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Abstract Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1 +/– mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies.

Abstract Background Radiographs play a key role in diagnosis of periodontal diseases. Deep learning models have been explored for image analysis in periodontal diseases. However, there is lacuna of research in the deep learning model-based detection of furcation involvements [FI]. The objective of this study was to determine the accuracy of deep learning model in the detection of FI in axial CBCT images. Methodology We obtained initial dataset 285 axial CBCT images among which 143 were normal (without FI) and 142 were abnormal (with FI). Data augmentation technique was used to create 600(300 normal and 300 abnormal) images by using 200 images from the training dataset. Remaining 85(43 normal and 42 abnormal) images were kept for testing of model. ResNet101V2 with transfer learning was used employed for the analysis of images. Results Training accuracy of model is 98%, valid accuracy is 97% and test accuracy is 91%. The precision and F1 score were 0.98 and 0.98 respectively. The Area under curve (AUC) was reported at 0.98. The test loss was reported at 0.2170. Conclusion The deep learning model (ResNet101V2) can accurately detect the FI in axial CBCT images. However, since our study was preliminary in nature and carried out with relatively smaller dataset, a study with larger dataset will further confirm the accuracy of deep learning models.

First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. Csf3r and Fkbp5). Some, e.g. Alox15 and Slc12a5, were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study.

Russia’s full-scale war on Ukraine in early 2022 has brought geopolitics, particularly classical geopolitics, back into the political and economic discussions and decision-making. Discursive, as well as real-world change, has been rapid, as the turn of the 21st century was the time of globalisation and neoliberal ideology – the free movement of people, products, and services. However, in this paper, we argue that classical geopolitics has defined the development of Northern industries even before the war began in 2022. Our interview data (n = 60) collected in the advent of the Russian invasion of Ukraine reveal that the themes of state power; ‘hard’ security meaning military armament; the economy as a field of national interests; and spill-over effects of geopolitical tensions between superpowers have framed economic fortunes in the European Arctic. It is concluded that the state actors’ interests in the European Arctic’s physical space and natural assets will be increasingly expanding.

Background: The diagnosis of meningitis in the infancy period is a challenging. Clinical evaluation and high index of suspicion with early empirical treatment guidelines continue to evolve and support physician efforts to decrease the morbidity and mortality associated with pediatric meningitis. Case report: We report a case of a previously healthy 2-month-old male who presented with excessive crying, preceded by subjective fever and watery diarrhea, for one day without any other symptoms. Parents gave multiple antipyretic doses at home for irritability which might mask his fever. The patient was tachycardic with an unremarkable physical exam. Full septic work-up done after stabilization of the patient and empirical antibiotics started. His blood culture grew Neisseria meningitides which caused meningoencephalitis and ventriculitis with bilateral extra-axial collection, the patient was in septic shock with multiple organ dysfunction. Conclusion: Meningococcal meningitis in the neonatal and infancy periods remains a serious health threat with high morbidity and mortality. This case report urges the physician to keep a high index of suspicion by taking detailed history and frequent assessment in each suspected cases as the clinical presentations, signs and symptoms in the infancy period are not specific nor classic to guide the physician. [SJEMed 2024; 5(2.000): 148-152]

Background/Objective: Pulmonary carcinoid tumors are a rare cause of Cushing’s syndrome and usually present with an indolent course. Here, we present a case of rapid onset and severe Cushing’s syndrome due to a typical pulmonary carcinoid tumor. Case Report: A 32-year-old woman developed diabetes, hypertension, and weight gain of 50 pounds over 3 months. Laboratory evaluation was significant for elevated cortisol and adrenocorticotropic hormone levels and levels were nonsuppressible on low and high-dose dexamethasone suppression tests. Chest computed tomography revealed a pulmonary nodule and biopsy showed a typical carcinoid tumor. She was treated with steroidogenesis inhibitors with a plan for surgical excision but developed worsening complications of hypercortisolemia. She eventually underwent cryoablation of the tumor, but unfortunately passed away just 6 months after her initial presentation. Discussion: Cushing’s syndrome in typical pulmonary carcinoid tumors is rarely seen and usually presents with mild hypercortisolism similar to Cushing’s disease. Severe hypercortisolemia from typical pulmonary carcinoid tumors can represent a more aggressive pathology or metastatic disease. Severe Cushing’s syndrome is associated with significant morbidity and mortality and requires rapid tumor localization as surgical resection can be curative. Conclusion: This case highlights a rare presentation of severe Cushing’s syndrome due to a typical pulmonary carcinoid.

Abstract Genetic generalized epilepsy (GGE) including childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), and GGE with tonic–clonic seizures (TCS) (GGE-TCS), is genetically influenced with a two- to four- fold increased risk in the first-degree relatives of patients. Since large families with GGE are very rare, international studies have focused on sporadic GGE patients using whole exome sequencing, suggesting that GGE are highly genetically heterogeneous and rather involve rare or ultra-rare variants. Moreover, a polygenic mode of inheritance is suspected in most cases. We performed SNP microarrays and whole exome sequencing in 20 families from Sudan, focusing on those with at least four affected members. Standard genetic filters and Endeavour algorithm for functional prioritization of genes selected likely susceptibility variants in FAT1, DCHS1 or ASTN2 genes. FAT1 and DCHS1 are adhesion transmembrane proteins interacting during brain development, while ASTN2 is involved in dendrite development. Our approach on familial forms of GGE is complementary to large-scale collaborative consortia studies of sporadic cases. Our study reinforces the hypothesis that GGE is genetically heterogeneous, even in a relatively limited geographic area, and mainly oligogenic, as supported by the low familial penetrance of GGE and by the Bayesian algorithm that we developed in a large pedigree with JME. Since populations with founder effect and endogamy are appropriate to study autosomal recessive pathologies, they would be also adapted to decipher genetic components of complex diseases, using the reported bayesian model. Graphical Abstract

Abstract Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

Abstract Objective The use of clear aligners (CAs) for orthodontic treatment has substantially increased in recent decades. However, limited empirical evidence exists regarding their potential effects on the temporomandibular joint (TMJ). The aim of this study was to assess the effect of maxillary molar distalization on the positional and dimensional TMJ parameters between CAs and conventional fixed orthodontic appliances (FAs) in skeletal class II malocclusion. Methods This is a retrospective cohort study examined 70 adult patients with skeletal class II malocclusion with similar baseline characteristics based on American Board of Orthodontics (ABO) discrepancy index scores. The patients were treated by maxillary distalization movement by CAs or FAs, of which there were two equal groups of 35 patients were included in each group. CBCTs on TMJs were performed before and after treatment through Anatomage Invivo Dental 6.0. The measured parameters included inclination, position, condyle and articular fossa dimensions, and the volumetric joint spaces. Results In both groups, linear measurements of the maxillary molar position revealed significant improvement after treatment (P

The electrochemical analysis is one of the most popular implementations of a dopamine-sensing brain implant. Its performance depends significantly on the interaction between the dopamine molecule and the working electrode. Carbon nanofiber is an allotrope of carbon nanotube and is effective in increasing the contact surface with dopamine molecules. Considering its simple fabrication protocols using photolithography, physical vapor deposition, and electrochemical deposition, this material is suitable for in-vivo implementation. COMSOL simulation confirms that carbon nanofiber implementation increases the redox current while maintaining its linearity to the user-controlled dopamine concentration.

