Advanced Chemical and Imaging Methods for Studying Structure Morphology and Excipients Solid State Transformations in Pharmaceutical Multiparticulate Formulations.

The formulation of paediatric medicines faces significant challenges to meet the requirements for safe and accurate administration, while maintaining a suitable taste. Multiparticulate formulations have a strong potential to address these challenges because they combine dose flexibility with ease of administration. Understanding the stability of multiparticulate formulations over storage as a function of time and environmental parameters, such as humidity and temperature, is important to manage their commercialisation and use. In this work, we have expanded the toolkit of available techniques for studying multiparticulates beyond those such as scanning electron microscopy (SEM) and confocal laser scanning microscopy. We include advanced methods of environmentally-controlled SEM to monitor temperature- and humidity-induced changes in-situ, and a variety of Raman spectroscopies including stimulated Raman scattering microscopy to identify and localise the different ingredients at the surface and inside the multiparticulates. These techniques allowed unprecedented monitoring of specific changes to the particulate structure and distribution of individual ingredients due to product aging. These methods should be considered as valuable novel tools for in-depth characterisation of multiparticulate formulations to further understand chemical changes occurring during their development, manufacturing and long-term storage. We envisage these techniques to be useful in furthering the development of future medicine formulations.

Prognostic models and factors identifying end-of-life in non-cancer chronic diseases: a systematic review.

BACKGROUND: Precise prognostic information, if available, is very helpful for guiding treatment decisions and resource allocation in patients with non-cancer non-communicable chronic diseases (NCDs). This study aimed to systematically review the existing evidence, examining prognostic models and factors for identifying end-of-life non-cancer NCD patients. METHODS: Electronic databases, including Medline, Embase, CINAHL, Cochrane Library, PsychINFO and other sources, were searched from the inception of these databases up until June 2023. Studies published in English with findings mentioning prognostic models or factors related to identifying end-of-life in non-cancer NCD patients were included. The quality of studies was assessed using the Quality in Prognosis Studies tool. RESULTS: The analysis included data from 41 studies, with 16 focusing on chronic obstructive pulmonary diseases (COPD), 10 on dementia, 6 on heart failure and 9 on mixed NCDs. Traditional statistical modelling was predominantly used for the identified prognostic models. Common predictors in COPD models included dyspnoea, forced expiratory volume in 1 s, functional status, exacerbation history and body mass index. Models for dementia and heart failure frequently included comorbidity, age, gender, blood tests and nutritional status. Similarly, mixed NCD models commonly included functional status, age, dyspnoea, the presence of skin pressure ulcers, oral intake and level of consciousness. The identified prognostic models exhibited varying predictive accuracy, with the majority demonstrating weak to moderate discriminatory performance (area under the curve: 0.5-0.8). Additionally, most of these models lacked independent external validation, and only a few underwent internal validation. CONCLUSION: Our review summarised the most relevant predictors for identifying end-of-life in non-cancer NCDs. However, the predictive accuracy of identified models was generally inconsistent and low, and lacked external validation. Although efforts to improve these prognostic models should continue, clinicians should recognise the possibility that disease heterogeneity may limit the utility of these models for individual prognostication; they may be more useful for population level health planning.

DNMT1 Y495C mutation interferes with maintenance methylation of imprinting control regions.

