Conectar
by Chi Peng Chan, Babaniji Omosule, Courtney Lightfoot, Ellesha A. Smith, Ffion Curtis, James O. Burton, Paul Gardner, Sarah Jasat, Sherna F. Adenwalla, Jyoti Baharani, Daniel S. March
BackgroundChronic pain affects up to 60% of people with chronic kidney disease (CKD), yet remains under-recognised and under-treated. Pain management in this population is complicated by altered drug pharmacokinetics, polypharmacy, and the potential nephrotoxicity of conventional analgesics. Despite the high prevalence and significant impact on quality of life, evidence-based guidance specific to pain management in CKD remains limited.
ObjectivesThis systematic review aims to evaluate the effectiveness and safety of both pharmacological and non-pharmacological interventions in reducing chronic pain intensity among people with CKD on dialysis, not on dialysis, and kidney transplant recipients, across all stages of CKD.
MethodsThe primary outcome is the effectiveness of interventions in reducing chronic pain intensity as assessed by pain assessment tools. We will conduct a comprehensive search of MEDLINE, Embase, CINAHL, Web of Science, and ClinicalTrials.gov from their inception to the present date to identify studies for chronic pain management in people living with CKD. Study screening will be conducted independently by two reviewers. One reviewer will extract data from each study, with a second reviewer cross-checking for accuracy and completeness. Data will be extracted on study characteristics, participant demographics, intervention components, pain outcomes, and adverse events. The certainty of evidence will be evaluated independently by two reviewers using the GRADE approach. Where applicable, data will be combined in meta-analyses using random-effects models. Additionally, a network meta-analysis will be performed if enough studies are available.
Expected resultsThis review will synthesise the current evidence for pain management strategies in CKD, by evaluating effectiveness of interventions among people receiving different renal replacement therapy modalities with varying pain and disease phenotypes. Findings will highlight the comparative effectiveness of various interventions while considering their safety profiles specific to the CKD context. The review will identify gaps in the literature and provide recommendations for clinical practice and future research.
SignificanceThis review seeks to deliver a thorough evaluation of pain management strategies for people living with CKD. This systematic review is supported by the UK Kidney Association (UKKA), and findings will inform the upcoming UKKA guideline on symptoms management in people with CKD, alongside the other symptoms including itch, fatigue, and gastrointestinal symptoms. This review will aid clinicians in making well-informed decisions regarding pain management strategies, ensuring a balance between effectiveness and the specific risks associated with CKD.
by Orit Wonderman Bar Sela, Shay Ofir Geva, Gaby S. Pell, Yiftach Roth, Jason Friedman, Afnan Muhana, Silvi Frenkel-Toledo, Nachum Soroker
Unidirectional transcranial magnetic stimulation (udTMS; e.g., via Figure-of-8 coil) depolarizes mainly neurons whose axonal orientation aligns with the direction of the induced electric field. A novel dual H-coil (T360°) TMS system (BrainsWayTM, Israel) generates a rotational magnetic field aimed to recruit a larger neuronal population by induction of a multidirectional electric field (rfTMS). This study aimed to comparatively assess the neurophysiological properties of motor evoked potentials (MEPs) elicited from the first dorsal interosseous (FDI) muscle following udTMS (via Figure-of-8 and H7 coils) vs. multidirectional rfTMS. In this study, 10 healthy adult subjects received TMS via the three coil configurations in a random order. The results showed that rfTMS elicited larger MEPs at a lower resting motor threshold (rMT) compared to the unidirectional coils. These findings suggest that rfTMS is likely to recruit larger populations of neurons compared to conventional udTMS coil configurations. This may be advantageous in efforts to enhance motor recovery following brain damage by treatments using TMS.by Viral D. Oza, Colin S. Williams, Jessica S. Blackburn