Abstract Natural killer (NK) cells are a promising allogeneic immunotherapy option due to their natural ability to kill tumor cells, and due to their apparent safety. This study describes the development of a GMP-compliant manufacturing protocol for the local production of functionally potent NK cells tailored for high-risk acute myeloid leukemia (AML) and neuroblastoma (NBL) patients. Moreover, the quality control strategy and considerations for product batch specifications in early clinical development are described. The protocol is based on the CliniMACS Prodigy platform and Natural Killer Cell Transduction (NKCT) (Miltenyi Biotec). NK cells are isolated from leukapheresis through CD3 depletion and CD56 enrichment, followed by a 12-hour activation with IL-2 and IL-15 cytokines. Three CliniMACS Prodigy processes demonstrated the feasibility and consistency of the modified NKCT process. A three-step process without expansion, however, compromised the NK cell yield. T cells were depleted effectively, indicating excellent safety of the product. Characterization of the NK cells before and after cytokine activation revealed a notable increase in the expression of activation markers, particularly CD69, consistent with enhanced functionality. Intriguingly, the NK cells exhibited increased killing efficacy against patient-derived CD33 + AML blasts and NBL cells in vitro, suggesting a potential therapeutic benefit in AML and NBL.

Abstract Natural killer (NK) cells recognize and may kill malignant cells via their cell surface receptors. Killer cell immunoglobulin-like receptor (KIR) genotypes of donors have been reported to adjust the risk of relapse after allogeneic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia. To test whether non-KIR NK cell receptors have a similar effect, we screened 1,638 genetic polymorphisms in 21 non-KIR NK cell receptor genes for their associations with relapse and graft-versus-host disease (GVHD) after HSCT in 1,491 HSCT donors (from Finland, the UK, Spain, and Poland), divided into a discovery and replication cohort. Eleven polymorphisms regulating or located in CD226, CD244, FCGR3A, KLRD1, NCR3, and PVRIG were associated with the risks for relapse and GVHD. These associations could not be confirmed in the replication cohort. Blood donor NK cells carrying alleles showing genetic protection for relapse had a higher in vitro NK cell killing activity than non-carriers whereas those with alleles genetically protective for GVHD had lower cytotoxicity, potentially indicating functional effects. Taken together, these results show no robust effects of genetic variation in the tested non-KIR NK cell receptors on the outcome of HSCT.

Background: Spirulina (Arthrospira platensis), a filamentous cyanobacterium, is renowned as a superfood due to its rich nutritional composition, including proteins, carbohydrates, essential fatty acids, vitamins, minerals, and phytochemicals. Historically consumed by the Aztecs and the Kanembu people near Lake Chad, it gained renewed interest in the 20th century as a potential astronaut food. Objective: This review aims to trace Spirulina's evolution from an ancient dietary staple to a modern superfood, emphasizing its immune support, antioxidant properties, and essential nutrients. It also highlights ongoing research on Spirulina's potential to address various health concerns and nutritional needs. Method: The review adopts a comprehensive approach to evaluate Spirulina's pharmacological and therapeutic potential. It systematically examines existing literature, research studies, and clinical trials on Spirulina's health benefits and applications, focusing on its ability to combat malnutrition, boost economies, and offer novel therapeutic interventions. Results: Spirulina is identified as a valuable natural resource with significant potential in nutrition and medicine. The review underscores its pharmacological and therapeutic attributes, particularly in addressing malnutrition and contributing to economic development. Conclusion: Spirulina's role as an effective medicinal resource is discussed, highlighting its implications for novel therapeutic interventions. Overall, the findings underscore Spirulina's nutritional significance, enduring appeal, and promising role in tackling contemporary health challenges.

Abstract Background PLA2G6-associated neurodegeneration (PLAN) comprises three diseases with overlapping features: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. INAD is an early onset disease characterized by progressive loss of vision, muscular control, and mental skills. The prevalence of PLA2G6-associated diseases has not been previously calculated. Methods To provide the most accurate prevalence estimate, we utilized two independent approaches: database-based approach which included collecting variants from ClinVar, Human Gene Mutation Database (HGMD) and high confidence predicted loss-of-function (pLoF) from gnomAD (Rare Genomes Project Genetic Prevalence Estimator; GeniE), and literature-based approach which gathered variants through Mastermind Genomic Search Engine (Genomenon, Inc). Genetic prevalence of PLAN was calculated based on allele frequencies from gnomAD, assuming Hardy–Weinberg equilibrium. Results In the PLA2G6 gene, our analysis found 122 pathogenic, 82 VUS, and 15 variants with conflicting interpretations (pathogenic vs VUS) between two approaches. Allele frequency was available for 58 pathogenic, 42 VUS, and 15 conflicting variants in gnomAD database. If pathogenic and/or conflicting variants are included, the overall genetic prevalence was estimated to be between 1 in 987,267 to 1 in 1,570,079 pregnancies, with the highest genetic prevalence in African/African-American (1 in 421,960 to 1 in 365,197) and East-Asian (1 in 683,978 to 1 in 190,771) populations. Conclusion Our estimates highlight the significant underdiagnosis of PLA2G6-associated neurodegeneration and underscores the need for increased awareness and diagnostic efforts. Furthermore, our study revealed a higher carrier frequency of PLA2G6 variants in African and Asian populations, stressing the importance of expanded genetic sequencing in non-European populations to ensure accurate and comprehensive diagnosis. Future research should focus on confirming our findings and implementing expanded sequencing strategies to facilitate maximal and accurate diagnosis, particularly in non-European populations.

Abstract This case report presents a 38‐year‐old male patient who, after a febrile infection, developed super‐refractory status epilepticus and multiorgan failure, and died in 2 weeks despite the best possible intensive care. Autopsy revealed findings suggestive of hemophagocytic lymphohistiocytosis (HLH). This case shows that a rare immunological cause such as HLH may cause febrile infection‐related epilepsy syndrome (FIRES), and complications of intensive care can mask the physiological and laboratory changes in HLH. Plain Language Summary This case report presents a 38‐year‐old man who, after a febrile infection, developed intractable epileptic activity requiring intensive care treatment. During the intensive care, the patient showed signs of multiple organ damage and died in 2 weeks despite the best possible treatment. Autopsy revealed findings suggestive of hemophagocytic lymphohistiocytosis (HLH), which is a rare immune system regulation disorder leading to persistent inflammatory state and organ damages. This case shows that an immunological disorder like HLH may underlie treatment resistant fever‐related epileptic seizures.

