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Pollen limitation has a considerable influence on forest masting, the highly variable and synchronised seed production, on which forest regeneration and ecosystem dynamics largely rely. Depending on the various mechanisms possibly involved in pollen limitation, the consequences of climate change on masting could be very different. These mechanisms were investigated in 10 oak populations along a climatic gradient using surveys of airborne pollen and fruiting rate as a proxy of pollen limitation. We found no support for the widely accepted hypothesis of the intra-annual synchrony of flower phenology when considered in isolation. Instead, the fruiting rate was largely explained by a combination of intra-annual flower phenology synchrony, annual investment in flowering and the effects of weather on pollen maturation and diffusion. These findings highlight the need for a cohesive theoretical framework for pollen limitation to accurately predict the impact of climate change on oak-dominated ecosystems., (© 2024 John Wiley & Sons Ltd.)

Etripamil is a calcium channel blocker currently in Phase 3 trials for the treatment of paroxysmal supraventricular tachycardia (PSVT). Systemic and local toxicity following once-weekly intranasal administration of etripamil was evaluated in cynomolgus macaques to support clinical development. Groups of animals (N = 8, 4 males and 4 females) were administered etripamil into the left nostril weekly at dose levels of 0 (vehicle), 1.9, 3.8, or 5.7 mg/kg/dose for 26 doses. Persistence, reversibility, and progression of findings were examined following a 28-day recovery period. Clinical signs were transient and were related to the intranasal administration (e.g., nasal discharge, sneezing, etc.) of etripamil. There were no macroscopic or systemic microscopic findings at any dose. Etripamil-related adaptive and reactive local changes affecting the nasal cavity, larynx, and nasopharynx were observed at ≥1.9 mg/kg/dose. Minimal to severe dose-dependent nasal epithelial damage was observed, mainly affecting respiratory and transitional epithelium. Following the 28-day recovery period, microscopic changes were confined to the left nasal cavity and nasopharynx. These changes were significantly lower in incidence and severity, with noticeable reversal of the adaptive and reactive changes, indicating partial to complete recovery of the epithelial lining. Based on the lack of systemic toxicity and the minimal and transient nasal changes, the systemic, no observable adverse effect level (NOAEL) of etripamil in monkeys was the high dose, 5.7 mg/kg/dose. The NOAEL for local toxicity was 1.9 mg/kg/dose. Collectively, these data support further study of etripamil in human trials as a potential treatment for PSVT., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Jean-Pierre Moreau is an employee of Recherche Continuum Research and was contracted by Milestone Pharmaceuticals to design and monitor the study. Charles River Laboratories was contracted by Milestone Pharmaceuticals to perform this study. Douglas Wight was an employee of Milestone Pharmaceuticals at the time of this study. Veronique Boulanger was an employee of Milestone Pharmaceuticals at the time of this study.

A cost-effective fiber laser architecture is introduced in which the output seed pulse is stretched and then returned in the oscillator for an additional single-pass amplification without spectral broadening. It is implemented in an all-PM-fiber configuration based on a Mamyshev oscillator with a low repetition rate of 1 MHz. It features a linear oscillator bounded by two offset chirped fiber Bragg gratings accompanied by a third one acting as a pulse recycling filter. The latter tailors the pulse profile in amplitude and phase to seed femtosecond chirped-pulse amplification systems without additional pre-amplification nor pulse stretching. A single-pump prototype generating 200-nJ, 100-ps pulses compressible to 290 fs at 1030 nm and at 960 kHz is demonstrated. Furthermore, simulations show how this new oscillator architecture can provide tailored seed pulses with high enough spectral energy density and low enough nonlinear phase to generate sub-200 fs, 40 µJ, > 180 MW pulses from an all-fiber setup involving a single tapered-fiber power amplifier, without pulse picking.

A femtosecond all-PM-fiber Mamyshev oscillator (MO) at 920 nm is presented. It is based on a neodymium-doped fiber with a W-type index profile that effectively suppresses the emission around 1064 nm. The linear cavity is bounded by two near-zero dispersion fiber Bragg gratings with Gaussian reflectivity profiles. The laser is self-starting and generates up to 10-nJ pulses at a repetition rate of 41 MHz. The pulses can be compressed to 53 fs with a grating-pair compressor. To our knowledge, this is the first Mamyshev oscillator and also the highest energy femtosecond fiber oscillator demonstrated in this spectral region.