The Genetically Encoded Death Indicator (GEDI) is a ratiometric, dual-fluorescence biosensor that enables real-time detection of cell death through calcium influx. Originally developed for use in neurodegeneration models, GEDI can be applied to cancer cells to quantify therapy-induced death at single-cell resolution. This protocol details how to generate GEDI-expressing cancer cell lines, empirically determine stress-induced GEDI thresholds using radiation or chemotherapeutic agents, and perform time-resolved imaging and image analysis to track cell fate. This workflow is optimized for high-throughput drug and radiation screening in heterogeneous populations and is especially useful for identifying chemo- and radio-resistant subclones. Key limitations include the need for empirical GEDI threshold calibration for each treatment condition and careful standardization of imaging parameters. The protocol outputs include GEDI ratio values, single-cell time-of-death annotations, and whole-cell morphological data in parallel, which can be linked to downstream applications such as FACS-based isolation of live or dying subpopulations, transcriptomic profiling of resistant clones, or in vivo validation using xenografts or organotypic slice culture.by David A. Green, Jesse M. Maestas, Jessica N. Sanchez, Nathan C. Nieto, Andrew S. Bridges, David K. Garcelon
The San Clemente Island fox (Urocyon littoralis clementae) is classified as a focal species for conservation management by the US Navy. They are considered vulnerable to a variety of vector-borne diseases due to their relatively high population density and low genetic diversity. During the dry (July–November) and wet (December–February) seasons of 2017–2018 we live-trapped 95 foxes and collected ectoparasites to test for the presence of pathogens. We found a significant difference in ectoparasite abundance on foxes between seasons, but no differences associated with sex or age. We found that foxes carried two species of flea (Echidnophaga gallinacea and Orchopeas howardi) and two tick species (Ixodes pacificus and Ixodes jellisoni). No evidence of Borrelia burgdorferi, Anaplasma phagocytophilum, or Borrelia miyamotoi bacteria were found. This paper is the first account of ectoparasite species identification, quantification, and pathogen testing for the San Clemente Island fox subspecies.by Farhan R. Chowdhury, M. Ismail Hossain, Tangerul A. Jepu, Nusrat U. A. Saleh, Fatema T. Zohora, Tasmim A. Saleh, Mrinmoy Sarker, Al Numan, Zainab Yousuf, M. Aftab Uddin, Muktadir S. Hossain
Pneumococcal diseases caused by the human pathogenic bacterium Streptococcus pneumoniae are a major public health concern worldwide. In this study, we examined the pathogenicity of a clinical isolate of S. pneumoniae in the silk moth, Bombyx mori, larvae infection model. The whole genome sequencing of a clinical isolate of S. pneumoniae, Spn1 identified the presence of genes responsible for its virulence and antibiotic resistance. Spn1 infection of Bombyx larvae resulted in death within 24 h concomitant with an increase of phenoloxidase activity in the hemolymph. The bacterial load increased in the hemolymph within 9 h post-infection (p.i.) Ampicillin, ceftriaxone, tetracycline, imipenem, and erythromycin showed therapeutic effect in infected larvae, although the bacterial strain was resistant to erythromycin in vitro. The Bombyx homologs of mammalian TLR2 and TLR4, known as BmToll2 and BmToll9 (BmToll9−1 and BmToll9−2 isoforms), were upregulated in both the fat body and trachea. The antimicrobial peptide (AMP) genes, BmdefensinA and BmdefensinB, known to be regulated by the Toll signaling pathway, were significantly upregulated in both fat body and trachea after S. pneumoniae infection through hemolymph. Our data indicate that the Bombyx larvae can be a suitable infection model to study the pathogenicity of S. pneumoniae.by Ernest V. Boiko, Elena V. Samkovich, Irina E. Panova, Alexander A. Ivanov, Sergey B. Shevchenko, Sergey L. Vorobyev, Elizaveta S. Kalashnikova, Victoria G. Gvazava, Elizaveta A. Masian, Alexandra E. Kim
PurposeTo define optimal exposure parameters and the therapeutic window for transscleral photodynamic therapy (TSPDT) with chlorin e6 by evaluating clinical, histological, and thermal effects of subthreshold, therapeutic, and suprathreshold settings in rabbit eyes.
