Development, Pharmacokinetics and Antimalarial Evaluation of Dose Flexible 3D Printlets of Dapsone for Pediatric Patients.

The focus of current studies was to fabricate dose flexible printlets of dapsone (DDS) for pediatric patients by selective laser sintering (SLS) 3D printing method, and evaluate its physicochemical, patient in-use stability, and pharmacokinetic attributes. Eight formulations were fabricated using Kollicoat® IR, Eudragit® L-100-55 and StarCap®as excipients and evaluated for hardness, disintegration, dissolution, amorphous phase by differential scanning calorimetry and X-ray powder diffraction, in-use stability at 30 oC/75% RH for a month, and pharmacokinetic study in Sprague Dawley rats. The hardness, and disintegration of the printlets varied from 2.6±1.0 (F4) to 7.7±0.9 (F3) N and 2.0±0.4 (F2) to 7.6±0.6 (F3) sec, respectively. The drug was partially present as an amorphous form in the printlets. The drug was completely (>85%) dissolved in 20 min. No change in drug form or dissolution extent was observed after storage at in use condition. Pharmacokinetic profiles of both formulations (tablets and printlets) were almost superimposable with no statistical difference in pharmacokinetic parameters (Tmax, Cmax, and AUC0-¥)between formulations (p>0.05). Values of EC50 (half maximal effective concentration) and EC90 (maximal concentration inducing 90% maximal response) were 0.50±0.15 and 1.32±0.26 mM, 0.41±0.06 and 1.11±0.21, and 0.42±0.13 and 1.36±0.19 mM for DDS, printlet and tablet formulations, respectively, and differences were statistically insignificant (p>0.05). In conclusion, tablet and printlet formulations are expected to be clinical similar, thus clinically interchangeable.

Structural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W.

Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN.

Comparative transcriptomics and phylostratigraphy of Argentine ant odorant receptors.

Nestmate recognition in ants is regulated through the detection of cuticular hydrocarbons by odorant receptors (ORs) in the antennae. These ORs are crucial for maintaining colony cohesion that allows invasive ant species to dominate colonized environments. In the invasive Argentine ant, Linepithema humile, ORs regulating nestmate recognition are thought to be present in a clade of nine-exon odorant receptors, but the identity of the specific genes remains unknown. We sought to narrow down the list of candidate genes using transcriptomics and phylostratigraphy. Comparative transcriptomic analyses were conducted on the antennae, head, thorax, and legs of Argentine ant workers. We have identified a set of twenty-one nine-exon odorant receptors enriched in the antennae compared to the other tissues, allowing for downstream verification of whether they can detect Argentine ant cuticular hydrocarbons. Further investigation of these ORs could allow us to further understand the mechanisms underlying nestmate recognition and colony cohesion in ants.

Mind the GAHP: A novel protocol for improved vascular access in the hypotensive patient.

Background: Obtaining intravenous access in hypotensive patients is challenging and may critically delay resuscitation. The Graduated Vascular Access for Hypotensive Patient (GAHP) protocol leverages intraosseous fluid boluses to specifically dilate proximal veins. This study aims to evaluate the efficacy of GAHP in maximizing venous targets through early distal intraosseous access and a small fluid bolus. Methods: This was a prospective randomized cadaveric pilot study to evaluate extremity venous engorgement during intraosseous infusion. Cadavers (n = 23) had an intraosseous needle inserted into four sites: distal radius, proximal humerus, distal femur, and distal tibia. Intraosseous saline was rapidly infused, venous optimization was measured using real-time ultrasound. Primary outcome was maximum vessel circumference increase with intraosseous infusion. Secondary outcomes were: time to maximum circumference, and infusion volume required. Statistical analyses included Levene's test for equality of variances, Wilcoxon signed-rank test, and generalized estimating equation. Results: There was a significant mean increase of 1.03 cm (95% CI 0.86, 1.20), representing a difference of 102%. We found no significant difference in time to optimize vessel circumference across sites, but volume required significantly differed. Conclusion: GAHP quickly and effectively increased the circumference of anatomically adjacent veins. Anatomical sites did not differ on time to reach maximum enlargement of vessels following intraosseous infusion but did differ in terms of volume required to maximize vessel circumference. Further research is needed using live, hypotensive patients.