Abstract The pace of technological advancement is accelerating, and one of the latest developments is the emergence of Augmented Reality (AR) and Mixed Reality (MR) glasses as an extension of smartphones. The key to success lies in innovative research and technology that can reach a wide audience. To ensure a positive user experience, AR/MR glasses must offer interfaces that are easy to use, memorable, and leave a lasting impression. While Nielsen's heuristics are widely accepted as the standard for usability, it is clear that non‐traditional applications require a rethinking of these heuristics to best suit their unique needs. A fresh usability heuristic for augmented and MR applications is designed by combining and modifying the existing models, such as Nielsen's 10 heuristics, Technology Acceptance Model, and Software Usability Measurement Inventory. The resulting framework incorporates 21 main heuristics and 60 sub heuristics. The 21 main heuristics are further grouped into the Norman's cognitive theory model based on the three levels of processing. The industry experts evaluated and validated the usability framework and established a higher level of effectiveness in identifying more usability problems compared with Nielsen's heuristics.

Background: This systematic review and meta-analysis aimed to investigate the current evidence on the efficacy of tympanostomy and adenoidectomy in children with otitis media with effusion in comparison with tympanostomy alone following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Materials and Methods: We completed a comprehensive search of PubMed, Web of Science, Scopus and Cochrane Library databases for relevant studies published in the literature with no date restrictions. We collected the results of the databases search and removed duplicated studies by Rayyan QCRI and EndNote Software X8. We used an Excel sheet for screening titles and abstracts, full text and data extraction. For quality assessment, we used Cochrane Handbook of Systematic Reviews of Interventions 5.1.0 using the quality assessment table provided in Part 2 and Chapter 8.5, and quantitative data synthesis was done using Review Manager (RevMan) software version 5.4. Results: The literature search showed 1510 studies, of which five studies were included in data synthesis. The study measured the effect through number of acute otitis media (AOM) episodes, cumulative number of AOM episodes, siblings with Otitis media (OM), hearing level hearing loss scale of the left, and right ears. The pooled effect estimates showed significant difference between tympanostomy with adenoidectomy versus tympanostomy alone in hearing level hearing loss scale of both ears (SMD -0.17, 95% CI [-0.29, -0.05], P-value=0.005). However, the pooled results were not heterogeneous (P < 0.25, I2 = 24%). Conclusions: Tympanostomy with adenoidectomy improves hearing compared to tympanostomy alone, but both treatments have similar effects on ear infection rates. Further research with larger samples is needed to confirm these findings and assess long-term benefits.

Background: After pancreatic surgery, the development of postoperative pancreatic fistula (POPF) is a serious concern. POPF involves the leakage of pancreatic fluids from the surgical site, which can lead to complications and even death. Preventing POPF is essential for enhancing patient recovery and lessening the impact on healthcare resources. This systematic review and meta-analysis evaluated medical methods and surgical techniques to prevent POPF. Methods: This study was registered under the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42024500938. An electronic search was conducted through the PubMed, Google Scholar, Web of Science, and ScienceDirect databases for all relevant articles published in English from 2018 to 2023. The following search terms were used: ((Whipple procedure OR Pancreaticojejunal OR Pancreaticogastrostomy) AND (Prevention of postoperative pancreatic fistula) AND (Prevention OR Octreotide OR Sealant agent OR Stent OR Postoperative drain)). Results: Of 260 papers, 28 articles extracted through the database search were considered suitable for the systematic review. The included studies investigated a variety of surgical approaches for pancreatic resection. Pancreaticoduodenectomy (PD) was the most prevalent intervention. The incidence rates for POPF varied widely across the studies, ranging from as low as 11.6% to as high as 100%. The incidence rate of clinically relevant POPF (CR-POPF) ranged from 11.7% to 33.3%. The length of postoperative hospital stays also varied significantly. Discussion: Postoperative pancreatic fistula (POPF) affects 13–41% of patients post-pancreatic surgery. Despite its high incidence, mortality rates are low. Postoperative hospital stay varies, with higher rates in older patients and overweight individuals. Advancements in surgical techniques and perioperative management have reduced mortality rates to Conclusions: This study provides insights into the outcomes of pancreatectomy, including the incidence of POPF, postoperative hospital stays, and mortality rate. The findings suggest that the incidence of POPF is similar to that suggested in the literature and is influenced by various factors.

Abstract Background Infective endocarditis (IE) is a severe condition characterized by inflammation of the heart endocardium and valves, commonly caused by Gram-positive bacteria. Complications such as embolic phenomena and organ abscesses can arise, necessitating timely diagnosis and intervention. Case presentation We report the case of a 20-year-old female with a history of cerebral and splenic infarctions due to IE. The patient presented with left-sided flank pain, urinary burning, and fever. Examination revealed mitral and aortic valve involvement, splenomegaly, and neurological deficits. Despite initial antibiotic therapy, the patient developed a splenic abscess and drug-induced neutropenia. She required aortic valve replacement and was successfully managed with a multidisciplinary approach. Conclusion Multidisciplinary management, including timely surgical intervention and advanced imaging, is essential for favorable outcomes in IE patients. This case underscores the importance of early detection and tailored treatment strategies in managing severe complications associated with IE.

Abstract Transactional sexual relationships (TSRs) take varied forms, with research emphasizing TSRs’ inherent risks, primarily to women. In South Africa, Blessed relationships have emerged as a prominent type of TSR. Blessers have become coveted male partners due to their relative wealth and willingness to ‘bless’ female partners with financial and material gifts, as well as the improved social status that accompanies such partnerships. Given the limited literature on Blesser partnerships, we investigated women’s implicit and explicit negotiated rewards and their perceived risk and ability to employ risk mitigation strategies, utilizing risk as a sociological concept to enhance understanding of risks women assume, and subsequent gendered implications. This qualitative study was conducted in 2017-2018 in KwaZulu-Natal (KZN) province, South Africa, a high HIV prevalence setting, with 22 women, using purposive and snowball sampling methods. We found that women in relationships with a Blesser recognize and navigate a number of risks, including: the threat of HIV acquisition, falling pregnant, experiencing an emotional void following a TSR, and expressed feelings of guilt and shame, as segments of South African society remain judgmental of TSRs. These risks are then weighed against the pursuit of sustained financial and social rewards achieved through such relationships.

