion and USD 92 billion. Both the 20% tax on sugar sweetened beverages and the mandatory kilojoule menu labelling were assessed for cost effectiveness and found dominant (health promoting and cost-saving). Conclusion All interventions evaluated yielded substantive health gains and economic benefits and should be considered for implementation in Kenya.

Glycerol is commonly employed for denitrification purposes in full-scale wastewater treatment. In non-acclimatized biomass, the glycerol is very inefficient resulting in a high C/N ratio and low-standard denitrification rates. The acclimatization is driven by the microbial enrichment of Saccharimonadales and Propionibacteriales as found in different sampled municipal sludges flanking the dominant presence of Burkholderiales. The selective strategy is based on a very efficient process in terms of C/N ratios and standard denitrification rates, but it leads to nitrite accumulation. As a result, severe and unexpected nitrous oxide emissions were found in full-scale with emission factors up to 2.5% kgN2O (kgKJNremoved)−1. Simultaneous dosage of isobutirate in a full-scale experiment could counter the nitrous oxide emissions. As nitrous oxide emissions were found proportional to the dosed glycerol-based COD, the authors suggest that, in case of acclimatization of biomass to glycerol, an emission factor based on the dosed COD should substitute the general nitrous oxide emission factors based on incoming or removed nitrogen to the plant. HIGHLIGHTS Acclimatization to glycerol leads to an increase in C/N ratios and standard denitrification rates.; We observed microbial enrichment of Saccharimonadales and Propionibacteriales and nitrite accumulation.; N2O emission factors reached up to 2.5% kgN2O/kgKJNremoved.; In case of acclimatization, the N2O emission factor is best expressed in function of the dosed glycerol COD.; Simultaneous isobutirate dosage countered the N2O emissions.;

Abstract Background The majority of patients with recurrent or metastasized head and neck squamous cell carcinoma (HNSCC) do not benefit from immune checkpoint blockade (ICB) while several patients experience severe and persistent immune-mediated side effects. Therefore, predictive biomarkers are urgently needed to allow for a personalized treatment. In this study, we investigated DNA methylation of the immune checkpoint gene CTLA4 with regard to its predictive value. Methods We analyzed CTLA4 promoter methylation in tumors of HNSCC patients (N = 29) treated with ICB at the University Medical Center Bonn with regard to response to ICB and progression-free survival. We further analyzed a second cohort (N = 138) of patients that did not receive ICB with regard to CTLA4 promoter methylation, CTLA-4 protein expression, and immune cell infiltrates. Finally, we tested inducibility of CTLA-4 protein expression in HNSCC cells using the DNA methyltransferase inhibitor decitabine. Results Lower CTLA4 promoter methylation correlated with response to ICB and prolonged progression-free survival. We could show that not only tumor infiltrating immune cells, but also HNSCC cells harbor cytoplasmic and nuclear CTLA-4 expression. CTLA4 promoter methylation inversely correlated with infiltrates of CD3+, CD4+, CD8+, and CD45+ immune cells. CTLA4 methylation did not correlate with protein expression in tumors, however, decitabine treatment led to decreased CTLA4 methylation and an induction of CTLA4 mRNA and CTLA-4 protein expression in HNSCC cell lines. Conclusions Our results indicate that CTLA4 DNA hypomethylation is a predictive biomarker for response to ICB in HNSCC. Our study warrants further analyses of the predictive value of CTLA4 DNA methylation in clinical trials of anti-PD-1 and/or anti-CTLA-4 immunotherapy in HNSCC.