The role of continuous glucose monitoring in pregnancy.

The risks associated with diabetes in pregnancy include congenital anomalies, stillbirth and miscarriage, and correlate with glycaemia. The optimisation of diabetes during pregnancy is therefore both challenging and essential. Technology has revolutionised how clinicians and patients manage diabetes. This review article focuses on the role of continuous glucose monitoring (CGM) in pregnancy, assessing the evidence available and providing an update on current guidance.

Multiple electrolyte disturbances as the presenting feature of multiple endocrine neoplasia type 1 (MEN-1).

Summary: A 49-year-old teacher presented to his general physician with lethargy and lower limb weakness. He had noticed polydipsia, polyuria, and had experienced weight loss, albeit with an increase in central adiposity. He had no concomitant illnesses and took no regular medications. He had hypercalcaemia (adjusted calcium: 3.34 mmol/L) with hyperparathyroidism (parathyroid hormone: 356 ng/L) and hypokalaemia (K: 2.7 mmol/L) and was admitted for i.v. potassium replacement. A contrast-enhanced CT chest/abdomen/pelvis scan revealed a well-encapsulated anterior mediastinal mass measuring 17 × 11 cm with central necrosis, compressing rather than invading adjacent structures. A neck ultrasound revealed a 2 cm right inferior parathyroid lesion. On review of CT imaging, the adrenals appeared normal, but a pancreatic lesion was noted adjacent to the uncinate process. His serum cortisol was 2612 nmol/L, and adrenocorticotrophic hormone was elevated at 67 ng/L, followed by inadequate cortisol suppression to 575 nmol/L from an overnight dexamethasone suppression test. His pituitary MRI was normal, with unremarkable remaining anterior pituitary biochemistry. His admission was further complicated by increased urine output to 10 L/24 h and despite three precipitating factors for the development of diabetes insipidus including hypercalcaemia, hypokalaemia, and hypercortisolaemia, due to academic interest, a water deprivation test was conducted. An 18flurodeoxyglucose-PET (FDG-PET) scan demonstrated high avidity of the mediastinal mass with additionally active bilateral superior mediastinal nodes. The pancreatic lesion was not FDG avid. On 68Ga DOTATE-PET scan, the mediastinal mass was moderately avid, and the 32 mm pancreatic uncinate process mass showed significant uptake. Genetic testing confirmed multiple endocrine neoplasia type 1. Learning points: In young patients presenting with primary hyperparathyroidism, clinicians should be alerted to the possibility of other underlying endocrinopathies. In patients with multiple endocrine neoplasia type 1 (MEN-1) and ectopic adrenocorticotrophic hormone syndrome (EAS), clinicians should be alerted to the possibility of this originating from a neoplasm above or below the diaphragm. Although relatively rare compared with sporadic cases, thymic carcinoids secondary to MEN-1 may also be associated with EAS. Electrolyte derangement, in particular hypokalaemia and hypercalcaemia, can precipitate mild nephrogenic diabetes insipidus.

Rhabdomyolysis and severe biphasic disturbance of calcium homeostasis secondary to COVID-19 infection.

We report a case of severe hypercalcaemia secondary to rhabdomyolysis in a woman with COVID-19 (SARS CoV-2) infection. The patient presented with myalgia and anuria with an acute kidney injury requiring haemodialysis. Creatine kinase peaked at 760 000 IU/L. A biphasic calcaemic response was observed with initial severe hypocalcaemia followed by severe, symptomatic hypercalcaemia, persistent despite haemodialysis. Control of the calcium levels was achieved by continuous haemofiltration.

Diabetic retinopathy is independently associated with increased risk of intubation: A single centre cohort study of patients with diabetes hospitalised with COVID-19.

In our study of 187 patients with diabetes hospitalised with COVID-19 we observed a more than 5 fold increased risk of intubation in patients with diabetic retinopathy. Further studies are required to understand the mechanisms that explain the associations between retinopathy and other indices of microangiopathy with severe COVID-19.

Diabetes technologies - what the general physician needs to know.

Technology has revolutionised our society. From the creation of the internet to smartphones and applications (apps), technology has changed how we communicate with each other, undertake regular tasks in our lives and access information at our fingertips. Technology has also transformed how we deliver healthcare with electronic patient records, more sensitive imaging modalities and newer treatments that are less invasive yet more cost-effective. The management of diabetes mellitus is an area that has kept pace with this revolution. With the emergence of a range of widely used technological options that can improve quality of life and metabolic outcomes, general physicians need to be aware of their application in diabetes, as well as how to manage acute diabetes presentations in people using these devices. This article aims to improve the knowledge that general physicians may have with diabetes technologies and guide them on the acute management in people using these technologies.

Thin silk fibroin films as a dried format for temperature stabilization of inactivated polio vaccine.

