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Walking on the tightrope: the shared roles of the bridging pericytes in the brain.
No full textThe vasculature of the central nervous system (CNS) is a highly specialized structure that delivers oxygen and nutrients to energy-demanding neural cells while protecting them from the toxicity of blood-borne substances. Pericytes, located alongside microvessels, coordinate with endothelial cells to maintain the integrity of the blood-CNS barriers and to regulate vascular responses to neural activity. Pericytes extend processes that typically wrap around or align the endothelial cells, remaining embedded within the vascular basement membrane. Occasionally, however, some of these processes detach and form bridges between separate capillaries. These bridging structures are the focus of ongoing debate. While some studies propose they serve as tunneling nanotubes mediating neurovascular coupling, others argue they may be remnants of vascular regression or involved in the process of pericyte migration. In this review, we aim to clarify these varying interpretations of bridging pericyte processes and provide a unified understanding to guide future research. We discuss their reported roles in both CNS health and disease, highlighting their potential significance in vascular aging and rejuvenation
Diagnostic Underuse and Antimicrobial Resistance Patterns Among Hospitalized Children in a National Referral Hospital in Kenya: A Five-Year Retrospective Study:Antibiotics
No full textBackground: Antimicrobial resistance (AMR) is a growing global health threat, with children in low- and middle-income countries bearing a disproportionate burden. Data on resistance patterns and diagnostic practices in pediatric populations remain limited. This study evaluated diagnostic utilization and AMR among children hospitalized with bacterial infections at a national referral hospital in Kenya. Methods: We conducted a retrospective cohort study of pediatric inpatients (0–12 years) admitted with bacterial infections between 2017 and 2021. Patient records were identified using ICD-10 codes and reviewed for diagnostic testing and antimicrobial susceptibility. Descriptive statistics were conducted to show infection counts, diagnostic testing, and resistance outcomes. Results: Among 1608 patients, 1009/1608 (63%) were infants under one year. Culture was conducted in 640/1608 (40%) and antimicrobial sensitivity testing in 111/640 (17%) patients. Gastroenteritis (46%) was the most common infection and blood the most frequently collected specimen (31%). Of 1039 cultured specimens, 896/1039 (86%) showed no growth. The most commonly isolated organisms were Klebsiella pneumoniae 19/128 (15%), Staphylococcus epidermidis (13%, 17/128), and Enterococcus faecium (13%, 16/128). Notably, K. pneumoniae showed 100% resistance to third-generation cephalosporins, suggestive of ESBL production. Among the tested samples, 92/128 (72%) had MDROs, and 26/92 (28%) were extensively drug-resistant (XDR). Among the patients tested, 84/111 (76%) had MDROs, of which 25/84 (30%) were XDR. Children under 5 years had higher odds (OR = 5.84, 95% CI: 1.17-38.21) of having MDRO infections, as well as those with multiple admissions (OR = 3.77, 95% CI: 1.06–20.34). Further, increasing age was inversely associated with MDRO presence. The odds of MDRO infection decreased by 24% for every year increase in age (aOR = 0.76; 95% CI: 0.60–0.93; p = 0.006). Conclusions: The findings highlight the limited diagnostic use and a high burden of MDROs and XDR infections in hospitalized children. Strengthening diagnostic capacity and pediatric antimicrobial stewardship is urgently needed in such settings
Investigating the ageing-Parkinson’s disease nexus: standardisation of in vitro models and techniques by the PD-AGE network
No full textAgeing is the primary risk factor for Parkinson’s disease, yet the intricate interplay between these processes remains ambiguous. This position paper, a collaborative output from the PD-AGE consortium, addresses the urgent need for standardising methods in in vitro modelling. A panel of international experts recommends human induced pluripotent stem cell (iPSC)-derived models, with chemically induced ageing methods, such as the SLO cocktail, as a robust system. Furthermore, the consortium highlights the value of direct and semi-direct reprogramming for retaining donor-specific ageing phenotypes. The paper also outlines a prioritised panel of measurable parameters, categorised into senescence, inflammaging, omics profiling, and mitochondrial dysfunction, providing a consistent framework to enhance research reproducibility, investigating the nexus of ageing and Parkinson’s. In addition, we provide links to SOPs (https://doi.org/10.5281/zenodo.15056603) [1] to measure the key measurable ageing parameters outlined in this review to facilitate consistency and reproducibility within the field