Nutrition is a key contributor to health. Recently, several studies have identified associations between factors such as microbiota composition and health-related responses to dietary intake, raising the potential of personalized nutritional recommendations. To further our understanding of personalized nutrition, detailed individual data must be collected from participants in their day-to-day lives. However, this is challenging in conventional studies that require clinical measurements and site visits. So-called digital or remote cohorts allow in situ data collection on a daily basis through mobile applications, online services, and wearable sensors, but they raise questions about study retention and data quality. "Food & You" is a personalized nutrition study implemented as a digital cohort in which participants track food intake, physical activity, gut microbiota, glycemia, and other data for two to four weeks. Here, we describe the study protocol, report on study completion rates, and describe the collected data, focusing on assessing their quality and reliability. Overall, the study collected data from over 1000 participants, including high-resolution data of nutritional intake of more than 46 million kcal collected from 315,126 dishes over 23,335 participant days, 1,470,030 blood glucose measurements, 49,110 survey responses, and 1,024 stool samples for gut microbiota analysis. Retention was high, with over 60% of the enrolled participants completing the study. Various data quality assessment efforts suggest the captured high-resolution nutritional data accurately reflect individual diet patterns, paving the way for digital cohorts as a typical study design for personalized nutrition., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Héritier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We have developed a compact all-PM-fiber ytterbium-doped Mamyshev oscillator-amplifier laser system generating compressed pulses of 102 nJ and 37 fs, thus having over 2 MW of peak power, at a repetition rate of 52 MHz. The pump power from a single diode is shared between a linear cavity oscillator and a gain-managed nonlinear amplifier. The oscillator is self-started by pump-modulation and a linearly polarized single-pulse operation is achieved without filter tuning. The cavity filters are near-zero dispersion fiber Bragg gratings with a Gaussian spectral response. To our knowledge, this simple and efficient source has the highest repetition rate and average power among all-fiber multi-megawatt femtosecond pulsed laser sources and its architecture holds potential for generating higher pulse energies.

Large interannual variation in seed production, called masting, is very common in wind-pollinated tree populations and has profound implications for the dynamics of forest ecosystems and the epidemiology of certain human diseases. 1 , 2 , 3 , 4 , 5 Comparing the reproductive characteristics of populations established in climatically contrasting environments would provide powerful insight into masting mechanisms, but the required data are extremely scarce. We built a database from an unprecedented fine-scale 8-year survey of 150 sessile oak trees (Quercus petraea) from 15 populations distributed over a broad climatic gradient, including individual recordings of annual flowering effort, fruiting rate, and fruit production. Although oak masting was previously considered to depend mainly on fruiting rate variations, 6 , 7 we show that the female flowering effort is highly variable from year to year and explains most of the fruiting dynamics in two-thirds of the populations. What drives masting was found to differ among populations living under various climates. In soft-climate populations, the fruiting rate increases initially strongly with the flowering effort, and the intensity of masting results mainly from the flowering synchrony level between individuals. By contrast, the fruiting rate of harsh-climate populations depends mainly on spring weather, which ensures intense masting regardless of the flowering synchronization level. Our work highlights the need for jointly measuring flowering effort and fruit production to decipher the diversity of masting mechanisms among populations. Accounting for such diversity will be decisive in proposing accurate, and possibly contrasted, scenarios about future reproductive patterns of perennial plants with ongoing climate change and their numerous cascading effects., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rare diseases impact the lives of an estimated 350 million people worldwide, and yet about 90% of rare diseases remain without an approved treatment. New technologies have become available, such as gene and oligonucleotide therapies, that offer great promise in treating rare diseases. However, progress toward the development of therapies to treat these diseases is hampered by a limited understanding of the course of each rare disease, how changes in disease progression occur and can be effectively measured over time, and challenges in designing and running clinical trials in diseases where the natural history is poorly characterized. Data that could be used to characterize the natural history of each disease has often been collected in various ways, including in electronic health records, patient-report registries, clinical natural history studies, and in past clinical trials. However, each data source contains a limited number of subjects and different data elements, and data is frequently kept proprietary in the hands of the study sponsor rather than shared widely across the rare disease community. The Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP) is an FDA-funded effort to overcome these persistent challenges. By aggregating data across all rare diseases and making that data available to the community to support understanding of rare disease natural history and inform drug development, RDCA-DAP aims to accelerate the regulatory approval of new therapies. RDCA-DAP curates, standardizes, and tags data across rare disease datasets to make it findable within the database, and contains a built-in analytics platform to help visualize, interpret, and use it to support drug development. RDCA-DAP will coordinate data and tool resources across non-profit, commercial, and for-profit entities to serve a diverse array of rare disease stakeholders that includes academic researchers, drug developers, FDA reviewers and of course patients and their caregivers. Drug development programs utilizing the RDCA-DAP will be able to leverage existing data to support their efforts and reach definitive decisions on the efficacy of their therapeutics more efficiently and more rapidly than ever., (© 2022. The Drug Information Association, Inc.)

