Basin-scale planning is needed to minimize impacts in mega-diverse rivers
The world's most biodiverse river basins—the Amazon, Congo, and Mekong—are experiencing an unprecedented boom in construction ...of hydropower dams. These projects address important energy needs, but advocates often overestimate economic benefits and underestimate far-reaching effects on biodiversity and critically important fisheries. Powerful new analytical tools and high-resolution environmental data can clarify trade-offs between engineering and environmental goals and can enable governments and funding institutions to compare alternative sites for dam building. Current site-specific assessment protocols largely ignore cumulative impacts on hydrology and ecosystem services as ever more dams are constructed within a watershed (
1
). To achieve true sustainability, assessments of new projects must go beyond local impacts by accounting for synergies with existing dams, as well as land cover changes and likely climatic shifts (
2
,
3
). We call for more sophisticated and holistic hydropower planning, including validation of technologies intended to mitigate environmental impacts. Should anything less be required when tampering with the world's great river ecosystems?
Measles causes a transient immune suppression, leading to increased susceptibility to opportunistic infections. In experimentally infected non-human primates (NHPs) measles virus (MV) infects and ...depletes pre-existing memory lymphocytes, causing immune amnesia. A measles outbreak in the Dutch Orthodox Protestant community provided a unique opportunity to study the pathogenesis of measles immune suppression in unvaccinated children. In peripheral blood mononuclear cells (PBMC) of prodromal measles patients, we detected MV-infected memory CD4
and CD8
T cells and naive and memory B cells at similar levels as those observed in NHPs. In paired PBMC collected before and after measles we found reduced frequencies of circulating memory B cells and increased frequencies of regulatory T cells and transitional B cells after measles. These data support our immune amnesia hypothesis and offer an explanation for the previously observed long-term effects of measles on host resistance. This study emphasises the importance of maintaining high measles vaccination coverage.
Objectives
To investigate the effect of pharmacy‐based medication reconciliation on the frequency of unintentional medication discrepancies in acutely admitted individuals aged 65 and older.
Design
...Multicenter intervention study with pre–post design.
Setting
Twelve Dutch hospitals.
Participants
One thousand five hundred forty‐three individuals aged 65 and older with an acute hospital admission through the emergency department.
Measurements
The intervention consisted of the Best Possible Medication History (BPMH), based on combining information from the community pharmacy record, the information provided by a structured interview with participants about their medication use, and medication containers. In nine hospitals, pharmacy technicians obtained the BPMH, and in three hospitals, a mixed model was used (physicians or pharmacy technicians obtained the BPMH). Primary outcome measure was the proportion of participants with one or more unintentional medication discrepancies. The primary outcome measure was stratified according to type of intervention (pharmacy based vs mixed model).
Results
The proportion of participants with one or more unintentional medication discrepancies was reduced from 62% to 32% odds ratio (OR) = 0.29, 95% confidence interval (CI) = 0.23–0.37. These results remained statistically significant after adjustment for type of department and hospital (OR = 0.20, 95% CI = 0.15–0.26), and this effect remained stable for 6 months. Stratified analysis showed that no effect from the intervention was evident in the three hospitals with a mixed‐model intervention, in contrast to the hospitals with a pharmacy‐based intervention. The medication discrepancy types “omission” and “dosage or strength” occurred most frequently and were the main types that the intervention influenced.
Conclusion
Pharmacy‐based medication reconciliation leads to a substantial reduction in medication discrepancies in acutely admitted elderly adults.
Preclinical data have shown that proton pump inhibitors (PPI) can modulate the microbiome, and single-arm studies suggested that antibiotics (ATB) may decrease the efficacy of immune checkpoint ...inhibitors (ICI), but randomized controlled trial data are lacking. This pooled analysis evaluated the effect of ATB and PPI on outcome in patients randomized between ICI and chemotherapy.
This retrospective analysis used pooled data from the phase II POPLAR (NCT01903993) and phase III OAK (NCT02008227) trials, which included 1512 patients with previously treated non-small-cell lung cancer (NSCLC) randomly assigned to receive atezolizumab (n = 757) or docetaxel (n = 755). The main objective of this analysis was to assess the impact of ATB and PPI use on overall survival (OS) and progression-free survival (PFS).
A total of 169 (22.3%) patients in the atezolizumab group and 202 (26.8%) in the docetaxel group received ATB, and 234 (30.9%) and 260 (34.4%), respectively, received PPI. Multivariate analysis in all patients revealed that ATB were associated with shorter OS hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04–1.39, as was PPI (HR 1.26, 95% CI 1.10–1.44). Within the atezolizumab population, OS was significantly shorter in patients who received ATB (8.5 versus 14.1 months, HR 1.32, 95% CI 1.06–1.63, P = 0.01) or PPI (9.6 versus 14.5 months, HR 1.45, 95% CI 1.20–1.75, P = 0.0001). PPI use was associated with shorter PFS in the atezolizumab population (1.9 versus 2.8 months, HR 1.30, 95% CI 1.10−1.53, P = 0.001). There was no association between ATB and PPI use and PFS or OS within the docetaxel population.