Dissecting the mechanisms of MASLD fibrosis in the era of single-cell and spatial omics
No full textMetabolic dysfunction-associated steatotic liver disease (MASLD), now the most common cause of chronic liver disease, is estimated to affect around 30% of the global population. In MASLD, chronic liver injury can result in scarring or fibrosis, with the degree of fibrosis being the best-known predictor of adverse clinical outcomes. Hence, there is huge interest in developing new therapies to inhibit or reverse fibrosis in MASLD. However, this has been challenging to achieve, as the biology of fibrosis and candidate antifibrotic therapeutic targets have remained poorly described in patient samples. In recent years, the advent of single-cell and spatial omics approaches that can be applied to human samples have started to transform our understanding of fibrosis biology in MASLD. In this Review, we describe these technological advances and discuss the new insights such studies have provided, focusing on the role of epithelial cell plasticity, mesenchymal cell activation, scar-associated macrophage accumulation, and inflammatory cell stimulation as regulators of liver fibrosis. We also consider how omics techniques can enhance our understanding of evolving concepts in the field, such as hot versus cold fibrosis and the mechanisms of liver fibrosis regression. Finally, we touch on future developments and how they are likely to inform a more mechanistic understanding about how fibrosis might differ between patients and how this could influence optimal therapeutic approaches.</p
HIPSTR: highest independent posterior subtree reconstruction in TreeAnnotator X
No full textIn Bayesian phylogenetic and phylodynamic studies, it is common to summarize the posterior distribution of trees with a time-calibrated summary phylogeny. While the maximum clade credibility (MCC) tree is often used for this purpose, we here show that a novel summary tree method—the highest independent posterior subtree reconstruction, or (HIPSTR)—contains consistently higher supported clades over MCC. We also provide faster computational routines for estimating both summary trees in an updated version of TreeAnnotator X, an open-source software program that summarizes the information from a sample of trees and returns many helpful statistics such as individual clade credibilities contained in the summary tree.HIPSTR and MCC reconstructions on two Ebola virus and two SARS-CoV-2 datasets show that HIPSTR yields summary trees that consistently contain clades with higher support compared to MCC trees. The MCC trees regularly fail to include several clades with very high posterior probability (≥0.95) as well as a large number of clades with moderate to high posterior probability (≥50%), whereas HIPSTR—in particular its majority-rule extension MrHIPSTR—achieves near-perfect performance in this respect. HIPSTR and MrHIPSTR also exhibit favourable computational performance over MCC in TreeAnnotator X. Comparison to the recent CCD0-MAP algorithm yielded mixed results and requires a more in-depth investigation in follow-up studies.TreeAnnotator X is available as part of the BEAST X (v10.5.0) software package, available at https://github.com/beast-dev/beast-mcmc/releases, and on Zenodo (DOI: https://doi.org/10.5281/zenodo.4895234)
Needle Matters: Addressing the Effect of the Needle on Contact Angle Hysteresis Surface Characterisation
No full textReliable measurements of Contact Angle Hysteresis (CAH) are crucial for understanding surface wettability and droplet mobility. Although sessile drop goniometry − where droplets are inflated and deflated using a syringe needle − is widely used, systematic errors can occur due to variations in needle properties and dosing flow rates. These influences are not well quantified, which limits the reproducibility and comparability of CAH data across studies. Additionally, CAH measurements can be highly sensitive to the specifics of the experimental setup, a sensitivity that remains to be fully established. In this work, we systematically investigate the effects of needle size, material, and dosing flow rate on CAH measurements. We assess needle-droplet interactions at the primary surface-droplet and at the secondary needle-droplet triple-phase contact line (TPCL) and how these interactions affect droplet shape during CAH characterization, impacting the baseline contact angle and contact line dynamics. Our findings demonstrate that needle size is the primary factor significantly affecting the accuracy of advancing and receding contact angle measurements. The needle material has a secondary influence, especially on hydrophobic surfaces with high hysteresis. In contrast, hydrophilic surfaces