Background: National surveillance of healthcare-associated infections (HAIs) is necessary to identify areas of concern, monitor trends, and provide benchmark rates enabling comparison between hospitals. Benchmark rates require representative and large sample sizes often based on pooling of surveillance data. We performed a scoping review to understand the organization of national HAI surveillance programs globally., Methods: The search strategy included a literature review, Google search and personal communications with HAI surveillance program managers. Thirty-five countries were targeted from four regions (North America, Europe, United Kingdom and Oceania). The following information was retrieved: name of surveillance program, survey types (prevalence or incidence), frequency of reports, mode of participation (mandatory or voluntary), and infections under surveillance., Results: Two hundred and twenty articles of 6,688 identified were selected. The four countries with most publications were the US (48.2%), Germany (14.1%), Spain (6.8%) and Italy (5.9%). These articles identified HAI surveillance programs in 28 of 35 countries (80.0%), operating on a voluntary basis and monitoring HAI incidence rates. Most HAIs monitored surgical site infections in hip (n=20, 71.4%) and knee (n=19, 67.9%) and Clostridoides difficile infections (n=17, 60.7%)., Conclusion: Most countries analyzed have HAI surveillance programs, with characteristics varying by country. Patient-level data reporting with numerators and denominators is available for almost every surveillance program, allowing for reporting of incidence rates and more refined benchmarks, specific to a given healthcare category thus offering data that can be used to measure, monitor, and improve the incidence of HAIs., Competing Interests: Competing interest: A MacLaurin is an employee of Healthcare Excellence Canada. The other authors have no conflict of interest to disclose., (Public Health Agency of Canada, 2022.)

The automatic recognition of food on images has numerous interesting applications, including nutritional tracking in medical cohorts. The problem has received significant research attention, but an ongoing public benchmark on non-biased (i.e., not scraped from web) data to develop open and reproducible algorithms has been missing. Here, we report on the setup of such a benchmark using publicly available food images sourced through the mobile MyFoodRepo app used in research cohorts. Through four rounds, the benchmark released the MyFoodRepo-273 dataset constituting 24,119 images and a total of 39,325 segmented polygons categorized in 273 different classes. Models were evaluated on private tests sets from the same platform with 5,000 images and 7,865 annotations in the final round. Top-performing models on the 273 food categories reached a mean average precision of 0.568 (round 4) and a mean average recall of 0.885 (round 3), and were deployed in production use of the MyFoodRepo app. We present experimental validation of round 4 results, and discuss implications of the benchmark setup designed to increase the size and diversity of the dataset for future rounds., Competing Interests: SM and MS are co-founders of AIcrowd. ES and GS have been among the top performing participants and have been invited to coauthor the paper. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mohanty, Singhal, Scuccimarra, Kebaili, Héritier, Boulanger and Salathé.)

