A Glucose-Responsive Glucagon-Micelle for the Prevention of Hypoglycemia.

While glucose-responsive insulin delivery systems are in widespread clinical use to treat insulin insufficiency, the on-demand supplementation of glucagon for acute hypoglycemia treatment remains understudied. A self-regulated glucagon release material is highly desired to mitigate the potential risks of severe insulin-induced hypoglycemia. Here, we describe a glucose-responsive polymeric nanosystem with glucagon covalently grafted to the end-group.

Site-Selective Zwitterionic Poly(caprolactone-carboxybetaine)-Growth Hormone Receptor Antagonist Conjugate: Synthesis and Biological Evaluation.

Zwitterionic polymers have been found to be biocompatible alternatives to poly(ethylene glycol) (PEG) for conjugation to proteins. This work reports the site-selective conjugation of poly(caprolactone-carboxybetaine) (pCLZ) to human growth hormone receptor antagonist (GHA) B2036-alkyne and investigation of safety, activity, and pharmacokinetics. Azide-end-functionalized pCLZs were synthesized and conjugated to GHA B2036-alkyne via copper-catalyzed click reaction.

Discordance between preclinical and clinical testing of NaV1.7-selective inhibitors for pain.

The voltage-gated sodium channel NaV1.7 plays an important role in pain processing according to genetic data. Those data made NaV1.

Estrogen deficiency in the menopause and the role of hormone therapy: integrating the findings of basic science research with clinical trials.

Menopause, defined by the cessation of menstrual cycles after 12 months of amenorrhea not due to other causes, is associated with significant hormonal changes, primarily a decrease in estrogen, androgen, and progesterone levels. This review delves into the effects of estrogen deficiency during the perimenopausal transition and postmenopause, integrating the findings of basic science with clinical trials. Here, we first outline the variation in endogenous estrogens before and after menopause, exploring both genomic and nongenomic actions of estrogen and its estrogen receptors throughout the body.

Uniform trehalose nanogels for glucagon stabilization.

Glucagon is a peptide hormone that acts receptor-mediated signaling predominantly in the liver to raise glucose levels by hepatic glycogen breakdown or conversion of noncarbohydrate, 3 carbon precursors to glucose by gluconeogenesis. Glucagon is administered to reverse severe hypoglycemia, a clinical complication associated with type 1 diabetes. However, due to low stability and solubility at neutral pH, there are limitations in the current formulations of glucagon.

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs.

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel Na1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting Na1.

Neuroendocrine, neurotransmitter, and gut microbiota imbalance contributing to potential psychiatric disorder prevalence in polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women, affecting up to 15% of reproductive-aged women. Polycystic ovarian syndrome is a heterogeneous disorder, both in the sense that many different factors may play a role in its manifestation and that multiple systems throughout the body can be affected. Polycystic ovarian syndrome has been linked to an increased prevalence of various psychiatric disorders, including depression and anxiety.

A prospective phase II clinical trial/IDEAL Stage 2a series of single-port robotic colorectal surgery for abdominal and transanal cases.

Aim: Slow laparoscopy adoption accelerated the uptake of robotic surgery. However, the current robotic platforms have limitations in transanal applications and multiple port sites. The da Vinci single-port (SP) robot is currently used on trial for colorectal surgery, and broad assessment of outcomes is needed.

Homeostatic regulation of neuronal function: importance of degeneracy and pleiotropy.

Neurons maintain their average firing rate and other properties within narrow bounds despite changing conditions. This homeostatic regulation is achieved using negative feedback to adjust ion channel expression levels. To understand how homeostatic regulation of excitability normally works and how it goes awry, one must consider the various ion channels involved as well as the other regulated properties impacted by adjusting those channels when regulating excitability.

Process development of a SARS-CoV-2 nanoparticle vaccine.

One of the outcomes from the global COVID-19 pandemic caused by SARS-CoV-2 has been an acceleration of development timelines to provide treatments in a timely manner. For example, it has recently been demonstrated that the development of monoclonal antibody therapeutics from vector construction to IND submission can be achieved in five to six months rather than the traditional ten-to-twelve-month timeline using CHO cells [1], [2]. This timeline is predicated on leveraging existing, robust platforms for upstream and downstream processes, analytical methods, and formulation.

Real world population pharmacokinetic study in children and young adults with inflammatory bowel disease discovers novel blood and stool microbial predictors of vedolizumab clearance.

Background: Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult-specific population pharmacokinetic models have identified limited covariates of drug clearance.

Aims: To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric-specific inter-patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients.

Anti-Carbamylated Protein (Anti-CarP) Antibodies in Patients Evaluated for Suspected Rheumatoid Arthritis.