Despite mathematics being multidisciplinary, sustainability and mathematics education are largely under-researched and in an infant stage. In the Namibian context, previous research has investigated in-service teachers' per­ceptions of education for sustainable development and teach­ing practices. Little is known about pre-service teachers' per­spectives on mathematics for sustainable development in terms of awareness, challenges, and how pedagogical mod­ules can be enhanced to develop students' pedagogical knowledge to integrate sustainability concepts in mathemat­ics. The study uses a qualitative approach with an exploratory case study design. Eight third-year pre-service Mathematics teachers were conveniently sampled and completed an open-ended questionnaire. The researcher, informed by the Repre­sentations, Educational approach, Didactic tools, and Skills model, conducted a content analysis of participants' aware­ness, challenges, and implications for training Mathematics teachers. In terms of awareness, the findings revealed that most of the pre-service teachers appear aware and knowl­edgeable of the role of mathematics in driving education for sustainable development. The study also found that the major challenges in incorporating ESD in the mathematics teaching and learning process are didactic tools and skills. Based on the study findings, teacher educators should develop student teachers' pedagogical ESD knowledge to be able to link Mathematics to appropriate SD themes, design learning tasks and materials, and present lessons that incorporate SD. The findings of the study provide direction on components to be considered to en­hance pedagogical modules for pre-service teachers. This study is limited to a case study of the chosen pre-service teachers and campus, thus cannot be extrapolated to a broader population.

Variations in the genetic code for proteins are considered to confer traits and underlying disease. Identifying the functional consequences of these genetic variants is a challenging endeavor. There are online databases that contain variant information. Many publications also have described variants in detail. Furthermore, there are tools that allow for the prediction of the pathogenicity of variants. However, navigating these disparate sources is time-consuming and sometimes complex. Finally, text mining and large language models offer promising approaches to understanding the textual form of this knowledge. This review discusses these challenges and the online resources and tools available to facilitate this process. Furthermore, a computational framework is suggested to accelerate and facilitate the process of identifying the phenotype caused by a particular genetic variant. This framework demonstrates a way to gather and understand the knowledge about variants more efficiently and effectively.

Abstract Background There has been a significant expansion in the measurement of healthcare system performance. However, there is a lack of a comprehensive performance measurement framework to assess the effects of telephone triage services on the urgent care system. The aim of our Delphi study was to construct and validate a performance measurement framework designed explicitly for telephone triage services. Methods This study was conducted in Finland with a group of eight experienced senior physicians from the country's 20 largest joint emergency departments, serving over 90% of the population for urgent care. The Nominal Group Technique (NGT) was utilised to achieve consensus on measuring telephone triage performance. Initially, performance indicators (PIs) were identified through Delphi method rounds from December 10th to December 27th, 2021, with eight experts participating, and from December 29th, 2021, to January 23rd, 2022, where five of these experts responded. NGT further deepened these themes and perspectives, aiding in the development of a comprehensive performance measurement framework. The final framework validation began with an initial round from February 13th to March 3rd, 2022, receiving five responses. Due to the limited number of responses, an additional validation round was conducted from October 29th to November 7th, 2023, resulting in two more responses, increasing the total number of respondents in the validation phase to seven. Results The study identified a strong desire among professionals to implement a uniform framework for measuring telephone triage performance. The finalised framework evaluates telephone triage across five dimensions: service accessibility, patient experience, quality and safety, process outcome, and cost per case. Eight specific PIs were established, including call response metrics, service utility, follow-up care type and distribution, ICPC-2 classified encounter reasons, patient compliance with follow-up care, medical history review during assessment, and service cost per call. Conclusions This study validated a performance measurement framework for telephone triage services, utilising existing literature and the NGT method. The framework includes five key dimensions: patient experience, quality and safety, outcome of the telephone triage process, cost per case, and eight PIs. It offers a structured and comprehensive approach to measuring the overall performance of telephone triage services, enhancing our ability to evaluate these services effectively.

Abstract A resilient immune system is characterized by its capacity to respond appropriately to challenges, such as infections, and it is crucial in vaccine response. Here we report a paired randomized intervention-control trial in which we evaluated the effect of microbially rich soil on immune resilience and pneumococcal vaccine response. Twenty-five age and sex matched pairs of volunteers were randomized to intervention and control groups. The intervention group rubbed hands three times a day in microbially rich soil until participants received a pneumococcal vaccine on day 14. Vaccine response, skin and gut bacteriome and blood cytokine levels were analyzed on days 0, 14 and 35. Peripheral blood mononuclear cells (PBMCs) were stimulated with vaccine components and autoclaved soil for cytokine production. Commensal bacterial community shifted only in the intervention group during the 14-day intervention period. When PBMCs collected on day 14 before the vaccination were stimulated with the vaccine components, IFN-y production increased in the intervention but not in the control group. On day 35, vaccination induced a robust antibody response in both groups. In parallel, gut bacterial community was associated with TGF-β plasma levels and TGF-β decrease in plasma was lower in the intervention group. The results indicate that exposure to microbially rich soil can modulate the cell-mediated immunity to components in pneumococcal vaccine.

Abstract The escalating threat posed by the Monkeypox virus (MPXV) to global health necessitates the urgent discovery of effective antiviral agents, as there are currently no specific drugs available for its treatment, and existing inhibitors are hindered by toxicity and poor pharmacokinetic profiles. This study aimed to identify potent MPXV inhibitors by screening a diverse library of small molecule compounds derived from marine fungi, focusing on the viral protein VP39, a key methyltransferase involved in viral replication. An extensive virtual screening process identified four promising compounds—CMNPD15724, CMNPD28811, CMNPD30883, and CMNPD18569—alongside a control molecule. Rigorous evaluations, including re-docking, molecular dynamics (MD) simulations, and hydrogen bond analysis, were conducted to assess their inhibitory potential against MPXV VP39. CMNPD15724 and CMNPD30883, in particular, demonstrated a superior binding affinity and stable interactions within the target protein's active site throughout the MD simulations, suggesting a capacity to overcome the limitations associated with sinefungin. The stability of these VP39-compound complexes, corroborated by MD simulations, provided crucial insights into the dynamic behavior of these interactions. Furthermore, Principal Component Analysis (PCA) based free energy landscape assessments offered a detailed understanding of the dynamic conformational changes and energetic profiles underlying these compounds' functional disruption of VP39. These findings establish CMNPD15724, CMNPD28811, CMNPD30883, and CMNPD18569 as promising MPXV inhibitors and highlight marine fungi as a valuable source of novel antiviral agents. These compounds represent potential candidates for further experimental validation, advancing the development of safer and more effective therapeutic options to combat this emerging viral infection.