Conventional conservation policies in Europe notably rely on the passive restoration of natural forest dynamics by setting aside forest areas to preserve forest biodiversity. However, since forest reserves cover only a small proportion of the territory, conservation policies also require complementary conservation efforts in managed forests in order to achieve the biodiversity targets set up in the Convention on Biological Diversity. Conservation measures also raise the question of large herbivore management in and around set-asides, particularly regarding their impact on understory vegetation. Although many studies have separately analyzed the effects of forest management, management abandonment, and ungulate pressure on forest biodiversity, their joint effects have rarely been studied in a correlative framework. We studied 212 plots located in 15 strict forest reserves paired with adjacent managed forests in European France. We applied structural equation models to test the effects of management abandonment, stand structure, and ungulate pressure on the abundance, species richness, and diversity of herbaceous vascular plants and terricolous bryophytes. We showed that stand structure indices and plot-level browsing pressure had direct and opposite effects on herbaceous vascular plant species diversity; these effects were linked with the light tolerance of the different species groups. Increasing canopy cover had an overall negative effect on herbaceous vascular plant abundance and species diversity. The effect was two to three times greater in magnitude than the positive effects of browsing pressure on herbaceous plants diversity. On the other hand, a high stand density index had a positive effect on the species richness and diversity of bryophytes, while browsing had no effect. Forest management abandonment had few direct effects on understory plant communities, and mainly indirectly affected herbaceous vascular plant and bryophyte abundance and species richness and diversity through changes in vertical stand structure. Our results show that conservation biologists should rely on foresters and hunters to lead the preservation of understory vegetation communities in managed forests since, respectively, they manipulate stand structure and regulate ungulate pressure. Their management actions should be adapted to the taxa at stake, since bryophytes and vascular plants respond differently to stand and ungulate factors., (© 2022 The Ecological Society of America.)

Background: Although Canada has both a national active surveillance system and administrative data for the passive surveillance of healthcare-associated infections (HAI), both have identified strengths and weaknesses in their data collection and reporting. Active and passive surveillance work independently, resulting in results that diverge at times. To understand the divergences between administrative health data and active surveillance data, a scoping review was performed., Method: Medline, Embase and Cumulative Index to Nursing and Allied Health Literature along with grey literature were searched for studies in English and French that evaluated the use of administrative data, alone or in comparison with traditional surveillance, in Canada between 1995 and November 2, 2020. After extracting relevant information from selected articles, a descriptive summary of findings was provided with suggestions for the improvement of surveillance systems to optimize the overall data quality., Results: Sixteen articles met the inclusion criteria, including twelve observational studies and four systematic reviews. Studies showed that using a single source of administrative data was not accurate for HAI surveillance when compared with traditional active surveillance; however, combining different sources of data or combining administrative with active surveillance data improved accuracy. Electronic surveillance systems can also enhance surveillance by improving the ability to detect potential HAIs., Conclusion: Although active surveillance of HAIs produced the most accurate results and remains the gold-standard, the integration between active and passive surveillance data can be optimized. Administrative data can be used to enhance traditional active surveillance. Future studies are needed to evaluate the feasibility and benefits of potential solutions presented for the use of administrative data for HAI surveillance and reporting in Canada., Competing Interests: Competing interests: None of the authors had any conflicts of interest to disclose.

We present a linear cavity self-polarizing Mamyshev oscillator at 1550 nm made fully of polarization-maintaining fibers. The cavity filters are chirped fiber Bragg gratings with a Gaussian reflectivity profile that allow for greater reflectivity, larger bandwidth, and dispersion control. This mode-locked fiber laser architecture shows an unprecedented simplicity while delivering 21.3-nJ pulses compressed to 108 fs with a competitive 22.3% pump conversion efficiency. Mode locking is initiated with an external saturable absorber mirror. Numerical simulations show how nonlinearity can be managed with highly dispersive filters inside a Mamyshev oscillator.

Globally, an estimated 350 million people are affected by a rare disease diagnosis. Knowledge limitations persist for the majority of rare conditions due to systemic and structural challenges in healthcare and research. Disease-specific patient populations are often small and geographically dispersed; funding support for research is restricted; and diagnostic delays are common due to disease complexities, limited medical training for practitioners, and evolving foundational knowledge related to disease characterization. Patient registries can be effective, convenient, and cost-efficient tools to support documentation of the natural history of a disease, centering patients as research partners in the process while uniting rare communities around a common initiative. Current global trends towards innovative and patient-centered healthcare are enabling patient registries to increasingly emerge as valuable tools for use within rare disease research and drug development. This article describes the value of and rationale for establishing rare disease patient registries and the considerations and challenges that stakeholders, such as researchers, industry, health care providers, and patient community organizations, may encounter.

