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Key Points Summarises the benefits of a health-promoting oral microbiome for oral and general health. Provides an overview of coevolution between humans and oral microbes. Reviews factors associated with dysbiosis and implications for caries and periodontal disease. Highlights existing strategies to preserve a balanced oral microbiome for practitioners and patients to follow. For millions of years, our resident microbes have coevolved and coexisted with us in a mostly harmonious symbiotic relationship. We are not distinct entities from our microbiome, but together we form a 'superorganism' or holobiont, with the microbiome playing a significant role in our physiology and health. The mouth houses the second most diverse microbial community in the body, harbouring over 700 species of bacteria that colonise the hard surfaces of teeth and the soft tissues of the oral mucosa. Through recent advances in technology, we have started to unravel the complexities of the oral microbiome and gained new insights into its role during both health and disease. Perturbations of the oral microbiome through modern-day lifestyles can have detrimental consequences for our general and oral health. In dysbiosis, the finely-tuned equilibrium of the oral ecosystem is disrupted, allowing disease-promoting bacteria to manifest and cause conditions such as caries, gingivitis and periodontitis. For practitioners and patients alike, promoting a balanced microbiome is therefore important to effectively maintain or restore oral health. This article aims to give an update on our current knowledge of the oral microbiome in health and disease and to discuss implications for modern-day oral healthcare.

Trophic rewilding is an ecological restoration strategy that uses species introductions to restore top-down trophic interactions and associated trophic cascades to promote self-regulating biodiverse ecosystems. Given the importance of large animals in trophic cascades and their widespread losses and resulting trophic downgrading, it often focuses on restoring functional megafaunas. Trophic rewilding is increasingly being implemented for conservation, but remains controversial. Here, we provide a synthesis of its current scientific basis, highlighting trophic cascades as the key conceptual framework, discussing the main lessons learned from ongoing rewilding projects, systematically reviewing the current literature, and highlighting unintentional rewilding and spontaneous wildlife comebacks as underused sources of information. Together, these lines of evidence show that trophic cascades may be restored via species reintroductions and ecological replacements. It is clear, however, that megafauna effects may be affected by poorly understood trophic complexity effects and interactions with landscape settings, human activities, and other factors. Unfortunately, empirical research on trophic rewilding is still rare, fragmented, and geographically biased, with the literature dominated by essays and opinion pieces. We highlight the need for applied programs to include hypothesis testing and science-based monitoring, and outline priorities for future research, notably assessing the role of trophic complexity, interplay with landscape settings, land use, and climate change, as well as developing the global scope for rewilding and tools to optimize benefits and reduce human–wildlife conflicts. Finally, we recommend developing a decision framework for species selection, building on functional and phylogenetic information and with attention to the potential contribution from synthetic biology.

Supplementation with fish oil–derived fatty acids during pregnancy reduced the incidence of cases of persistent wheeze or asthma in offspring. The incidence of asthma and wheezing disorders has more than doubled in westernized countries in recent decades. 1 These conditions often originate in early childhood 2 and currently affect one in five young children. 3 Concomitantly, the increased use of vegetable oils in cooking and of grain in the feeding of livestock has resulted in an increase in the intake of n−6 polyunsaturated fatty acids and a decrease in the intake of n−3 polyunsaturated fatty acids, especially the long-chain polyunsaturated fatty acids (LCPUFAs) — eicosapentaenoic acid (20:5n–3, EPA) and docosahexaenoic acid (22:6n–3, DHA) — found in cold-water fish. 4 Observational studies have suggested an . . .

Infection leading to necrosis of any bone can lead to chronic osteomyelitis (CO), sometimes resulting in permanent orthopedic sequelae. There are no published guidelines on the optimal management of adult or pediatric CO The objective of this study was to analyze published evidence for the epidemiology and management of pediatric CO. Inclusion criteria were studies of any design (minimum 2 patients) in any language that included patients with CO up to 17 years of age and described the epidemiology or management of CO. Ovid Medline(R) ALL, Embase (via Ovid), CINAHL Plus with Full Text (via EBSCOhost) and Scopus were screened Jan 1, 1989 to Feb 13, 2025. Quality assessment was based on the degree of bias if one were to use that study to make decisions about management of CO. Studies were divided into those from middle-high and high-income countries versus studies from lower income countries. Data were extracted on demographics, biomarkers, pathogens, treatments offered, recurrences and orthopedic sequelae. There were 41 included studies - 26 from middle-high- and high-income countries (904 cases total) and 15 from lower income countries (975 cases total). All were observational and only 19 of the 41 studies reported 7 or 8 of the 8 items deemed essential to make decisions about management of CO. Definitions of CO varied markedly. Analyzing the 17 studies that included a minimum of 10 consecutive cases, 627 of 1073 cases (58%) occurred in males. In these 17 studies, the tibia or femur accounted for 630 of 934 cases (67%). In 212 of 287 cases (74%) with a single pathogen reported, that pathogen was Staphylococcus aureus. There were no apparent differences in sex, bones involved or pathogens by country income level. Most cases (with the notable exception of those in recent case series from the United States) were managed with debridement. This was typically followed by sequential intravenous/per os (IV/ PO) antibiotics with almost no patients managed with PO antibiotics alone. Twelve case series reported use of local antibiotic delivery in addition to systemic antibiotics, but none of these studies had a control group. Studies were too heterogeneous in design to allow for data to be directly compared or combined. However, there was no obvious relationship between the route or duration of antimicrobials and the incidence of recurrences or orthopedic sequalae. There is a great need for high quality studies of all aspects of diagnosis and treatment of CO. Empiric coverage should target S. aureus. The evidence is poor quality, but there is no evidence that prolonged courses of antibiotics prevent recurrences.