Abstract Background Osteoarthritis in the lower extremities becomes more common as people age. In addition to conservative treatments, hip or knee arthroplasty is often needed. The aim of this study was to evaluate total knee arthroplasty (later TKA) in patients, comparing those who had previously undergone THA (later THA/TKA), with those who had not undergone such procedure. Pain, walking ability and functional capacity were assessed. Methods Patients who underwent primary TKA between 1987 and 2017 at a single orthopaedic hospital was included in this study. The patients participated in clinical preoperative and postoperative examinations by an orthopaedic surgeon after one- and five- years. The final study group consisted of 418 patients who had undergone 502 knee arthroplasties. Of these 502 TKA cases, 462 had not undergone previous THA and 40 had undergone previous THA. To evaluate the patients’ physical function and walking ability, a structure form for knee arthroplasty based on the Hungerford score was used. The registry data from the Finnish National Institute of Health and Welfare was used. The data included TKA revision(s) and mortality events. Results At the baseline and after one- and five- years primary TKA, no statistical differences were found in the total Hungerford score between TKA patients and THA/TKA patients. In both groups, the total score increased per surgery year. However, when analysing the relationship between the year of operation and the total score, no statistical differences were found between the groups (TKA and THA/TKA) at five years (p = 0.61). The only statistical difference found between the groups was in walking distance points after one year; THA/TKA patients (mean 83 [SD 17]) could walk remarkably shorter distances than TKA patients (91 [14]) one year after arthroplasty (p < 0.001). Conclusions In conclusion, walking distance improved more rapidly in TKA patients than in THA/TKA patients. However, patients who underwent more than one arthroplasty in their lower extremities managed their lives, activities, and pain almost as well as those who underwent only one knee arthroplasty.

Micarea (Ascomycota, Pilocarpaceae) is a large cosmopolitan genus of crustose lichens. We investigated molecular systematics and taxonomy of the poorly known Micarea melaeniza group focussing on M. melaeniza, M. nigella and M. osloensis. A total of 54 new sequences were generated and using Bayesian and maximum likelihood analysis of two markers (nuITS and mtSSU), we discovered two previously unrecognized phylogenetic lineages, one of which is described here as Micarea eurasiatica Kantelinen & G. Thor, sp. nov., morphologically characterized by pycnidia that are sessile to emergent, cylindrically shaped, with greenish-black K+ olive green, wall pigmentation and containing large mesoconidia up to 6 µm in length. The species is known from Japan and Finland. In addition, we show that the reproduction biology of M. osloensis has been poorly understood and that the species often occurs as an anamorph with stipitate pycnidia. We present a species synopsis and notes on pigments. Our research supports previous results of asexuality being an important reproductive strategy of species growing on dead wood.

Abstract Fabrication of porous tissue-engineering scaffolds from bioactive glasses (BAG) is complicated by the tendency of BAG compositions to crystallize in thermal treatments during scaffold manufacture. Here, experimental biocompatible glass S59 (SiO2 59.7 wt%, Na2O 25.5 wt%, CaO 11.0 wt%, P2O5 2.5 wt%, B2O3 1.3 wt%), known to be resistant to crystallization, was used in sintering of glass granules (300–500 µm) into porous scaffolds. The dissolution behavior of the scaffolds was then studied in vivo in rabbit femurs and under continuous flow conditions in vitro (14 days in vitro/56 days in vivo). The scaffolds were osteoconductive in vivo, as bone could grow into the scaffold structure. Still, the scaffolds could not induce sufficiently rapid bone ingrowth to replace the strength lost due to dissolution. The scaffolds lost their structure and strength as the scaffold necks dissolved. In vitro, S59 dissolved congruently throughout the 14-day experiments, resulting in only a slight reaction layer formation. Manufacturing BAG scaffolds from S59 that retain their amorphous structure was thus possible. The relatively rapid and stable dissolution of the scaffold implies that the glass S59 may have the potential to be used in composite implants providing initial strength and stable, predictable release of ions over longer exposure times. Graphical Abstract

Diana Harrison Wall passed away on 25 March 2024 in Fort Collins, CO, USA, her home for more than 25 years and where she was the Director of the School of Global Environmental Sustainability (SoGES) and Distinguished Professor of Biology at Colorado State University (CSU) after having been faculty at the Natural Resource Ecology Laboratory (NREL) there for more than a decade. While Diana was to become respected globally for her work in soil ecology, soil biodiversity, and sustainability science, she began her career as a nematologist, receiving her PhD from the University of Kentucky-Lexington in plant pathology. When faced with the challenges of being a woman scientist in a male-dominated era, Diana blazed trails. Undoubtedly, her early-career years were formative. The meticulousness and focus she honed-in her science during these early years extended to the expectations she held for her mentees, and in her approach to leadership as she progressed in her career. Those of us who were mentored by Diana wish to honor her and her legacy by providing a glimpse of not only her research and achievements, but what lessons she left us, her mentees, to carry with us through our careers and lives. Those of us who were close collaborators and co-editors wish to honor Diana’s exemplary approach to science, forward-looking approach, and impact on the science community as a whole.

Immunoassay interferences, including those from exogenous substances like biotin, can lead to misinterpretation of laboratory results and clinical decision-making challenges. A 28-year-old unmarried female presented to dermatologist with 4-year history of acne, hirsutism, and hair loss. Hormonal assays using chemiluminescence immunoassays (CLIA) and enzyme-linked immunosorbent assays (ELISA) revealed alarmingly high testosterone levels, suggesting neoplastic androgen excess and severe insulin resistance. This prompted referral to endocrinology for further evaluation. Patient's menarche occurred at age 11, with regular menstrual cycles. Family history indicated diabetes and hirsutism, but not infertility. Physical examination revealed body mass index (BMI) of 21.8 kg/m2 and Ferriman-Gallwey score of 11. Despite severe biochemical hyperandrogenism, her clinical presentation was mild. Differential diagnoses included polycystic ovary syndrome (PCOS) and late-onset congenital adrenal hyperplasia (CAH). Repeat hormonal testing, performed at multiple laboratories using liquid chromatography-mass spectrometry (LCMS), CLIA, and ELISA, showed normal testosterone, free testosterone, and insulin levels, suggesting that the initial results were falsely elevated. Review of her dermatology prescriptions revealed that she had taken a single 10 mg tablet of biotin 33 hours before first blood draw, leading to diagnosis of biotin interference in immunoassays. After the two-week biotin washout period, her subsequent endocrinology work-up had indicated “normalized” hormonal levels. Pelvic and abdominal ultrasound imaging revealed normal ovaries and adrenal areas. Thus, biotin associated testosterone (and insulin) immunoassay interference can confound clinical diagnosis and management. Any observed discordance between clinical symptoms, signs and hormonal levels should raise possibility of immunoassay interferences, reemphasizing need for heightened physician awareness.