In this unplanned analysis from two randomized trials, data suggest that ATB or PPI use in patients with metastatic NSCLC is associated with poor outcome and may influence the efficacy of ICI.
•Use of antibiotics or proton pump inhibitors in patients with non-small cell lung cancer is associated with poor outcome.•The effect of antibiotics and proton pump inhibitors on outcome after immunotherapy warrants further investigation.•Treating physicians should carefully evaluate the need for co-medications such as antibiotics or proton pump inhibitors.
Summary Background Modified vaccinia virus Ankara (MVA) is a promising viral vector platform for the development of an H5N1 influenza vaccine. Preclinical assessment of MVA-based H5N1 vaccines showed ...their immunogenicity and safety in different animal models. We aimed to assess the safety and immunogenicity of the MVA-haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals. Methods In a single-centre, double-blind phase 1/2a study, young volunteers (aged 18–28 years) were randomly assigned with a computer-generated list in equal numbers to one of eight groups and were given one injection or two injections intramuscularly at an interval of 4 weeks of a standard dose (108 plaque forming units pfu) or a ten times lower dose (107 pfu) of the MVA-H5-sfMR (vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus H5N1 subtype) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians who examined and administered the vaccine were masked to vaccine assignment. Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster immunisation 1 year after the first immunisation. Primary endpoint was safety. Secondary outcome was immunogenicity. The trial is registered with the Dutch Trial Register, number NTR3401. Findings 79 of 80 individuals who were enrolled completed the study. No serious adverse events were identified. 11 individuals reported severe headache and lightheadedness, erythema nodosum, respiratory illness (accompanied by influenza-like symptoms), sore throat, or injection-site reaction. Most of the volunteers had one or more local (itch, pain, redness, and swelling) and systemic reactions (rise in body temperature, headache, myalgia, arthralgia, chills, malaise, and fatigue) after the first, second, and booster immunisations. Individuals who received the 107 dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 108 pfu induced significantly higher antibody responses after one and two immunisations than did 107 pfu when assessed with haemagglutination inhibition geometric mean titre at 8 weeks against H5N1 A/Vietnam/1194/2004 (30·2 SD 3·8 vs 9·2 2·3 and 108·1 2·4 vs 15·8 3·2). 27 of 39 eligible individuals were enrolled in the booster immunisation study. A single shot of MVA-H5-sfMR 108 pfu prime immunisation resulted in higher antibody responses after the booster immunisation than did two shots of MVA-H5-sfMR at the ten times lower dose. Interpretation The MVA-based H5N1 vaccine was well tolerated and immunogenic and therefore the vaccine candidates arising from the MVA platform hold great promise for rapid development in response to a future influenza pandemic threat. However, the immunogenicity of this vaccine needs to be compared with conventional H5N1 inactivated non-adjuvanted vaccine candidates in head-to-head clinical trials. Funding European Research Council.
Necroptosis is a form of programmed cell death that depends on the activation of receptor interacting protein kinase-1 (RIPK1) and RIPK3 by receptors such as tumor necrosis factor (TNF) receptor-1. ...Structural studies indicate that activation of RIPK3 by RIPK1 involves the formation of oligomers via interactions of the RIP homotypic interaction motif (RHIM) domains shared by both proteins; however, the molecular mechanisms by which this occurs are not fully understood. To gain insight into this process, we constructed versions of RIPK3 that could be induced to dimerize or oligomerize in response to a synthetic drug. Using this system, we find that although the formation of RIPK3 dimers is itself insufficient to trigger cell death, this dimerization seeds a RHIM-dependent complex, the propagation and stability of which is controlled by caspase-8 and RIPK1. Consistent with this idea, we find that chemically enforced oligomerization of RIPK3 is sufficient to induce necroptosis, independent of the presence of the RHIM domain, TNF stimulation or RIPK1 activity. Further, although RIPK1 contributes to TNF-mediated RIPK3 activation, we find that RIPK1 intrinsically suppresses spontaneous RIPK3 activation in the cytosol by controlling RIPK3 oligomerization. Cells lacking RIPK1 undergo increased spontaneous RIPK3-dependent death on accumulation of the RIPK3 protein, while cells containing a chemically inhibited or catalytically inactive form of RIPK1 are protected from this form of death. Together, these data indicate that RIPK1 can activate RIPK3 in response to receptor signaling, but also acts as a negative regulator of spontaneous RIPK3 activation in the cytosol.