MethodsThe study was conducted on 21 healthy rabbits. TSPDT was performed using a 660 nm laser and chlorin e6 (2.5 mg/kg). Transscleral probes (5 mm: 0.1 W, 0.17 W, 0.3 W; 10 mm: 0.3 W, 0.6 W) with integrated thermosensors were used. Enucleation and histological analysis were performed 14 days post-irradiation.
ResultsFundus examination on day 14 revealed distinct treatment zones correlating with laser settings. The therapeutic window was defined as 0.14–0.17 W (5 mm probe; power density: 0.693–0.866 W/cm²; energy density: 415.8–519.6 J/cm²) and 0.48–0.6 W (10 mm probe; 0.611–0.764 W/cm²; 366.6–458.4 J/cm²) with 600 s exposure time, achieving selective choroidal damage without scleral or retinal injury (ΔT ≤ 4.5°C). Suprathreshold settings (≥0.3 W for 5 mm; ≥ 0.6 W for 10 mm) induced retinal necrosis (up to 50%) and scleral coagulation (ΔT ≥ 8°C) with power densities exceeding 0.866 W/cm² (5 mm) and 0.764 W/cm² (10 mm).
ConclusionTSPDT with chlorin e6 enables selective targeting of intraocular pathological tissues while preserving scleral and retinal integrity. Defining the therapeutic window and using real-time thermal monitoring enhances treatment safety. These findings lay a foundation for clinical protocols for uveal melanoma and other intraocular tumors.
by Akram J. Alahmar, Noha M. Elhosseiny, Rehab R. Mahmoud, Ahmed S. Attia
Acinetobacter baumannii is a growing threat characterized by worrisome antibiotic resistance. A deeper understanding of its resistance and virulence mechanisms is essential for developing new and effective treatments. Herein, we explore the role of the two-component (NtrB-NtrC) signal transduction system and two distinct glutamine synthetases (GlnA-1 and GlnA-2) in the nitrogen assimilation, stress response, and virulence in A. baumannii. Under nitrogen-limited conditions, the ntrC mutant showed significantly defective growth kinetics when ammonium was the sole source of nitrogen, whereas the glnA2 mutant exhibited an obvious growth defect when putrescine was the sole source of nitrogen. Moreover, under nitrogen limitation, the glnA1 and glnA2 expression increased by approximately twofold and ninefold, respectively. An enzymatic activity assay demonstrated that the A. baumannii extracellular glutamine synthetase activity is dependent on the type II secretion system (T2SS), confirming our previous results from a T2SS secretome study. Interestingly, this activity is also regulated by NtrC. An infection model using Galleria mellonella revealed that the ntrC mutant was significantly less virulent than both the wild-type and glnA2 mutant strains. These results provide new insights into the nitrogen regulatory network and its contribution to the A. baumannii virulence, underscoring NtrC as a promising target for future antimicrobial strategies.by Artiom Gruzdev, Wendy N. Jefferson, Thomas B. Hagler, Gregory J. Scott, Manas K. Ray, Ginger W. Muse, Rani S. Sellers, Carmen J. Williams
FVB/N mice, which are commonly used for cancer studies, have accelerated onset of endometrial cancer following developmental estrogenic chemical exposure. These mice also have a polymorphism in the mitochondrial gene, mt-Atp8, leading to increased production of reactive oxygen species. We hypothesized that this polymorphism contributes to the enhanced endometrial cancer phenotype in FVB/N mice. To test this idea, we generated conplastic FVB/N-mt129S6/SvEvTac mice (FVB/N nuclear genome; 129S6/SvEvTac mitochondria: FVB/N-mt129). The impact of 129S6 versus FVB/N mitochondrial genomes on endometrial cancer development following neonatal exposure to the xenoestrogen, diethylstilbestrol, was tested by comparing the cancer phenotypes of FVB/N mice to FVB/N-mt129 mice. There was no difference in cancer incidence regardless of mitochondria source, but cancer grade was higher in the conplastic strain. Additionally, while the FVB/N genetic background is considered non-permissive for generation of pluripotent mouse embryonic stem cells, blastocysts from the conplastic background readily generated mouse embryonic stem cell clones that supported gene editing in culture and subsequently generated germline competent chimeric founder mice. FVB/N-mt129 mice are a potentially powerful resource for generating germline competent embryonic stem cells with an FVB/N nuclear genome and for studying cancer phenotypes.by Elizabeth Youens, Dan G. O’Neill, Zoe Belshaw, Johanna Neufuss, Mickey S. Tivers, Rowena M. A. Packer