The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

Background Internationally, older patients (≥65 years) account for more than 40% of acute admissions. Older patients admitted to the emergency department (ED) are frequently malnourished and exposed to inappropriate medication prescribing, due in part to the inaccuracy of creatinine-based equations for estimated glomerular filtration rate (eGFR). The overall aims of this trial are to investigate: (1) the efficacy of a medication review (MED intervention) independent of nutritional status, (2) the accuracy of eGFR equations based on various biomarkers compared to measured GFR (mGFR) based on 99m Technetium–diethylenetriaminepentaacetic acid plasma clearance, and (3) the efficacy of an individualized multimodal and transitional nutritional intervention (MULTI-NUT-MED intervention) in older patients with or at risk of malnutrition in the ED. Methods The trial is a single-center block randomized, controlled, observer-blinded, superiority and explorative trial with two parallel groups. The population consists of 200 older patients admitted to the ED: 70 patients without malnutrition or risk of malnutrition and 130 patients with or at risk of malnutrition defined as a Mini Nutritional Assessment-Short Form score ≤11. All patients without the risk of malnutrition receive the MED intervention, which consists of a medication review by a pharmacist and geriatrician in the ED. Patients with or at risk of malnutrition receive the MULTI-NUT-MED intervention, which consists of the MED intervention in addition to, dietary counseling and individualized interventions based on the results of screening tests for dysphagia, problems with activities of daily living, low muscle strength in the lower extremities, depression, and problems with oral health. Baseline data are collected upon study inclusion, and follow-up data are collected at 8 and 16 weeks after discharge. The primary outcomes are (1) change in medication appropriateness index (MAI) score from baseline to 8 weeks after discharge, (2) accuracy of different eGFR equations compared to mGFR, and (3) change in health-related quality of life (measured with EuroQol-5D-5L) from baseline to 16 weeks after discharge. Discussion The trial will provide new information on strategies to optimize the treatment of malnutrition and inappropriate medication prescribing among older patients admitted to the ED. Trail registration ClinicalTrials.gov NTC03741283 . Retrospectively registered on 14 November 2018.

A family history of schizophrenia is the strongest single indicator of individual schizophrenia risk. Bipolar affective disorder and schizo-affective disorders have been documented to occur more frequently in parents and siblings of schizophrenia patients, but the familial occurrence of the broader range of mental illnesses and their role as confounders have not been studied in large population-based samples. All people born in Denmark between 1955 and 1991 (1.74 million) were followed for the development of schizophrenia (9324 cases) during 28 million person-years at risk. Information of schizophrenia in cohort members and psychiatric history in parents and siblings was established through linkage with the Danish Psychiatric Central Register. Data were analysed using log-linear Poisson regression. Schizophrenia was, as expected, strongly associated with schizophrenia and related disorders among first-degree relatives. However, almost any other psychiatric disorder among first-degree relatives increased the individual's risk of schizophrenia. The population attributable risk associated with psychiatric family history in general was 27.1% whereas family histories including schizophrenia only accounted for 6.0%. The general psychiatric family history was a confounder of the association between schizophrenia and urbanization of place of birth. Clinically diagnosed schizophrenia is associated with a much broader range of mental disorders in first-degree relatives than previously reported. This may suggest risk haplotypes shared across many disorders and/or shared environmental factors clustering in families. Failure to take the broad range of psychiatric family history into account may bias results of all risk-factor studies of schizophrenia.

Background Carbonic anhydrases catalyze CO 2 /HCO 3 – buffer reactions with implications for effective H + mobility, pH dynamics, and cellular acid–base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear. Methods We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas. Results Carbonic anhydrases—particularly the extracellular isoforms CA4 , CA6 , CA9 , CA12 , and CA14 —undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H + elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3 + T cells, CD19 + B cells, F4/80 + macrophages), lowers inflammatory cytokine ( Il1a , Il1b , Il6 ) and transcription factor ( Nfkb1 ) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis. Conclusions We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H + elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival.