Hereditary Sensory and Autonomic Neuropathy Type 1E (HSAN1E) is a rare autosomal dominant neurological disorder due to missense mutations in DNA methyltransferase 1 (DNMT1). To investigate the nature of the dominant effect, we compared methylomes of transgenic R1wtDnmt1 and R1Dnmt1Y495C mouse embryonic stem cells (mESCs) overexpressing WT and the mutant mouse proteins respectively, with the R1 (wild-type) cells. In case of R1Dnmt1Y495C, 15 out of the 20 imprinting control regions were hypomethylated with transcript level dysregulation of multiple imprinted genes in ESCs and neurons. Non-imprinted regions, minor satellites, major satellites, LINE1 and IAP repeats were unaffected. These data mirror the specific imprinting defects associated with transient removal of DNMT1 in mESCs, deletion of the maternal-effect DNMT1o variant in preimplantation mouse embryos, and in part, reprogramming to naïve human iPSCs. This is the first DNMT1 mutation demonstrated to specifically affect Imprinting Control Regions (ICRs), and reinforces the differences in maintenance methylation of ICRs over non-imprinted regions. Consistent with nervous system abnormalities in the HSAN1E disorder and involvement of imprinted genes in normal development and neurogenesis, R1Dnmt1Y495C cells showed dysregulated pluripotency and neuron marker genes, and yielded more slender, shorter, and extensively branched neurons. We speculate that R1Dnmt1Y495C cells produce predominantly dimers containing mutant proteins, leading to a gradual and specific loss of ICR methylation during early human development.

The effect of addition of 2DCT scans and 3DCT scans for the classification of tibial plateau fractures: a systematic review.

PURPOSE: In this systematic review, we evaluate the effect of radiographs and 2D and 3D imaging techniques on the interobserver agreement of six commonly used classification systems for tibial plateau fractures. METHODS: In accordance with PRISMA guidelines, PubMed, Cochrane, Embase and Web of Science were searched for studies regarding the effect of 2D and 3D imaging techniques on the interobserver agreement of tibial plateau classification systems. Studies validating new classification systems, not providing own data or only providing information on the interobserver agreement for radiographs were excluded. Studies were scored based on the ROBINS-I risk of bias tool. RESULTS: Our review analysed 14 studies on different classification systems used for tibial plateau fractures in clinical practice, with the Schatzker classification being the most commonly used classification system. The results showed that the addition of 2D CT led to a significant improvement of interobserver agreement for one study. However, other included studies showed varying levels of interobserver agreement, ranging from fair to substantial according to the interpretation by Landis and Koch. The addition of 3D CT resulted in a significant deterioration in one study for the Schatzker classification. Similar to the addition of 2D CT, the interobserver agreement for the Schatzker classification with the addition of 3D CT were heterogeneous ranging from fair to almost perfect according to the interpretation by Landis and Koch. CONCLUSIONS: The use of 2D CT can be recommended for classifying tibial plateau fractures with the Schatzker classification, AO/OTA classification and Hohl classification. The value of 3D CT on the interobserver agreement of commonly used classification systems remains uncertain and unproven. Therefore, we do not recommend the use of 3D CT for the classification of tibial plateau fractures. Overall, the advancement of imaging techniques is not in line with the advancement in interobserver agreement on fracture classification.

Calvarial hyperpigmentation.

Background: Osseous hyperpigmentation of the calvarium is an extremely rare finding with only few reported cases in literature. Case Description: The case is of a 59-year-old Caucasian male who presented with an acute history of generalized tonic clonic seizures and progressive weakness of the right upper limb. He had a background history of a malignant melanoma which had been resected from his left external acoustic meatus 4 weeks prior. Neuroimaging of the brain showed an intra-axial space-occupying lesion in his left parietal lobe with no associated osseous changes. A left mini parietal craniotomy was performed which revealed black discoloration of the parietal bone. The lesion was successfully resected and the bone flap was secured back in place. The patient was discharged on the 4th day postoperatively with no complications. The unusual finding of black discoloration of the calvarium was found to be secondary to adolescent tetracycline use. Conclusion: Calvarial hyperpigmentation is a phenomenon encountered incidentally and will often come as surprise for surgeons. Once encountered, thorough history taking and examination should be done to investigate the cause.

Passive Wireless Pressure Gradient Measurement System for Fluid Flow Analysis.