Background:. The Finnish Shaft of the Humerus (FISH) trial compared open reduction and internal plate fixation (ORIF) with functional bracing in adult patients with displaced, closed humeral shaft fractures. Here, we compare the results of the patients in the randomized clinical trial (RCT [the randomized cohort]) with those of the cohort of patients who were also eligible but declined randomization (the nonrandomized cohort) to investigate if patients’ treatment preference was associated with the outcomes during a 2-year follow-up. Methods:. A total of 321 patients were treated at 2 university hospitals in Finland between November 2012 and January 2018. Of the 140 eligible patients, 82 were randomized to ORIF or functional bracing. Of the 58 patients declining randomization, 42 consented to participate in a nonrandomized cohort in which the patients were able to choose the treatment method. The primary outcome of this study was the Disabilities of the Arm, Shoulder and Hand (DASH) score. Patients in the randomized cohort and the nonrandomized cohort were analyzed separately in 3 groups: those who had (1) initial surgery, (2) successful functional bracing, and (3) late surgery due to failed functional bracing. We used mixed-model, repeated-measures analysis of variance to compare the treatment effect among the 3 groups. Results:. In the randomized cohort, 38 patients had an initial surgical procedure. Of the 44 patients randomized to functional bracing, 30 (68%) healed successfully and 14 (32%) underwent a late surgical procedure. In the nonrandomized cohort, 9 patients preferred an initial surgical procedure. Of the 33 patients preferring functional bracing, 26 (79%) healed successfully and 7 (21%) underwent late surgery. The DASH scores in the randomized cohort and the nonrandomized cohort were 6.8 (95% confidence interval [CI], 2.3 to 11.4) and 12.3 (95% CI, 0.3 to 24.3) for the initial surgery groups, 6.0 (95% CI, 1.0 to 11.0) and 3.4 (95% CI, 0 to 9.3) for the bracing groups, and 17.5 (95% CI, 10.5 to 24.5) and 20.5 (95% CI, 9.4 to 31.6) for the late surgery groups at 2 years. Conclusions:. The results of the randomized cohort and the nonrandomized cohort were comparable and suggest that patients’ treatment preferences are not associated with the treatment outcomes of these injuries. Level of Evidence:. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Emerging insights in osteoimmunology have enabled researchers to explore in depth the role of immune modulation in regulating bone health. Bone is one of the common sites of metastasis notably in case of breast cancer, prostate cancer and several other cancer types. High calcium ion concentration and presence of several factors within the mineralized bone matrix including TGF-β, BMP etc., aid in tumor growth and proliferation. Accumulating evidence has substantiated the role of the gut-microbiota (GM) in tumorigenesis, further providing a strong impetus for the growing “immune-cancer-gut microbiota” relationship. Recent advancements in research further highlight the importance of the intra-tumor microbiota in conjunction with GM in cancer metastasis. Intratumoral microbiota owing to their ability to cause genetic instability, mutations, and epigenetic modifications within the tumor microenvironment, has been recognized to affect cancer cell physiology. The host microbiota and immune system crosstalk shapes the innate and adaptive arms of the immune system, which is the key player in cancer progression. In this review, we aim to decipher the role of microorganisms mediating bone metastasis by shedding light on the immuno-onco-microbiome (IOM) axis. We discussed the feasible cancer therapeutic interventions based on the modulation of the microbiome-immune cell axis which includes prebiotics, probiotics, and postbiotics. Here, we leverage the conceptual framework based on the published articles on microbiota-based therapies to target bone metastases. Understanding this complicated nexus will provide insights into fundamental factors governing bone metastases which will subsequently help in managing this malignancy with better efficacy.

Aim: There is limited research on Out-of-hospital cardiac arrest (OHCA) in the Gulf Cooperation Council (GCC) and especially in Bahrain. This is the first study to describe the incidence, characteristics, and outcomes of OHCA in Bahrain. Methods: This was a retrospective national observational study on OHCA patients in Bahrain using the Utstein framework for resuscitation. Data was collected between 1st July 2022 to 30th June 2023 from the electronic medical records of the only three governmental hospitals emergency departments (EDs) and National Ambulance (NA). Results: The annual incidence of OHCA attended by (Emergency Medical Services) EMS was nearly 21 per 100,000 population. The majority were males (n = 228, 68.8 %) with median age of 65 years (IQR=49–78). Most OHCA cases were witnessed (n = 265, 81 %), with (n = 247, 76 %) happened at home/residence. Rates for bystander CPR was low (n = 122, 36.8 %) and bystander automated external defibrillator (AED) was not performed in any of the cases. The OHCA cases transported by the NA was (n = 314, 94.8 %), with median response time of 9 min (IQR=7–12). However, only (n = 20, 6.0 %) were witnessed by EMS, and (n = 7, 2.1 %) received EMS defibrillation for shockable rhythms. First monitored rhythms included shockable rhythm in (n = 28, 8.5 %) versus non-shockable rhythm in (n = 303, 91.5 %). In the EDs, return of spontaneous circulation was achieved in (n = 60, 18.1 %) cases. But survival rate to hospital discharge at 30-day was (n = 4, 1.2 %) and survival rate to hospital discharge with good neurological outcomes was (n = 0, 0 %). Conclusion: In Bahrain the estimated annual incidence of OHCA is 21 individuals per 100,000 population, with a very low survival rate. Solutions should focus on community-level CPR and AED training, evaluating OHCA care provided by EMS, and establishing OHCA registry.

AbstractBackground: There is a pressing need for effective treatments for major depressive disorder (MDD).Objective To examine the feasibility of an integrated mind-body MDD treatment combining cognitive behavioral therapy (CBT) and whole-body hyperthermia (WBH).Methods In this single-arm trial, 16 adults with MDD initially received 8 weekly CBT sessions and 8 weekly WBH sessions. Outcomes included WBH sessions completed (primary), self-report depression assessments completed (secondary), and pre-post intervention changes in depression symptoms (secondary). We also explored changes in mood and cognitive processes and assessed changes in mood as predictors of overall treatment response.Results Thirteen participants (81.3%) completed ≥ 4 WBH sessions (primary outcome); midway through the trial, we reduced from 8 weekly to 4 bi-weekly WBH sessions to increase feasibility. The n = 12 participants who attended the final assessment visit completed 100% of administered self-report depression assessments; all enrolled participants (n = 16) completed 89% of these assessments. Among the n = 12 who attended the final assessment visit, the average pre-post-intervention BDI-II reduction was 15.8 points (95% CI: −22.0, −9.70), p = 0.0001, with 11 no longer meeting MDD criteria (secondary outcomes). Pre-post intervention improvements in negative automatic thinking, but not cognitive flexibility, achieved statistical significance. Improved mood from pre-post the initial WBH session predicted pre-post treatment BDI-II change (36.2%; rho = 0.60, p = 0.038); mood changes pre-post the first CBT session did not.Limitations Small sample size and single-arm design limit generalizability.Conclusion An integrated mind-body intervention comprising weekly CBT sessions and bi-weekly WBH sessions was feasible. Results warrant future larger controlled clinical trials.Clinivaltrials.gov Registration: NCT05708976