Extreme conformation and reduced genetic diversity are recognised to lead to severely reduced health, welfare and longevity in certain dog breeds. There is growing interest in applying strategic crossbreeding to promote more moderate conformations and greater genetic diversity within currently problematic breeds. Crossbreeding could therefore lead to more rapid and effective improvements in welfare compared to current practices of within-breed selection. Deliberate crossbreeding between distinct different dog breeds is not a new concept; it was historically commonly used to create the current pure breeds, to increase genetic diversity and to bring new physical and/or temperament traits into existing breeds. However, a recent surge in the popularity of ‘designer crossbreeds’ (intentional crosses between established purebreds) has elicited fresh interest around the potential positives and negatives of crossbreeding practices. Further research on crossbred brachycephalic dogs is urgently required for a greater understanding of the motivators and barriers to their acquisition. An online survey explored factors that motivate dog breed choice and acquisition of both crossbreed and purebred dogs. In addition, the survey used both closed and open questioning to explore the UK public’s perceptions of crossbreeding, specifically (i) between a brachycephalic breed and a non-brachycephalic breed, and (ii) between two non-brachycephalic breeds. Free-text results were analysed using content analysis and subsequently quantified. Results from 4,899 participants identified that key motivators to acquire a brachycephalic crossbreed vs a brachycephalic purebred included perceptions of improved health, including the reduction in risk of breed and conformation-related disorders, and increased genetic diversity. However, the desire to acquire a purebred dog, or even a specific breed, remained a significant barrier to crossbreed acquisition, alongside concerns surrounding the ethics of crossbreeding. Other barriers included perceived negative changes to appearance and temperament of the offspring from crossbreeding. The current study identified a common set of acquisition decision-making factors across all ownership groups, including desiring a dog who the owner perceives to enjoy being loved and to enjoy physical affection, but further demonstrated that good health is of motivational low priority to some dog owners, particularly to owners of purebred brachycephalic dogs. The mix of positive and negative public perceptions and beliefs around crossbreeding and crossbreed dogs demonstrate the need for further research into the health, temperament and appearance of brachycephalic crossbreed dogs. The suitability of crossbreed dogs as an alternative to certain current purebred breeds with high risk of genetic or conformational disorders depends on both public desire and on evidence-based selection of suitable breeds to encourage crosses which maximise canine welfare.by Mary O’Keeffe, Nathan Skidmore, Arianna Bagnis, Przemysław Bąbel, Elżbieta A. Bajcar, Alessandra De Palma, Andrea W.M. Evers, Eveliina Glogan, Julia W. Haas, Stefanie H. Meeuwis, Marek Oleszczyk, Antonio Portolés, Johan W.S. Vlaeyen, Katia Mattarozzi, on behalf of PANACEA Consortium
BackgroundPlacebo and nocebo effects significantly influence health outcomes, yet healthcare professionals receive limited training and guidance on their mechanisms and clinical application, creating a gap in education and practical understanding. Conducted within the European PANACEA Consortium, this study evaluated healthcare professionals’ knowledge, attitudes, and practices regarding placebo and nocebo effects, and assessed their needs in further education.
MethodsAn online cross-sectional survey among a European multi-country convenience sample of healthcare professionals collected data assessing participants’ knowledge, perceptions, and experiences regarding placebo and nocebo effects; their application and ethical considerations in clinical practice; and investigated educational needs and interest in further training. Quantitative data were analyzed using descriptive statistics, and thematic analysis was applied to the free-text responses.