Using distributed MEMS pressure sensors to measure small flow rates in high resistance fluidic channels is fraught with challenges far beyond the performance of the pressure sensing element. In a typical core-flood experiment, which may last several months, flow-induced pressure gradients are generated in porous rock core samples wrapped in a polymer sheath. Measuring these pressure gradients along the flow path requires high resolution pressure measurement while contending with difficult test conditions such as large bias pressures (up to 20 bar) and temperatures (up to 125 °C), as well as the presence of corrosive fluids. This work is directed at a system for using passive wireless inductive-capacitive (LC) pressure sensors that are distributed along the flow path to measure the pressure gradient. The sensors are wirelessly interrogated with readout electronics placed exterior to the polymer sheath for continuous monitoring of experiments. Using microfabricated pressure sensors that are smaller than ø15 × 3.0 mm3, an LC sensor design model for minimizing pressure resolution, accounting for sensor packaging and environmental artifacts is investigated and experimentally validated. A test setup, built to provide fluid-flow pressure differentials to LC sensors with conditions that mimic placement of the sensors within the wall of the sheath, is used to test the system. Experimental results show the microsystem operating over full-scale pressure range of 20,700 mbar and temperatures up to 125 °C, while achieving pressure resolution of <1 mbar, and resolving gradients of 10-30 mL/min, which are typical in core-flood experiments.

A Distinct Nasal Microbiota Signature in Peritoneal Dialysis Patients.

Rationale & Objective: The nasal passages harbor both commensal and pathogenic bacteria. In this study, we sought to characterize the anterior nasal microbiota in PD patients using 16S rRNA gene sequencing. Study Design: Cross-sectional. Setting & Participants: We recruited 32 PD patients, 37 kidney transplant (KTx) recipients, 22 living donor/healthy control (HC) participants and collected anterior nasal swabs at a single point in time. Predictors: We performed 16S rRNA gene sequencing of the V4-V5 hypervariable region to determine the nasal microbiota. Outcomes: Nasal microbiota profiles were determined at the genus level as well as the amplicon sequencing variant level. Analytical Approach: We compared nasal abundance of common genera among the 3 groups using Wilcoxon rank sum testing with Benjamini-Hochberg adjustment. DESeq2 was also utilized to compare the groups at the ASV levels. Results: In the entire cohort, the most abundant genera in the nasal microbiota included: Staphylococcus, Corynebacterium, Streptococcus , and Anaerococcus . Correlational analyses revealed a significant inverse relationship between the nasal abundance of Staphylococcus and that of Corynebacterium . PD patients have a higher nasal abundance of Streptococcus than KTx recipients and HC participants. PD patients have a more diverse representation of Staphylococcus and Streptococcus than KTx recipients and HC participants. PD patients who concurrently have or who developed future Staphylococcus peritonitis had a numerically higher nasal abundance of Staphylococcus than PD patients who did not develop Staphylococcus peritonitis. Limitations: 16S RNA gene sequencing provides taxonomic information to the genus level. Conclusions: We find a distinct nasal microbiota signature in PD patients compared to KTx recipients and HC participants. Given the potential relationship between the nasal pathogenic bacteria and infectious complications, further studies are needed to define the nasal microbiota associated with these infectious complications and to conduct studies on the manipulation of the nasal microbiota to prevent such complications.

Ultra-stable CO2-in-water foam by generating switchable Janus nanoparticles in-situ.

HYPOTHESIS: The surface of silica nanoparticles (NP) may be covalently grafted with two amino ligands to balance colloidal stability and interfacial activity via formation of in situ Janus particles. The modified NP may be combined with a like-charged diamine surfactant to create ultra-stable CO2 foam at low NP concentrations. EXPERIMENTS: The NP colloidal stability was measured up to 80 °C in 230 g/L TDS brine with dynamic light scattering. The NP surface was characterized using zeta potential, TEM, TGA, conductometric and potentiometric titrations, NMR and interfacial measurement. CO2/brine foam was generated at 60-80 °C and 15 MPa and apparent viscosity was measured vs foam quality. The foam stability was measured in-situ with an optical microscope. FINDINGS: Upon adding only 0.1 wt% NP, ultra-stable CO2 foam was observed at 60 °C with a bubble coarsening rate 3 orders of magnitude lower than with surfactant alone. Foam bubbles were spherical with NP present, but became polyhedral for the much less stable surfactant-only foams. For this novel like-charged surfactant-NP system, the limited surfactant adsorption on the NP resulted in NP stabilized CO2 foam, while maintaining NP colloidal stability at high surfactant concentrations and high salinity, providing a new perspective of NP-surfactant design.