Deeply rooted in human cognition, metaphors have always intrigued researchers to examine what motivates them across different cultures. This paper attempts to investigate how HEART metaphors are generated and used in Arabic and English within economic discourses in light of conceptual metaphor theory. Drawing evidence from economic discourse exclusively, the study at hand targets instances of figurative language outside the realm of creative writing and literature. Utilizing discourse analysis as its primary method, it combines theoretical veins from cognitive linguistics and cognitive translation hypothesis with digitalized techniques using SketchEngine, a corpus processing software package, to highlight patterns of universality and cultural situatedness. A sample of 562 metaphorical contexts (252 from Arabic and 310 from English) were selected and analyzed discursively. Results indicated the prominence of three major target domains, CENTRAL POSITION, AFFECTION, and VITALITY, which were quite universal and similar in both languages. Another three subordinate target domains were identified: UNITY/SOLIDARITY, COGNITIVE ABILITY, and DEPTH/ESSENCE revealing more linguistic and cultural variations than the major ones. Both major and subordinate target domains proved to have similar mapping conditions in terms of their cognitive translation load. Nevertheless, while the major target domains were quite straightforward in such mapping, some subordinate ones were realized differently on a lexical level. These findings are further discussed in terms of their wider ideological and cultural contexts as well as the constructionist take on discourse. Some translation implications are presented accordingly.

Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber. It is also accompanied by a behavioral phenotype: Darters reliably show decreased freezing compared to Non-darters and males and reach higher velocities in response to the foot shock (“shock response”). However, the relationship between shock response and conditioned darting is not known. This study investigated if this link is due to differences in general processing of aversive stimuli between Darters, Non-darters and males. Across a variety of modalities, including corticosterone measures, the acoustic startle test, and sensitivity to thermal pain, Darters were found not to be more reactive or sensitive to aversive stimuli, and, in some cases, they appear less reactive to Non-darters and males. Analyses of cFos activity in regions involved in pain and fear processing following fear conditioning identified discrete patterns of expression among Darters, Non-darters, and males exposed to low and high intensity foot shocks. The results from these studies further our understanding of the differences between Darters, Non-darters and males and highlight the importance of studying individual differences in fear conditioning as indicators of fear state.

Heterobasidion parviporum is a destructive forest pathogen causing root and stem rot of Norway spruce (Picea abies) in northern hemisphere. Previous research has suggested that a gene form of PaLAR3 that encodes for the leucoanthocyanidin reductase enzyme, may increase resistance to H. parviporum in Norway spruce, whether heterozygous or homozygous. Our experiment was initially focused on testing this assertion with materials from the Finnish Norway spruce breeding program, comprising 52 full-sib families. Additionally, we investigated the influence of mycoviruses on the growth of H. parviporum. The frequencies of the three PaLAR3 genotypes AA, AB, and BB were 64%, 30%, and 6%, respectively. We found no significant differences in the necrotic response to H. parviporum between the homozygous (BB) and heterozygous (AB) genotypes vs. the homozygous (AA) genotype across the two fungal strains tested, suggesting the gene is rather ineffective as a marker for overall H. parviporum resistance. The two H. parviporum strains used in the study showed significantly different necrosis responses from the control. Mycovirus infection in H. parviporum strains led to a significant reduction in lesion width in phloem and sapwood. Furthermore, the growth of the fungus was notably restricted when hyphae hosted mycoviruses, indicating a high potential of mycoviruses to reduce fungal growth and necrosis development.

This study aims to compare the characterization of three Lactobacillus strains (L. helveticus, L. acidophilus, and L. paracasei subsp. paracasei) in camel milk and bovine milk during fermentation. Our finding showed that the average total viable counts of all three Lactobacilli strains in both milk types reached more than 7.0 log CFU/mL after 16 h of fermentation and continued to increase significantly (p

BackgroundTelomere length (TL) has been linked to cognitive function, decline and dementia. This study aimed to explore whether both measured TL and genetic disposition for TL predict dimensions of cognitive performance in a longitudinal sample of older UK adults.MethodsWe analysed data from PROTECT study participants aged ≥50 years without a dementia diagnosis, who had completed longitudinal cognitive testing. We calculated polygenic scores for telomere length (PGS-TL) for 7,877 participants and measured relative telomere length (RTL) in a subgroup of 846 participants using DNA extracted from saliva samples collected within 6 months either side of their baseline cognitive testing. Latent growth models were used to examine whether RTL and PGS-TL predict both baseline and longitudinal changes in cognitive performance (4 time-points, annually).ResultsIn the whole sample, we did not observe significant associations between either measure of telomere length and initial or longitudinal changes in cognitive performance. Stratifying by median age, in older adults (≥ ∼62 years), longer baseline RTL showed a nominal association with poorer baseline verbal reasoning performance (n = 423, Mintercept = 47.58, B = −1.05, p = .011) and PGS-TL was associated with performance over time (n = 3,939; slope factor, Mslope = 3.23, B = −0.45, p = .001; slope2 factor, Mslope2 = 0.21, B = 0.13, p = .002).ConclusionOur findings suggest either the absence of a significant relationship between telomere length (RTL and PGS-TL) and cognitive performance (baseline and change over time), or possibly a weak age-dependent and domain-specific relationship, in older adults of European ancestry. More research is needed in representative and ancestrally diverse samples over a longer assessment period. Alternative biological ageing indicators may still provide utility in the early detection of individuals at risk for cognitive decline (e.g., pace-of ageing epigenetic clocks).

Summary: Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disorder characterised by life-long mechanically induced skin blistering, fibrosis-driven pseudosyndactyly, and multi-organ involvement. Preclinical studies have suggested mitigated progression by angiotensin II type I receptor blockade through losartan. We aimed to determine the safety and tolerability of systemic losartan treatment among children with RDEB, and to obtain initial data on its clinical benefit. Methods: We conducted an open-label, single-arm, phase 1/2 trial at the Medical Center-University of Freiburg, Germany. Children with molecularly-confirmed RDEB, aged 2–16 years (starting from the 25th month of life) were eligible. Key exclusion criteria comprised anaemia with haemoglobin