ResultsAmongst 807 participants, 71.7% reported taking advantage of placebo effects in their practice, and over half of participants (55.8%) observing nocebo effects. Participants reported feeling somewhat confident (53.3%) in harnessing placebo effects with 47.5% feeling confident in preventing nocebo effects. The majority of respondents had not received formal training on placebo and nocebo effects, with most expressing an interest in further training in areas such as healthcare education, emphasizing communication skills to enhance placebo effects, and knowledge to recognize and reduce nocebo effects.
ConclusionsThere is a significant need for more comprehensive training on placebo and nocebo effects, particularly in early health professional education. These findings informed the development of educational resources and best practice recommendations developed as part of the outcomes from the PANACEA Consortium, improving the understanding and application of these effects among healthcare professionals across Europe.
by Qian Yue Tan, Kinda Ibrahim, Helen C. Roberts, Khaled Amar, Simon D.S. Fraser
BackgroundPeople with Parkinson’s (PwP) and their caregivers have to manage multiple daily healthcare tasks (treatment burden). This can be challenging and may lead to poor health outcomes.
ObjectiveTo assess the extent of treatment burden in Parkinson’s disease(PD), identify key modifiable factors, and develop recommendations to improve treatment burden.
MethodsA mixed-methods study was conducted consisting of: 1) a UK-wide cross-sectional survey for PwP and caregivers using the Multimorbidity Treatment Burden Questionnaire (MTBQ) to measure treatment burden levels and associated factors and 2) focus groups with key stakeholders to discuss survey findings and develop recommendations.
Results160 PwP (mean age = 68 years) and 30 caregivers (mean age = 69 years) completed the surveys. High treatment burden was reported by 21% (N = 34) of PwP and 50% (N = 15) of caregivers using the MTBQ. Amongst PwP, higher treatment burden was significantly associated with advancing PD severity, frailty, a higher number of non-motor symptoms, and more frequent medication timings (>3 times/day). Caregivers reporting higher treatment burden were more likely to care for someone with memory issues, had lower mental well-being scores and higher caregiver burden. Three online focus groups involved 11 participants (3 PwP, 1 caregiver and 7 healthcare professionals) recruited from the South of England. Recommendations to reduce treatment burden that were discussed in the focus groups include improving communication. clear expectation setting, and better signposting from healthcare professionals, increasing education and awareness of PD complexity, flexibility of appointment structures, increasing access to healthcare professionals, and embracing the supportive role of technology.
ConclusionsTreatment burden is common amongst PwP and caregivers and could be identified in clinical practice using the MTBQ. There is a need for change at individual provider and system levels to recognise and minimise treatment burden to improve health outcomes in PD.
by Darren Curnoe, Mohammed S. Sauffi, Hsiao Mei Goh, Xue-feng Sun, Roshan Peiris
The rarity of Late Pleistocene hominin remains from Insular Southeast Asia (ISEA) has hampered our ability to understand a crucial episode of human evolutionary history, namely, the global dispersal of Homo sapiens from Africa. Moreover, recent discoveries indicate a surprising level of taxic diversity during this time with at least two species—H. floresiensis and H. luzonensis—endemic to the region when H. sapiens first arrived. A third hominin dubbed the ‘Denisovans’ is shown from DNA evidence to have interbred with the ancestors of contemporary Indigenous populations across ISEA, New Guinea and Australia. Yet, the Denisovans have not been identified from the fossil record of the area despite recent breakthroughs in this regard on mainland East Asia. New excavations by our team at the Trader’s Cave in the Niah National Park (‘Niah Caves’), northern Borneo, have yielded an isolated hominin upper central permanent incisor dated with Optically Stimulated Luminescence dating of sediments to about 52 − 55 thousand years ago. Specimen SMD-TC-AA210 has a massive crown absolutely and relative to its root size, the crown is wide (mesiodistally) and relatively short (labiolingually). Morphologically, it exhibits a very strong degree of labial convexity, pronounced shovelling, and the bulging basal eminence exhibits several upward finger-like projections. Labial enamel wrinking on the enamel-dentine junction is expressed as two large ridges exhibiting numerous spine-like projections, and the lingual extensions on the enamel surface of the basal eminence are expressed as six extensions. This combination of crown size and morphological traits is not normally found in H. sapiens and instead characterises archaic members of Homo such as H. erectus, H. neanderthalensis and Middle Pleistocene hominins sharing a clade with H. heidelbergensis. The Trader’s Cave tooth suggests that an archaic hominin population inhabited northern Borneo just prior to or coincident with the arrival of H. sapiens as documented at the nearby West Mouth of the Niah Great Cave.by Shirley Ge, Hope Lappen, Luz Mercado, Kaylee Lamarche, Theodore J. Iwashyna, Catherine L. Hough, Virginia W. Chang, Adolfo Cuevas, Thomas S. Valley, Mari Armstrong-Hough
BackgroundRacial and ethnic disparities in the delivery and outcomes of critical care are well documented. However, interventions to mitigate these disparities are less well understood. We sought to review the current state of evidence for interventions to promote equity in critical care processes and patient outcomes.