Macroeconomic consequences of the COVID-19 pandemic.

We estimate the economic impacts of COVID-19 in the U.S. using a disaster economic consequence analysis framework implemented by a dynamic computable general equilibrium (CGE) model. This facilitates identification of relative influences of several causal factors as "shocks" to the model, including mandatory business closures, disease spread trajectories, behavioral responses, resilience, pent-up demand, and government stimulus packages. The analysis is grounded in primary data on avoidance behavior and healthcare parameters. The decomposition of the influence of various causal factors will help policymakers offset the negative influences and reinforce the positive ones during the remainder of this pandemic and future ones.

Contemporary Biological Insights and Clinical Management of Craniopharyngioma.

Craniopharyngiomas (CPs) are clinically aggressive tumors because of their invasive behavior and recalcitrant tendency to recur after therapy. There are 2 types based on their distinct histology and molecular features: the papillary craniopharyngioma (PCP), which is associated with BRAF-V600E mutations and the adamantinomatous craniopharyngioma (ACP), characterized by mutations in CTNNB1 (encoding ß-catenin). Patients with craniopharyngioma show symptoms linked to the location of the tumor close to the optic pathways, hypothalamus, and pituitary gland, such as increased intracranial pressure, endocrine deficiencies, and visual defects. Treatment is not specific and mostly noncurative, and frequently includes surgery, which may achieve gross total or partial resection, followed by radiotherapy. In cystic tumors, frequent drainage is often required and intracystic instillation of drugs has been used to help manage cyst refilling. More recently targeted therapies have been used, particularly in PCP, but also now in ACP and clinical trials are underway or in development. Although patient survival is high, the consequences of the tumor and its treatment can lead to severe comorbidities resulting in poor quality of life, in particular for those patients who bear tumors with hypothalamic involvement. Accordingly, in these patients at risk for the development of a hypothalamic syndrome, hypothalamus-sparing treatment strategies such as limited resection followed by irradiation are recommended. In this review, we provide an update on various aspects of CP, with emphasis on recent advances in the understanding of tumor pathogenesis, clinical consequences, management, and therapies.

Debating New Media: Rewriting Communications History.

Many historians, journalists, and media mavens have traced the genealogy of Victorian communications networks backward, beginning with radio after World War I and continuing with personal computing in the 1980s and ending with the internet today. This impulse has accelerated with the rise of electronic commerce, social media, and virtual reality. This essay proposes a different agenda. Drawing on recent historical writing on mythmaking, materiality, and political economy and illustrated with case studies from Europe, North America, Asia, and North Africa, it reenvisions the history of new media by telling the story of Victorian communications networks in relation to the issues of their day, not ours. The essay spans five networks in the period between 1830 and 1914: the landline telegraph, the undersea cable, the telephone, the wireless telegraph, and the mail.

Experimental prosopis management practices and grassland restoration in three Eastern African countries.