Background: Middle East Respiratory Syndrome (MERS) has become a severe zoonotic disease, posing significant public health concerns due to the lack of specific medications. This urgently demands the development of novel therapeutic molecules. Understanding MERS's genetic underpinnings and potential therapeutic targets is crucial for developing effective treatments. Methods: Two gene expression datasets (GSE81909 and GSE100504) were analyzed to identify differentially expressed genes (DEGs) using GEO2R. Furthermore, gene ontology (GO), pathway enrichment analysis, and protein-protein interaction (PPI) network were performed to understand the gene’s functions. A possible drug target was identified, and an FDA-approved drug library was screened against the selected target using molecular docking and validated the findings through molecular dynamics simulation, principal component analysis, free energy landscape, and MM/GBSA calculations. Results: The study on GSE81909 and GSE100504 datasets with icMERS and MOCK samples at 24 and 48 h revealed an upregulation in 73 and 267 DEGs, respectively. In the network pharmacology, STAT1, MX1, DDX58, EIF2AK2, ISG15, IFIT1, IFIH1, OAS1, IRF9, and OASL were identified as the top 10 hub genes. STAT1 was identified as the most connected hub gene among these top 10 hub genes, which plays a crucial role in the immune response to the MERS virus. Further study on STAT1 showed that PPARG helps reduce STAT1, which could modulate the immune response. Therefore, by inhibiting PPARG, the immunological response can be successfully enhanced. The known inhibitor of PPARG, 570 (Farglitazar), was used as a control. Further, screening using Tanimoto and K-mean clustering was performed, from which three compounds were identified: 2267, 3478, and 40326. Compound 3478 showed characteristics similar to the control, indicating robust binding to PPARG. 3478 showed the highest negative binding free energy with −41.20 kcal/mol, indicating strong binding with PPARG. Conclusions: These findings suggest that 3478 promises to be a potential inhibitor of PPARG, and further experimental investigations can explore its potential as a MERS inhibitor.

Background: Corticosteroids raise blood glucose concentrations; however, it remains unknown which form of administration, oral or intravenous, is associated with the greatest degree of blood glucose rise in hospitalised patients. Furthermore, it is not known whether the pattern of the associated hyperglycaemia throughout the day differs depending on the route of administration. Methods: This was a single centre retrospective study of 384 adult inpatients receiving oral or intravenous hydrocortisone and dexamethasone. Data on capillary glucose concentrations and time taken over 7 days were collected. A mixed model for repeated measures was applied to compare changes in glucose concentration over time for oral and intravenous corticosteroids. An auto-regressive covariance structure was employed to model correlations between repeated measurements. This was adjusted for age, sex, pre-admission diabetes, and/or pre-admission corticosteroid status. Results: No significant difference was found between oral and intravenous hydrocortisone on day 1 or across all 7 days (mean difference 0.17 mmol/L (−1.39, 1.75), p = 0.827, and mean difference 0.20 mmol/L (−0.61, 1.01), p = 0.639 respectively). There were no differences in mean glucose concentrations between those on oral or intravenous dexamethasone on day 1 or across all 7 days (mean difference 0.41 mmol/L (−0.55, 1.38), p = 0.404 and mean difference −0.09 mmol/L (−1.05,0.87), p = 0.855, respectively). Conclusion: This study found that oral and intravenous administration of hydrocortisone and dexamethasone do not have a significantly differing impact on blood glucose levels. Capillary glucose monitoring is strongly recommended in all individuals who are on either oral or intravenous corticosteroids.

IMPORTANCE:. Timely intervention for clinically deteriorating ward patients requires that care teams accurately diagnose and treat their underlying medical conditions. However, the most common diagnoses leading to deterioration and the relevant therapies provided are poorly characterized. OBJECTIVES:. We aimed to determine the diagnoses responsible for clinical deterioration, the relevant diagnostic tests ordered, and the treatments administered among high-risk ward patients using manual chart review. DESIGN, SETTING, AND PARTICIPANTS:. This was a multicenter retrospective observational study in inpatient medical-surgical wards at four health systems from 2006 to 2020. Randomly selected patients (1000 from each health system) with clinical deterioration, defined by reaching the 95th percentile of a validated early warning score, electronic Cardiac Arrest Risk Triage, were included. MAIN OUTCOMES AND MEASURES:. Clinical deterioration was confirmed by a trained reviewer or marked as a false alarm if no deterioration occurred for each patient. For true deterioration events, the condition causing deterioration, relevant diagnostic tests ordered, and treatments provided were collected. RESULTS:. Of the 4000 included patients, 2484 (62%) had clinical deterioration confirmed by chart review. Sepsis was the most common cause of deterioration (41%; n = 1021), followed by arrhythmia (19%; n = 473), while liver failure had the highest in-hospital mortality (41%). The most common diagnostic tests ordered were complete blood counts (47% of events), followed by chest radiographs (42%) and cultures (40%), while the most common medication orders were antimicrobials (46%), followed by fluid boluses (34%) and antiarrhythmics (19%). CONCLUSIONS AND RELEVANCE:. We found that sepsis was the most common cause of deterioration, while liver failure had the highest mortality. Complete blood counts and chest radiographs were the most common diagnostic tests ordered, and antimicrobials and fluid boluses were the most common medication interventions. These results provide important insights for clinical decision-making at the bedside, training of rapid response teams, and the development of institutional treatment pathways for clinical deterioration.

This publication is intended for both the general public and mosquito control professionals. It outlines the use of the bacterium Wolbachia pipientis as a tool to control mosquito populations and reduce the spread of mosquito-borne disease. Biting mosquitoes transmit many pathogens that cause deadly diseases in people, our pets, and our livestock. Collectively, malaria, dengue, West Nile, filariasis, and other mosquito-borne diseases result in millions of infections and hundreds of thousands of deaths every year. Effective vaccines for most of these have not been developed or are not yet available to the general public, and disease management is focused on controlling mosquito populations. Insecticides have become less effective over the past fifty years as mosquito populations all over the world have developed resistance. This has driven scientists to explore new options for controlling mosquitoes, including using the bacterium Wolbachia pipientis.

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The debate on decolonizing monuments has provoked a great deal of covering and shrouding of public sculptures. This paper looks at three examples and shows how textile interventions alter a monument’s visibility and, as products of (post)colonial trade or communal handicraft, add semantic layers. Ranging from The Kudzu Project’s marking of Confederate monuments in Charlottesville, VA, through the covering of the Robert Milligan statue by protesters in London, to a curated artwork by Joiri Minaya in Hamburg, the examples span both geographical regions and the recent history of the debate. The paper proposes that textile ephemerality questions concepts of history embedded in the traditional materiality of public sculptures and provides a model for imagining other practices of commemoration.

Summary: The major lactiferous ducts of the human breast branch out and end at terminal ductal lobular units (TDLUs). Despite their functional and clinical importance, the three-dimensional (3D) architecture of TDLUs has remained undetermined. Our quantitative and volumetric imaging of healthy human breast tissue demonstrates that highly branched TDLUs, which exhibit increased proliferation, are uncommon in the resting tissue regardless of donor age, parity, or hormonal contraception. Overall, TDLUs have a consistent shape and branch parameters, and they contain a main subtree that dominates in bifurcation events and exhibits a more duct-like keratin expression pattern. Simulation of TDLU branching morphogenesis in three dimensions suggests that evolutionarily conserved mechanisms regulate mammary gland branching in humans and mice despite their anatomical differences. In all, our data provide structural insight into 3D anatomy and branching of the human breast and exemplify the power of volumetric imaging in gaining a deeper understanding of breast biology.