Muscle-invasive bladder cancer (MIBC) is an aggressive form of urothelial bladder carcinoma (UBC) with poorer outcomes compared to the non-muscle invasive form (NMIBC). Higher recurrent rates and rapid progression after relapse in UBC is known to be linked with chronic inflammation. Here, the preclinical murine models of NMIBC (MB49) and MIBC (MB49-I) were used to assess the antitumor effects of DAB-1, an anti-inflammatory aminobenzoic acid derivative we have developed in order to target cancer-related inflammation. A subchronic toxicity study on cancer-free mice shown that DAB-1 treatment did not affect normal mouse development or normal function of vital organs. In mice bearing MB49-I tumors, whole body accumulation of the radioconjugate [ 131 I]DAB-1 was higher than in control mice, the main sites of [ 131 I]DAB-1 accumulation being the liver (34%), the intestines (21%), and the tumors (18%). In vivo molecular therapy of ectopic and orthotopic tumors indicated that treatment with DAB-1 efficiently inhibited tumor growth, metastasis formation, and mortality rate. The antitumor efficacy of DAB-1 was associated with strong decreased tumor cell proliferation and iNOS expression in tumor tissues and deactivation of macrophages from tumor-bearing mice. Mechanistic investigations revealed that DAB-1 efficiently inhibited i) TNFα/NFΚB and IL6/STAT3 signaling pathways activation; ii) TNFα-induced NO production by decreasing NFΚB transcriptional activation and functional iNOS expression; and iii) cellular proliferation with minimal or no effects on cell mortality or apoptosis. In conclusion, this study provides preclinical and biological/mechanistic data highlighting the potential of DAB-1 as a safe and efficient therapeutic agent for the treatment of patients with NMIBC and MIBC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We report on an ytterbium-free erbium-doped aluminophosphosilicate all-fiber laser, producing an output power of 25 W at a wavelength of 1584 nm with a slope efficiency of 30% with respect to the 976 nm absorbed pump power. The simple cavity design proposed takes advantage of fiber Bragg gratings written directly in the gain fiber. The single-mode erbium-doped aluminophosphosilicate fiber was fabricated in-house and was doped with 0.06 mol.% of Er 2 O 3 , 1.77 mol.% of Al 2 O 3 and 1.04 mol.% of P 2 O 5 . The incorporation of aluminium and phosphorus into the fiber core allowed for an increased concentration of erbium without inducing significant clustering, while keeping the numerical aperture low to ensure a single-mode laser operation.

Many perennial plants display masting, that is, fruiting with strong interannual variations, irregular and synchronized between trees within the population. Here, we tested the hypothesis that the early flower phenology in temperate oak species promotes stochasticity into their fruiting dynamics, which could play a major role in tree reproductive success. From a large field monitoring network, we compared the pollen phenology between temperate and Mediterranean oak species. Then, focusing on temperate oak species, we explored the influence of the weather around the time of budburst and flowering on seed production, and simulated with a mechanistic model the consequences that an evolutionary shifting of flower phenology would have on fruiting dynamics. Temperate oak species release pollen earlier in the season than do Mediterranean oak species. Such early flowering in temperate oak species results in pollen often being released during unfavorable weather conditions and frequently results in reproductive failure. If pollen release were delayed as a result of natural selection, fruiting dynamics would exhibit much reduced stochastic variation. We propose that early flower phenology might be adaptive by making mast-seeding years rare and unpredictable, which would greatly help in controlling the dynamics of seed consumers., (© 2019 The Authors. New Phytologist © 2019 New Phytologist Trust.)

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

We investigated the possibility of reaching nanojoule-level pulse energies in a femtosecond erbium-doped fiber Mamyshev oscillator. In experiments, lasers generate stable pulse trains with energy up to 31.3 nJ, which is comparable to the highest achieved by prior ultrafast erbium fiber lasers. The pulse duration after a grating compressor is around 100 fs. However, as the pulse energy increases, the pulse quality degrades significantly, with a substantial fraction of the energy going into a picosecond pedestal. Numerical simulations agree with the experimental observations, and allow us to identify the gain spectrum and the nonlinearity of the erbium-doped fibers as challenges to the operation of such oscillators at high pulse energy.