The Role of the MiR-181 Family in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues-this up-regulation induced epithelial-mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC.

Salmonella carriage by geckos detected within households in Malawi.

Salmonella was isolated from 23/79 (29.1%) pooled gecko stool samples from households in southern Malawi. Whole genome sequencing of 47 individual isolates within this collection revealed 27 Salmonella serovars spanning two subspecies. Our results demonstrate that geckos play an important role in the carriage of Salmonella within households.

Functional and evolutionary insights into chemosensation and specialized herbivory from the genome of the red milkweed beetle, Tetraopes tetrophthalmus (Cerambycidae: Lamiinae).

Tetraopes are aposematic longhorn beetles (Cerambycidae) that feed primarily on toxic plants in the genus Asclepias (milkweeds). Studies of Tetraopes and their host plants have revealed compelling evidence for insect-plant coevolution and cospeciation. We sequenced, assembled and annotated the genome of the common red milkweed beetle, Tetraopes tetrophthalmus, and explored gene content and evolution, focusing on annotated genes putatively involved in chemosensation, allelochemical detoxification, and phytophagy. Comparisons were made to the Asian longhorned beetle (Anoplophora glabripennis) genome. The genome assembly comprised 779 Mb distributed across 1057 contigs, with an N50 of 2.21 Mb and 13,089 putative genes, including 97.3% of expected single-copy orthologs. Manual curation identified 122 putative odorant receptors (OR) and 162 gustatory receptors (GR), the former number similar to A. glabripennis but the latter only 69% of the A. glabripennis suite. We also documented a greater percentage of pseudogenic GRs and ORs compared to A. glabripennis, suggesting an ongoing reduction in chemosensory function, perhaps related to host specialization. We found lower diversity within certain well-studied gene families predicted to encode putative plant cell wall degrading enzymes in the T. tetrophthalmus genome, perhaps also due to host specialization. Exploring genes relevant to stress and allelochemical detoxification revealed evidence of an abundance of ABC-family genes in the T. tetrophthalmus genome, which may be related to sequestering toxic cardiac glycosides. Our studies further illuminate the genomic basis and evolution of chemosensation in longhorn beetles and provide a new vantage point from which to explore the ecology and evolution of specialized plant-feeding in Tetraopes and other phytophagous beetles.

Examining the neurostructural architecture of intelligence: The Lothian Birth Cohort 1936 study.

Examining underlying neurostructural correlates of specific cognitive abilities is practically and theoretically complicated by the existence of the positive manifold (all cognitive tests positively correlate): if a brain structure is associated with a cognitive task, how much of this is uniquely related to the cognitive domain, and how much is due to covariance with all other tests across domains (captured by general cognitive functioning, also known as general intelligence, or 'g')? We quantitatively address this question by examining associations between brain structural and diffusion MRI measures (global tissue volumes, white matter hyperintensities, global white matter diffusion fractional anisotropy and mean diffusivity, and FreeSurfer processed vertex-wise cortical volumes, smoothed at 20mm fwhm) with g and cognitive domains (processing speed, crystallised ability, memory, visuospatial ability). The cognitive domains were modelled using confirmatory factor analysis to derive both hierarchical and bifactor solutions using 13 cognitive tests in 697 participants from the Lothian Birth Cohort 1936 study (mean age 72.5 years; SD = .7). Associations between the extracted cognitive factor scores for each domain and g were computed for each brain measure covarying for age, sex and intracranial volume, and corrected for false discovery rate. There were a range of significant associations between cognitive domains and global MRI brain structural measures (r range .008 to .269, p < .05). Regions implicated by vertex-wise regional cortical volume included a widespread number of medial and lateral areas of the frontal, temporal and parietal lobes. However, at both global and regional level, much of the domain-MRI associations were shared (statistically accounted for by g). Removing g-related variance from cognitive domains attenuated association magnitudes with global brain MRI measures by 27.9-59.7% (M = 46.2%), with only processing speed retaining all significant associations. At the regional cortical level, g appeared to account for the majority (range 22.1-88.4%; M = 52.8% across cognitive domains) of regional domain-specific associations. Crystallised and memory domains had almost no unique cortical correlates, whereas processing speed and visuospatial ability retained limited cortical volumetric associations. The greatest spatial overlaps across cognitive domains (as denoted by g) were present in the medial and lateral temporal, lateral parietal and lateral frontal areas.