(1) Background: Anti-carbamylated protein (CarP) antibodies have been studied as novel markers to aid in the diagnosis and prognosis of rheumatoid arthritis. (2) Methods: A total of 265 samples were included in the evaluation, for which 98 had results for anti-cyclic citrullinated peptide (CCP), 86 for rheumatoid factor (RF), and 212 for 14-3-3 eta protein. Anti-CarP antibodies were measured using a fetal calf serum-based single-step assay (research use only, Inova Diagnostics, San Diego, CA).

Continuity of community-based healthcare provision during COVID-19: a multicountry interrupted time series analysis.

Background: Pandemics often precipitate declines in essential health service utilisation, which can ultimately kill more people than the disease outbreak itself. There is some evidence, however, that the presence of adequately supported community health workers (CHWs), that is, financially remunerated, trained, supplied and supervised in line with WHO guidelines, may blunt the impact of health system shocks. Yet, adequate support for CHWs is often missing or uneven across countries.

TRPC4 and GIRK channels underlie neuronal coding of firing patterns that reflect G-G coincidence signals of variable strengths.

Transient receptor potential canonical 4 (TRPC4) is a receptor-operated cation channel codependent on both the Gq/11–phospholipase C signaling pathway and Gi/o proteins for activation. This makes TRPC4 an excellent coincidence sensor of neurotransmission through Gq/11- and Gi/o-coupled receptors. In whole-cell slice recordings of lateral septal neurons, TRPC4 mediates a strong depolarizing plateau that shuts down action potential firing, which may or may not be followed by a hyperpolarization that extends the firing pause to varying durations depending on the strength of Gi/o stimulation.

Cross-Attention and Deep Supervision UNet for Lesion Segmentation of Chronic Stroke.

Stroke is an acute cerebrovascular disease with high incidence, high mortality, and high disability rate. Determining the location and volume of the disease in MR images promotes accurate stroke diagnosis and surgical planning. Therefore, the automatic recognition and segmentation of stroke lesions has important clinical significance for large-scale stroke imaging analysis.

Microbiome-by-ethanol interactions impact Drosophila melanogaster fitness, physiology, and behavior.

The gut microbiota can affect how animals respond to ingested toxins, such as ethanol, which is prevalent in the diets of diverse animals and often leads to negative health outcomes in humans. Ethanol is a complex dietary factor because it acts as a toxin, behavioral manipulator, and nutritional source, with both direct effects on the host as well as indirect ones through the microbiome. Here, we developed a model for chronic, non-intoxicating ethanol ingestion in the adult fruit fly, , and paired this with the tractability of the fly gut microbiota, which can be experimentally removed.

Minimal requirements for a neuron to coregulate many properties and the implications for ion channel correlations and robustness.

Neurons regulate their excitability by adjusting their ion channel levels. Degeneracy - achieving equivalent outcomes (excitability) using different solutions (channel combinations) - facilitates this regulation by enabling a disruptive change in one channel to be offset by compensatory changes in other channels. But neurons must coregulate many properties.

Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn's disease.

Background: Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance.

Aims: We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn's disease cohort with 1-year follow-up.

Deep Convolutional Neural Network With a Multi-Scale Attention Feature Fusion Module for Segmentation of Multimodal Brain Tumor.

As a non-invasive, low-cost medical imaging technology, magnetic resonance imaging (MRI) has become an important tool for brain tumor diagnosis. Many scholars have carried out some related researches on MRI brain tumor segmentation based on deep convolutional neural networks, and have achieved good performance. However, due to the large spatial and structural variability of brain tumors and low image contrast, the segmentation of MRI brain tumors is challenging.

Effect of mobile application user interface improvements on minimum expected home visit coverage by community health workers in Mali: a randomised controlled trial.

Background: Proactive community case management (ProCCM) has shown promise to advance goals of universal health coverage (UHC). ProCCM community health workers (CHWs) face operational challenges when pursuing their goal of visiting every household in their service area at least twice monthly to proactively find sick patients. We developed a software extension (UHC Mode) to an existing CHW mobile application featuring user interface design improvements to support CHWs in planning daily home visits.

Antibody-Free Quantification of Serum Chromogranin A by Targeted Mass Spectrometry.

Background: Chromogranin A (CgA) is a 48 kDa protein that serves as a diagnostically sensitive, but nonspecific, serum biomarker for neuroendocrine tumors. Immunoassays for CgA are not standardized and have a narrow dynamic range, which requires dilution of concentrated specimens. We developed and validated an antibody-free, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method for CgA without these limitations.

Detection and risk assessments of multi-pesticides in 1771 cultivated herbal medicines by LC/MS-MS and GC/MS-MS.

Focus on the safety of herbal medicines has mainly been directed towards the presence of intrinsic toxicity, as found in the cases of renal and hepatic dysfunction caused by aristolochic acids. However, contamination from extrinsic hazards may impart an even greater reduction in their safety and efficacy. This study reveals that pesticides were present in the majority (88%) of a comprehensive cross-section (n = 1771) of herbal medicine samples.