MethodsFour bibliographic databases (MEDLINE/PubMed, Web of Science Core Collection, CINAHL, and Embase) and a list of core journals, conference abstracts, and clinical trial registries were queried with a pre-specified search strategy. We analyzed the content of interventions by categorizing each as single- or multi-component, extracting each intervention component during review, and grouping intervention components according to strategy to identify common approaches.
ResultsThe search strategy yielded 11,509 studies. Seven-thousand seventeen duplicate studies were removed, leaving 4,491 studies for title and abstract screening. After screening, 93 studies were included for full-text review. After full-text review by two independent reviewers, eleven studies met eligibility criteria. We identified ten distinct intervention components under five broad categories: education, communication, standardization, restructuring, and outreach. Most examined effectiveness using pre-post or other non-randomized designs.
ConclusionsDespite widespread recognition of disparities in critical care outcomes, few interventions have been evaluated to address disparities in the ICU. Many studies did not describe the rationale or targeted disparity mechanism for their intervention design. There is a need for randomized, controlled evaluations of interventions that target demonstrated mechanisms for disparities to promote equity in critical care.
by Dilara Tank, Bianca G. S. Schor, Lisa M. Trommelen, Judith A. F. Huirne, Iacer Calixto, Robert A. de Leeuw
PurposeTransvaginal ultrasound (TVUS) is pivotal for diagnosing reproductive pathologies in individuals assigned female at birth, often serving as the primary imaging method for gynecologic evaluation. Despite recent advancements in AI-driven segmentation, its application to gynecological ultrasound still needs further attention. Our study aims to bridge this gap by training and evaluating two state-of-the-art deep learning (DL) segmentation models on TVUS data.
Materials and methodsAn experienced gynecological expert manually segmented the uterus in our TVUS dataset of 124 patients with adenomyosis, comprising still images (n = 122), video screenshots (n = 472), and 3D volume screenshots (n = 452). Two popular DL segmentation models, U-Net and nnU-Net, were trained on the entire dataset, and each imaging type was trained separately. Optimization for U-Net included varying batch size, image resolution, pre-processing, and augmentation. Model performance was measured using the Dice score (DSC).
ResultsU-Net and nnU-Net had good mean segmentation performances on the TVUS uterus segmentation dataset (0.75 to 0.97 DSC). We observed that training on specific imaging types (still images, video screenshots, 3D volume screenshots) tended to yield better segmentation performance than training on the complete dataset for both models. Furthermore, nnU-Net outperformed the U-Net across all imaging types. Lastly, we report the best results using the U-Net model with limited pre-processing and augmentations.
ConclusionsTVUS datasets are well-suited for DL-based segmentation. nnU-Net training was faster and yielded higher segmentation performance; thus, it is recommended over manual U-Net tuning. We also recommend creating TVUS datasets that include only one imaging type and are as clutter-free as possible. The nnU-Net strongly benefited from being trained on 3D volume screenshots in our dataset, likely due to their lack of clutter. Further validation is needed to confirm the robustness of these models on TVUS datasets. Our code is available on https://github.com/dilaratank/UtiSeg.
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