Standard diet and animal source influence hippocampal spatial reference learning and memory in congenic C57BL/6J mice.

Background: Assessing learning and memory has become critical to evaluate brain function in health, aging or neurological disease. The hippocampus is crucially involved in these processes as illustrated by H.M.'s remarkable case and by the well-established early symptoms of Alzheimer's disease. Numerous studies have reported the impact of gut microbiota on hippocampal structure and function using pro-, pre- and antibiotics, diet manipulations, germ-free conditions or fecal transfer. However, most diet manipulations have relied on Western diet paradigms (high fat, high energy, high carbohydrates). Here, we compared the impact of two standard diets, 5K52 and 2918 (6% fat, 18% protein, 3.1kcal/g), and how they influenced hippocampal learning and memory in adult 6-month-old congenic C57BL/6J mice from two sources. Results: Using a hippocampal-dependent task, we found that 5K52-fed mice performed consistently better than 2918-fed animals in the Barnes circular maze. These behavioral differences were accompanied with marked changes in microbiota, which correlated with spatial memory retention performance. We next tested whether 2918-induced alterations in behavior and microbiome could be rescued by 5K52 diet for 3 months. Changing the 2918 diet to 5K52 diet mid-life improved spatial learning and memory in mice. Shotgun sequencing and principal component analyses revealed significant differences at both phylum and species levels. Multivariate analyses identified Akkermansia muciniphila or Bacteroidales bacterium M11 and Faecalibaculum rodentium as the strongest correlates to spatial memory retention in mice depending on the animal source. In both settings, the observed behavioral differences only affected hippocampal-dependent performance as mice fed with either diet did similarly well on the non-spatial variant of the Y-maze. Conclusions: In summary, these findings demonstrate the diverging effects of seemingly equivalent standard diets on hippocampal memory. Based on these results, we strongly recommend the mandatory inclusion of the diet and source of animals used in rodent behavioral studies.

Evaluating global research trends in special needs dentistry: A systematic bibliometrix analysis.

OBJECTIVES: Special needs dentistry (SND) is a vast and fragmented field of study. This comprehensive bibliometric analysis aimed to evaluate the scope of SND, including the existing knowledge base, distribution structure, quantitative relationships, and research trends. MATERIAL AND METHODS: A systematic search was conducted on March 10, 2022, using the Web of Science Core Collection database, covering the period from 1985 to 2021, focusing on studies reporting on special needs populations in a dentally relevant context. Records were title-screened and analyzed for key bibliometric indicators. RESULTS: Among 48,374 articles, 13,869 underwent bibliometric analysis. Peak SND research occurred during 1985-1997. United States led in productivity, trailed by Brazil and Japan. University of Sao Paulo excelled in Brazil, University of Washington and University of North Carolina in the United States. The Journal of Dental Research was the most productive source of research and also had the highest number of citations, followed by Community Dentistry and Oral Epidemiology. Keyword analysis revealed that "elderly", "caries", and "epidemiology" were the most commonly used author keywords. CONCLUSIONS: This study represents the first bibliometric analysis of SND literature. It emphasizes the need for increased collaboration between institutions and authors. Furthermore, it suggests focusing on research input from non-dental disciplines and populations with rarer intellectual or developmental conditions.

Prehospital Whole Blood Administration for Pediatric Gastrointestinal Hemorrhage: A Case Report.

The management of gastrointestinal (GI) hemorrhage in a prehospital setting presents significant challenges, particularly in arresting the hemorrhage and initiating resuscitation. This case report introduces a novel instance of prehospital whole blood transfusion to an 8-year-old male with severe lower GI hemorrhage, marking a shift in prehospital pediatric care. The patient, with no previous significant medical history, presented with acute rectal bleeding, severe hypotension (systolic/diastolic blood pressure [BP] 50/30 mmHg), and tachycardia (148 bpm). Early intervention by Emergency Medical Services (EMS), including the administration of 500 mL (16 mL/kg) of whole blood, led to marked improvement in vital signs (BP 97/64 mmHg and heart rate 93 bpm), physiology, and physical appearance, underscoring the potential effectiveness of prehospital whole blood transfusion in pediatric GI hemorrhage. Upon hospital admission, a Meckel's diverticulum was identified as the bleeding source, and it was successfully surgically resected. The patient's recovery was ultimately favorable, highlighting the importance of rapid, prehospital intervention and the potential role of whole blood transfusion in managing acute pediatric GI hemorrhage. This case supports the notion of advancing EMS protocols to include interventions historically reserved for the hospital setting that may significantly impact patient outcomes from the field.