are less affected by needle properties due to strong adhesion and high pinning forces, while low-hysteresis surfaces are also less affected owed to their low resistance to droplet movement. Although dosing flow rate significantly impacts contact angle measurements, particularly on hydrophobic surfaces, the effects of needle size and material are more pronounced. A flow rate of 10 μL/min, combined with recommended needle properties depending on the surface characterized, is suggested to facilitate quasi-steady droplet volume changes and minimize dynamic effects. These findings illuminate the intricate relationship between surface wettability, needle characteristics, and droplet mobility, providing quantitative criteria for optimizing experimental conditions and enhancing measurement accuracy.<br/
Patent Rights, the Right to Health, and the WTO Dispute Settlement System
No full textThis paper critically assesses the extent to which a WTO member can rely on its right-to-health obligations to justify the implementation of measures relating to patent rights that are designed to improve access to medicines and the local production of medicines and vaccines. Focusing specifically on local working requirements, the paper is structured into three main sections. The first section examines the relationship between patent rights, TRIPS flexibilities, and the right-to-health obligations of states. The second section critically assesses the extent to which human rights law can play a role in WTO disputes. In light of this assessment, the third section evaluates what role, if any, the right to health can play in disputes involving patents and other intellectual property rights at the WTO
Changes in body composition and average daily energy expenditure of men and women during arduous extended polar travel
No full textManaging Dystonia in Partington Syndrome
No full textBACKGROUND: Bilateral focal hand dystonia is an almost pathognomonic sign of Partington syndrome, frequently accompanied by intellectual disability and oromotor dyspraxia. However, a few studies have focused on the treatment of this focal dystonia, making patient management uncertain.CASES: We present 2 cases of Partington syndrome featuring Aristaless-related homeobox (ARX) gene mutations, hand dystonia, and other clinical signs. Various drug treatments were attempted, including levodopa (l-dopa), trihexyphenidyl, tetrabenazine, and benzodiazepines, as well as botulinum toxin. Additionally, a blinded dystonia protocol was used to assess l-dopa's efficacy in 1 patient, which confirmed only mild benefit.LITERATURE REVIEW: Through a systematic review of the literature, we found that only l-dopa and baclofen might result in mild improvement, whereas propranolol, gabapentin, and haloperidol were reported as ineffective. The descriptions in those studies were, however, imprecise and the improvement rather mild, hindering definitive conclusions about their effectiveness.CONCLUSIONS: Treatment options in Partington syndrome-associated dystonia remain elusive. Further research and additional case studies are needed to fully characterize the clinical features of Partington syndrome and to identify effective treatments.</p
Latest developments in Paget's disease of bone
No full textPaget's disease of bone is characterised by focal increases in osteoclastic bone resorption coupled to increased but disorganised bone formation. It is a relatively rare disease affecting up to 1% of individuals in the United Kingdom, but many cases are not diagnosed clinically. The most common presentation is with musculoskeletal pain which in some cases is due to increased bone turnover, but which can also be due to complications such as bone deformity, nerve compression syndromes and osteoarthritis. Predisposition to Paget's disease is regulated by pathogenic variants in or close to genes that regulate osteoclast differentiation and function. The most important of these is SQSTM1 which encodes p62 - a signalling protein in the NFκB pathway. Environmental factors also influence susceptibility to PDB and disease severity, but the mechanisms are not well understood. Medical management is based on the use of bisphosphonates to supress the abnormal bone turnover and are indicated for the treatment of bone pain associated with the disease. Of the bisphosphonates currently available, intravenous zoledronic acid is the treatment of choice. The diagnosis can usually be made by typical features on X-ray and radionuclide bone scan. Genetic testing for pathogenic variants in the SQSTM1 gene in people with a family history of Paget's disease has been used to detect people with early asymptomatic disease, and in these individuals, prophylactic treatment with zoledronic acid favourably affects disease progression.</p
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