ABSTRACT
We searched for an isotropic stochastic gravitational wave background in the second data release of the International Pulsar Timing Array, a global collaboration synthesizing decadal-length ...pulsar-timing campaigns in North America, Europe, and Australia. In our reference search for a power-law strain spectrum of the form $h_c = A(f/1\, \mathrm{yr}^{-1})^{\alpha }$, we found strong evidence for a spectrally similar low-frequency stochastic process of amplitude $A = 3.8^{+6.3}_{-2.5}\times 10^{-15}$ and spectral index α = −0.5 ± 0.5, where the uncertainties represent 95 per cent credible regions, using information from the auto- and cross-correlation terms between the pulsars in the array. For a spectral index of α = −2/3, as expected from a population of inspiralling supermassive black hole binaries, the recovered amplitude is $A = 2.8^{+1.2}_{-0.8}\times 10^{-15}$. None the less, no significant evidence of the Hellings–Downs correlations that would indicate a gravitational-wave origin was found. We also analysed the constituent data from the individual pulsar timing arrays in a consistent way, and clearly demonstrate that the combined international data set is more sensitive. Furthermore, we demonstrate that this combined data set produces comparable constraints to recent single-array data sets which have more data than the constituent parts of the combination. Future international data releases will deliver increased sensitivity to gravitational wave radiation, and significantly increase the detection probability.
Efficient carrier multiplication has been reported for several semiconductor nanocrystals: PbSe, PbS, PbTe, CdSe, InAs, and Si. Some of these reports have been challenged by studies claiming that ...carrier multiplication does not occur in CdSe, CdTe, and InAs nanocrystals, thus raising legitimate doubts concerning the occurrence of carrier multiplication in the remaining materials. Here, conclusive evidence is given for its occurrence in PbSe nanocrystals using femtosecond transient photobleaching. In addition, it is shown that a correct determination of carrier-multiplication efficiency requires spectral integration over the photobleach feature. The carrier multiplication efficiency we obtain is significantly lower than what has been reported previously, and it remains an open question whether it is higher in nanocrystals than it is in bulk semiconductors.
Excisional procedures of cervical intraepithelial neoplasia (CIN) may increase the risk of preterm birth. It is unknown whether this increased risk is due to the excision procedure itself, to the ...underlying CIN, or to secondary risk factors that are associated with both preterm birth and CIN. The aim of this study is to assess the risk of spontaneous preterm birth in women with treated and untreated CIN and examine possible associations by making a distinction between the excised volume of cervical tissue and having cervical disease. This Dutch population-based observational cohort study identified women aged 29 to 41 years with CIN between 2005 and 2015 from the Dutch pathology registry (PALGA) and frequency matched them with a control group without any cervical abnormality based on age at and year of pathology outcome (i.e., CIN or normal cytology) and urbanization (<100,000 inhabitants or greater than or equal to100,000 inhabitants). All their 45,259 subsequent singleton pregnancies with a gestational age greater than or equal to16 weeks between 2010 and 2017 were identified from the Dutch perinatal database (Perined). Nineteen potential confounders for preterm birth were identified. Adjusted odds ratios (ORs) were calculated for preterm birth comparing the 3 different groups of women: (1) women without CIN diagnosis; (2) women with untreated CIN; and (3) women with treated CIN prior to each childbirth. In this study, we observed a strong correlation between preterm birth and a volume of greater than or equal to0.5 cc excised cervical tissue, regardless of the severity of CIN. Caution should be taken when performing excisional treatment in women of reproductive age as well as prudence in case of multiple biopsies. Fertile women with a history of performing multiple biopsies or excisional treatment for CIN may benefit from close surveillance during pregnancy.
Background
Compared to the previous cytology-based program, the introduction of primary high-risk human papillomavirus (hrHPV) based screening in 2017 has led to an increased number of referrals. To ...counter this, triage of hrHPV-positive women in cervical cancer screening can potentially be optimized by taking sociodemographic and lifestyle risk factors for cervical abnormalities into account. Therefore, it is essential to gain knowledge of the views of women (30–60 years) eligible for cervical cancer screening.
Objective
The main goal of this qualitative study was to gain insight in the aspects that influence acceptability of risk-based triage in cervical cancer screening.
Design
A focus group study in which participants were recruited via four general medical practices, and purposive sampling was used to maximize heterogeneity with regards to age, education level, and cervical cancer screening experiences.
Approach
The focus group discussions were transcribed verbatim and analyzed using reflexive thematic analysis.
Participants
A total of 28 women (average age: 45.2 years) eligible for cervical cancer screening in The Netherlands participated in seven online focus group discussions. Half of the participants was higher educated, and the participants differed in previous cervical cancer screening participation and screening result.
Key results
In total, 5 main themes and 17 subthemes were identified that determine the acceptability of risk-stratified triage. The main themes are: 1) adequacy of the screening program: an evidence-based program that is able to minimize cancer incidence and reduce unnecessary referrals; 2) personal information (e.g., sensitive topics and stigma); 3) emotional impact: fear and reassurance; 4) communication (e.g., transparency); and 5) autonomy (e.g., prevention).
Conclusion
The current study highlights several challenges regarding the development and implementation of risk-based triage that need attention in order to be accepted by the target group. These challenges include dealing with sensitive topics and a transparent communication strategy.
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