Enthesitis in a European registry-based cohort of patients with psoriatic arthritis treated with tumour necrosis factor inhibitors: clinical burden, patient-reported outcomes, and treatment response.

OBJECTIVE: To explore the registration of enthesitis among biologic-naïve patients with psoriatic arthritis (PsA) initiating tumour necrosis factor inhibitor (TNFi) treatment across 12 European registries, compare the disease burden and patient-reported outcomes (PROs) between patients with and without enthesitis, and assess the enthesitis treatment response. METHOD: Demographics, clinical characteristics, and PROs at first TNFi (TNFi-1) initiation (baseline) were assessed in patients with PsA, diagnosed by a rheumatologist, with versus without assessment of entheses and between those with versus without enthesitis. Enthesitis scores and resolution frequency were identified at follow-up. RESULTS: Of 10 547 patients in the European Spondyloarthritis (EuroSpA) Research Collaboration Network initiating TNFi, 1357 underwent evaluation for enthesitis. Eight registries included a validated scoring system for enthesitis. At baseline, 874 patients underwent entheses assessment [Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) 485 patients, Spondyloarthritis Research Consortium of Canada (SPARCC) 389 patients]. Enthesitis was detected by MASES in 170/485 (35%, mean score ± sd 3.1 ± 2.4) and by SPARCC in 236/389 (61%, 4 ± 3.4). Achilles enthesitis was most frequent, by both MASES (unilateral/bilateral 28%/9%) and SPARCC (48%/18%). MASES/SPARCC baseline and follow-up scores for TNFi-1 were available for 100/105 patients. Of these, 63 patients (63%) (MASES) and 46 (43.8%) (SPARCC) achieved resolution of enthesitis. The site-specific enthesitis resolution was overall lower at SPARCC sites (peripheral; 63-80%) than at MASES sites (mainly axial; 82-100%) following TNFi-1. Disease activity and PROs were worse in patients with versus without enthesitis. CONCLUSION: Entheseal assessments are only registered in a minority of patients with PsA in routine care. When assessed, enthesitis was common, and a substantial proportion demonstrated resolution following treatment with TNFi-1.

Do Implant Retained Prostheses Improve the Quality of Life of Patients with Extraoral Maxillofacial Defects - A Systematic Review.

BACKGROUND: There is limited evidence available regarding patient satisfaction and quality of life assessment in patients with extraoral maxillofacial prostheses. OBJECTIVES: This systematic review aims to understand the impact of extraoral implant retained prosthesis in improving the quality of life in patients with extraoral maxillofacial defects/abnormalities. METHODS: A comprehensive search was performed of nine electronic databases up to August 2022, which yielded three articles that satisfied the inclusion criteria. The study characteristics and findings were extracted, and the included studies were assessed for quality. RESULTS: Three cohort studies were selected. Despite the lack of uniformity in the quality of life instruments, there was a general trend in improvement in the quality of life for patients with implant retained extraoral prostheses. The studies were also deemed to be of high quality on assessment. CONCLUSION: Given the limitations of this systematic review, there exists limited evidence indicating that implant prostheses may enhance the quality of life for individuals with extraoral maxillofacial defects or abnormalities.

Quality of life following repair of large hiatal hernia is not influenced by the use of mesh-Longer-term follow-up from a randomized trial.