Woody species have been introduced in many parts of the world to provide economic benefits, but some of those species are now among the worst invaders, causing widespread economic and environmental damage. Management of woody species to restore original ecosystem services, such as biodiverse grassland that can provide fodder and sequester carbon, are needed to limit the impacts of alien species. However, the best management methods, i.e., the most economically efficient and effective way to remove trees and the most effective way to restore or rehabilitate the cleared land, are not developed for many species. In Eastern Africa, prosopis (Prosopis julifora) has invaded large areas of savanna and grassland, thereby affecting, among other things, fodder and water for livestock, access to dry season grazing lands and ultimately pastoral livelihoods. We tested three prosopis treatments (manual uprooting and cut stump and basal bark herbicide application) in combination with three incremental restoration interventions (divots, divots + mulching, divots + mulching + grass seed sowing). The three-year study was replicated in Ethiopia (Afar National Regional State), Kenya (Baringo county) and Tanzania (Moshi district). Prosopis survival and vegetation development, both diversity and biomass, were recorded. The prosopis treatments were all highly effective (between 85 and 100% tree mortality in almost all cases), but the two treatments that involved the complete removal of the aboveground biomass (manual and cut stump) yielded a more productive and more diverse vegetation than the treatment that killed the trees standing (basal bark). Compared to the effect of prosopis removal, the effect of restoration interventions on vegetation composition was small, indicating that most species re-established from the soil seed bank. The results show that it is possible to restore land previously invaded by prosopis. Despite the different rates of vegetation establishment and variation in species composition, the restoration interventions resulted in vegetation that in some cases contained a substantial fraction of perennial grasses. The method chosen to control prosopis depends on the availability of resources, including herbicides, and the need to remove rootstocks if the intention is to plant crops. Supplementary Information: The online version contains supplementary material available at 10.1186/s43170-023-00163-5.

Disclosing Individual Results in Dementia Research: A Proposed Study Participant's Bill of Rights.

This Study Participant's Bill of Rights is a call to action for researchers in Alzheimer's disease and related dementias (ADRD) to proactively design clinical studies that provide the option for research participants to learn their individual research results if they choose, and in a manner that ensures study integrity. This Bill of Rights was crafted by a committee of study participants, care partners, representatives of dementia advocacy organizations, and other stakeholders in dementia research for the Advisory Group on Risk Education for Dementia (AGREEDementia). The framework developed by the Multi-Regional Clinical Trials (MRCT) Return of Individual Research Results provides a useful context for researchers to plan their studies and disclosure.

Keyhole Approaches Applied to Clipping of Acutely Ruptured Intracerebral Aneurysms-A Technical Note and Case Series.

BACKGROUND: Evolution of keyhole techniques in aneurysm surgery allows for definitive surgical management of aneurysmal pathology with little disruption of normal surrounding tissue. While experienced vascular neurosurgeons are increasingly applying keyhole techniques to unruptured aneurysms, experience with ruptured aneurysms is limited. OBJECTIVE: We sought to explore technical nuances and present operative outcomes for our series of 40 consecutive patients presenting with ruptured intracerebral aneurysms treated with surgical clipping via a keyhole approach. METHODS: This study is a consecutive, single-surgeon, single-center retrospective case series of aneurysms clipped with keyhole approaches at Helen Joseph Hospital in Johannesburg, South Africa. Patients presenting with subarachnoid hemorrhage were worked up exclusively with computed tomography. On the basis of vessel location and unique anatomic features, aneurysms were clipped through one of these approaches: minipterional, supraorbital, or keyhole interhemispheric. Operative details were assessed on retrospective file review, and patient outcomes were assessed on clinic follow-up. RESULTS: A minipterional approach was used for 55% of cases, the supraorbital approach in 30% of cases, and the mini-interhemispheric approach in 15% of cases. The intraoperative aneurysm rupture rate was 26.2%. Complete aneurysm occlusion was achieved in 97.4% with none of the 40 cases requiring conversion of a keyhole to a larger craniotomy. A good outcome was achieved for 72.5% of patients (modified Rankin Scale score ≤2). For patients presenting with World Federation of Neurological Surgeons grade I to III subarachnoid hemorrhage, 92.9% achieved a good outcome. CONCLUSIONS: The present series supports the concept that sound technical execution of keyhole approaches, even in the setting of acutely ruptured cerebral aneurysms, is a viable option for clipping of intracranial aneurysms.