The main organelles of the secretory and endocytic pathways—the endoplasmic reticulum (ER) and endosomes, respectively—are connected through contact sites whose numbers increase as endosomes mature 1 , 2 , 3 . One function of such sites is to enable dephosphorylation of the cytosolic tails of endosomal signalling receptors by an ER-associated phosphatase 4 , whereas others serve to negatively control the association of endosomes with the minus-end-directed microtubule motor dynein 5 or mediate endosome fission 6 . Cholesterol transfer and Ca 2+ exchange have been proposed as additional functions of such sites 2 , 3 . However, the compositions, activities and regulations of ER–endosome contact sites remain incompletely understood. Here we show in human and rat cell lines that protrudin, an ER protein that promotes protrusion and neurite outgrowth 7 , forms contact sites with late endosomes (LEs) via coincident detection of the small GTPase RAB7 and phosphatidylinositol 3-phosphate (PtdIns(3)P). These contact sites mediate transfer of the microtubule motor kinesin 1 from protrudin to the motor adaptor FYCO1 on LEs. Repeated LE–ER contacts promote microtubule-dependent translocation of LEs to the cell periphery and subsequent synaptotagmin-VII-dependent fusion with the plasma membrane. Such fusion induces outgrowth of protrusions and neurites, which requires the abilities of protrudin and FYCO1 to interact with LEs and kinesin 1. Thus, protrudin-containing ER–LE contact sites are platforms for kinesin-1 loading onto LEs, and kinesin-1-mediated translocation of LEs to the plasma membrane, fuelled by repeated ER contacts, promotes protrusion and neurite outgrowth. Repeated contacts between the endoplasmic reticulum (ER) and a subset of endosomes called late endosomes (LEs) is shown to promote microtubule-dependent translocation of LEs to the cell periphery and their subsequent fusion with the plasma membrane to induce outgrowth of neuronal protrusions. Role of endosomes in neuronal protrusion outgrowth The endoplasmic reticulum (ER) makes contact with various other cellular organelles including endosomes. Although the functional significance of ER–endosome contact sites is known, the composition, activity and regulation of these sites is poorly explored. Harald Stenmark and co-workers provide a glimpse into these enigmatic aspects. They show that the ER protein protrudin makes contact with the small GTPase RAB7 and phosphatidylinositol 3-phosphate (PtdIns(3)P) on a subset of endosomes called late endosomes (LEs). This allows transfer of the microtubule motor protein kinesin-1 from protrudin to the motor adaptor FYCO1 on LEs. Thus repeated ER–LE contacts promote microtubule-dependent translocation of LEs to the cell periphery and their subsequent fusion with the plasma membrane to induce neurite outgrowth of neuronal protrusions.

The time delay from an interplanetary driver arriving at the magnetopause to the response in the ionosphere has never been quantified separately for different types of storm drivers. This study investigates the delay for storms driven by high‐speed streams and associated stream interaction regions (HSS/SIR), or by interplanetary coronal mass ejection sheaths and magnetic clouds (MC). The total field‐aligned current (FAC) and SME index lag the Newell coupling function (NCF) by 40 ± 10 min during storms driven by HSS/SIR and sheaths, and by 60 ± 10 min for MCs. The correlation coefficient between FAC and NCF reaches maximum value as NCF is averaged over the preceding 80 min for sheath, 90 min for HSS/SIR, and 140 min for MC storms. Plain Language Summary The Sun causes perturbations in the solar wind, which may drive geomagnetic storms associated with strong field‐aligned currents to the ionosphere. The solar wind drivers studied in this paper are high‐speed stream/stream interaction regions (HSS/SIR), and sheath and magnetic cloud (MC) interplanetary coronal mass ejections. The exact time from the arrival of the solar wind interplanetary driver at the magnetopause to the response in the ionospheric and field‐aligned currents (FAC) have not been quantified for different types of solar wind drivers. We study this time delay during geomagnetic storms and find that it is typically 40 min for HSS/SIR‐ and sheath‐driven storms, and 60 min for MC‐driven storms. Additionally, the total FAC best correlate with the solar wind averaged over the preceding 80 min for sheath, 90 min for HSS/SIR, and 140 min for MC‐driven storms. These results may help improve the accuracy of forecasting solar wind disturbances on the high‐latitude ionosphere. Key Points Correlation between Newell coupling function (NCF) and total field‐aligned current (FAC) is studied for different storm drivers Best correlation for sheath, high‐speed stream, and magnetic cloud storms is found by integrating NCF over 80, 90, and 140 min, respectively Sheath‐driven storms are associated with the highest values of total FAC and NCF