INTRODUCTION: The use of prosthetic mesh in laparoscopic repair of large hiatus hernias remains controversial. Clinical and quality of life outcomes from a randomized controlled trial of mesh versus suture repair previously showed few differences at early follow-up. This study evaluated longer-term quality of life outcomes from that trial. METHODS: A prospective, multicentre, double blind randomized controlled trial assessed three methods of repair for large hiatus hernias: sutures-only versus absorbable mesh versus non-absorbable mesh. Quality of life was assessed using the Short-Form 36 (SF-36) questionnaire which was completed preoperatively and then at 3, 6, 12 months following surgery and annually thereafter. SF-36 outcomes were compared across the three repair techniques at longer-term follow-up (3-6 years), and to earlier baseline and 12-month outcomes. RESULTS: 126 patients were randomized; 43-suture-only, 41-absorbable mesh and 42-non-absorbable mesh. Questionnaires were completed by 118 patients preoperatively, 115 at 12 months and 98 at longer-term follow-up (median 5 years). There were no significant differences between the repair techniques for the subscale and composite scores at longer-term follow-up. The mental component score improved significantly after surgery and was sustained across follow-up for all techniques. The physical component score also improved significantly but was lower at longer-term follow-up compared to the 12-month follow up in both mesh groups. CONCLUSION: Surgical repair of large hiatus hernias provides sustained long-term improvement in quality of life. The addition of mesh does not improve quality of life. TRIAL REGISTRATION: This trial is registered with the Australia and New Zealand Clinical Trials Registry ACTRN12605000725662.

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning.

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

Differential Responses to Immune Checkpoint Inhibitors are Governed by Diverse Mismatch Repair Gene Alterations.

PURPOSE: The response to immune checkpoint inhibitors (ICI) in deficient mismatch repair (dMMR) colorectal cancer and endometrial cancer is variable. Here, we explored the differential response to ICIs according to different mismatch repair alterations. EXPERIMENTAL DESIGN: Colorectal cancer (N = 13,701) and endometrial cancer (N = 3,315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan-Meier. The prediction of high-, intermediate-, and low-affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2). RESULTS: Compared with mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all colorectal cancer (54.6 vs. 36 months; P = 0.0.025) and endometrial cancer (81.5 vs. 48.2 months; P < 0.001) patients. In ICI-treated patients, the mOS was longer in mutS co-loss in colorectal cancer [not reached (NR) vs. 36 months; P = 0.011). In endometrial cancer, the mOS was NR vs. 42.2 months; P = 0.711]. The neoantigen load (NAL) in mutS co-loss compared with mutL co-loss was higher in colorectal cancer (high-affinity epitopes: 25.5 vs. 19; q = 0.017, intermediate: 39 vs. 32; q = 0.004, low: 87.5 vs. 73; q < 0.001) and endometrial cancer (high-affinity epitopes: 15 vs. 11; q = 0.002, intermediate: 27.5 vs. 19; q < 0.001, low: 59 vs. 41; q < 0.001), respectively. R2 ranged from 0.25 in mutS co-loss colorectal cancer to 0.95 in mutL co-loss endometrial cancer. CONCLUSIONS: Patients with mutS co-loss experienced longer mOS in colorectal cancer and endometrial cancer and better response to ICIs in colorectal cancer. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.

The global distribution of special needs dentistry across dental school curricula.

INTRODUCTION: Special needs dentistry (SND) is an emerging dental specialty, with ongoing developments in education and clinical practice focused towards the tailored management of individuals with special needs (SN). Patients with SN have a higher prevalence of oral diseases and unmet dental needs compared to the general population. Although inadequate training and experience in managing patients with SN has been highlighted as a significant barrier to accessing care, there is limited data about the extent of SND teaching at the entry-to-practice or higher levels. METHODS: This work is the first to map SND curricula globally, across 180 countries and 1265 dental schools. RESULTS: Although 74.62% of dental schools were found in developing economies, the distribution of programs that reported SND in their courses was highly skewed towards developed countries. In terms of advanced degrees, beyond basic entry-to-practice training, the USA delivered 60% of the SND programs, followed by Canada (15.56%), UK (13.33%), and Australia (8.89%). The term SND appeared in 33.95% of entry-to-practice level program curricula and was less commonly used in transitioning economies. Only 112 SND-specialized practitioners enter the workforce globally each year from developed economies, and all but three advanced degrees are found in G7 countries. CONCLUSION: By exploring the impact of economic status on its distribution, this paper highlighted the lack of SND representation in dental curricula, especially amongst programs in transitioning or developing economies. Education of both general dentists and specialists is critical as a collaborative effort is needed to manage the growing population of patients with SN.