Regenerative medicine technologies applied to transplant medicine. An update.

Regenerative medicine (RM) is changing how we think and practice transplant medicine. In regenerative medicine, the aim is to develop and employ methods to regenerate, restore or replace damaged/diseased tissues or organs. Regenerative medicine investigates using tools such as novel technologies or techniques, extracellular vesicles, cell-based therapies, and tissue-engineered constructs to design effective patient-specific treatments. This review illustrates current advancements in regenerative medicine that may pertain to transplant medicine. We highlight progress made and various tools designed and employed specifically for each tissue or organ, such as the kidney, heart, liver, lung, vasculature, gastrointestinal tract, and pancreas. By combing both fields of transplant and regenerative medicine, we can harbor a successful collaboration that would be beneficial and efficacious for the repair and design of de novo engineered whole organs for transplantations.

Low-loss microwave photonics links using hollow core fibres.

There are a host of applications in communications, sensing, and science, in which analogue signal transmission is preferred over today's dominant digital transmission. In some of these applications, the advantage is in lower cost, while in others, it lies in superior performance. However, especially for longer analogue photonics links (up to 10 s of km), the performance is strongly limited by the impairments arising from using standard single-mode fibres (SSMF). Firstly, the three key metrics of analogue links (loss, noise figure, and dynamic range) tend to improve with received power, but this is limited by stimulated Brillouin scattering in SSMF. Further degradation is due to the chromatic dispersion of SSMF, which induces radio-frequency (RF) signal fading, increases even-order distortions, and causes phase-to-intensity-noise conversion. Further distortions still, are caused by the Kerr nonlinearity of SSMF. We propose to address all of these shortcomings by replacing SSMFs with hollow-core optical fibres, which have simultaneously six times lower chromatic dispersion and several orders of magnitude lower nonlinearity (Brillouin, Kerr). We demonstrate the advantages in this application using a 7.7 km long hollow-core fibre sample, significantly surpassing the performance of an SSMF link in virtually every metric, including 15 dB higher link gain and 6 dB lower noise figure.

A Community-Based Education Program for Overactive Bladder in a Predominantly Minority Older Female Population: A Pilot Study.

INTRODUCTION: Knowledge gaps regarding available treatment and social stigmatization are barriers to care in patients with overactive bladder (OAB). We assessed the feasibility of an OAB education program targeting older community-dwelling females. METHODS: Community-dwelling women over 55 years old were recruited. Eligible participants underwent an education program covering continence-promotion strategies. The Overactive Bladder Questionnaire-Short Form and Short Form-12 were completed at baseline, 1 week, 3 months, and 6 months post-intervention to measure symptom bother and condition-specific and general quality of life (QoL). Data were analyzed using a linear mixed-effects model for repeated measures. RESULTS: Thirty-seven female patients with OAB symptoms at baseline were assessed with the majority from Latino/Hispanic or Black/African American ethnic/racial backgrounds. For our youngest subgroup (≤68 years old), significant improvements were observed at 3 and 6 months compared to 1 week post-intervention for symptom bother (3 months, -22.75, p = 0.006; 6 months, -25.76; p = 0.001) and condition-specific and health-related QoL subscale scores for concern (3 months, +23.76, p = 0.006; 6 months, +22.15, p = 0.011) and social interaction (3 months, +21.11, p = 0.017; 6 months, +20.51; p = 0.021). For all age subgroups, improvements in general QoL measures for mental health were seen at 3 and 6 months compared to baseline (3 months, +7.57, p = 0.02; 6 months, +6.70; p = 0.048). CONCLUSIONS: Statistically significant improvements in symptom bother, condition-specific, and general QoL measures were observed following an OAB education program pilot study in a predominantly minority female population. Further studies are needed to support efficacy and optimize program design.