Current inactivated polio vaccine (IPV) products are sensitive to both freezing and elevated temperatures and therefore must be shipped and stored between 2 °C and 8 °C, a requirement that imposes financial and logistical challenges for global distribution. As such, there is a critical need for a robust, thermally stable IPV to support global polio eradication and post-eradication immunization needs. Here, we present the development of air-dried thin films for temperature stabilization of IPV using the biomaterial silk fibroin. Thin-film product compositions were optimized for physical properties as well as poliovirus D-antigen recovery and were tested under accelerated and real-time stability storage conditions. Silk fibroin IPV films maintained 70% D-antigen potency after storage for nearly three years at room temperature, and greater than 50% potency for IPV-2 and IPV-3 serotypes at 45 °C for one year. The immunogenicity of silk fibroin IPV films after 2-week storage at 45 °C was assessed in Wistar rats and the stressed films generated equivalent neutralizing antibody responses to commercial vaccine for IPV-1 and IPV-2. However, the absence of IPV-3 responses warrants further investigation into the specificity of ELISA for intact IPV-3 D-antigen. By demonstrating immunogenicity post-storage, we offer the air-dried silk film format as a means to increase IPV vaccine access through innovative delivery systems such as microneedles.

Stabilization of RNA Encapsulated in Silk.

The use of mRNA and miRNA as diagnostic parameters and therapeutic agents has drawn wide interest both clinically and in research. However, RNA is a labile molecule, which requires strict storage conditions, often including cold temperatures or dry environments, in order to preserve RNA integrity. Achieving this requires huge costs for storage and added difficulty in transport. To address these issues, we introduce a system to encapsulate and store it long-term in dried silk fibroin matrices. At temperatures up to 45 °C, mRNA samples stored in lyophilized silk matrices showed good stability over 1 week, as measured by real-time PCR to assess transcript recovery. While the presence of the silk interfered with the generation of cDNA required for quantitation at roughly 1% w/v (400:1 silk:RNA mass), this phenomenon was resolved by the use of commercial RNA purification kits for silk concentrations up to 4% w/v. A higher concentration of silk correlated with increased thermal protection. As an alternative to lyophilization, RNA was simply air-dried in the presence of aqueous fibroin to create storage matrices. While air-dried matrices composed of low silk content were not protective, higher concentrations were protective and progressively lost additional water over time of storage because of the overall hydrophobic nature of the system. Taken together, these findings provide a new and potentially simpler method for preserving RNA samples for long-term storage and transportation, acting primarily on a water exclusion mechanism.

Enhanced Stabilization in Dried Silk Fibroin Matrices.

Preliminary studies have shown that silk fibroin can protect biomacromolecules from thermal degradation, but a deeper understanding of underlying mechanisms needed to fully leverage the stabilizing potential of this matrix has not been realized. In this study, we investigate stabilization of plasma C-reactive protein (CRP), a diagnostic indicator of infection or inflammation, to gain insight into stabilizing mechanisms of silk. We observed that the addition of antiplasticizing excipients that suppress ß-relaxation amplitudes in silk matrices resulted in enhanced stability of plasma CRP. These observations are consistent with those made in sugar-glass-based protein-stabilizing matrices and suggest fundamental insight into mechanisms as well as practical strategies to employ with silk protein matrices for enhanced stabilization utility.

Silk-based blood stabilization for diagnostics.

Advanced personalized medical diagnostics depend on the availability of high-quality biological samples. These are typically biofluids, such as blood, saliva, or urine; and their collection and storage is critical to obtain reliable results. Without proper temperature regulation, protein biomarkers in particular can degrade rapidly in blood samples, an effect that ultimately compromises the quality and reliability of laboratory tests. Here, we present the use of silk fibroin as a solid matrix to encapsulate blood analytes, protecting them from thermally induced damage that could be encountered during nonrefrigerated transportation or freeze-thaw cycles. Blood samples are recovered by simple dissolution of the silk matrix in water. This process is demonstrated to be compatible with a number of immunoassays and provides enhanced sample preservation in comparison with traditional air-drying paper approaches. Additional processing can remediate interactions with conformational structures of the silk protein to further enhance blood stabilization and recovery. This approach can provide expanded utility for remote collection of blood and other biospecimens empowering new modalities of temperature-independent remote diagnostics.

Silk-based stabilization of biomacromolecules.

Silk fibroin is a high molecular weight amphiphilic protein that self-assembles into robust biomaterials with remarkable properties including stabilization of biologicals and tunable release kinetics correlated to processing conditions. Cells, antibiotics,monoclonal antibodies and peptides, among other biologics, have been encapsulated in silk using various processing approaches and material formats. The mechanistic basis for the entrapment and stabilization features, along with insights into the modulation of release of the entrained compounds from silks will be reviewed with a focus on stabilization of bioactive molecules.

Comparison of delayed transvenous reimplantation and immediate surgical epicardial approach in pacing-dependent patients undergoing extraction of infected permanent pacemakers.

BACKGROUND: Pacemaker infection in pacing-dependent patients is challenging. After extraction, temporary pacing usually is utilized before delayed reimplantation (after an appropriate course of antibiotics), resulting in prolonged hospital stays. A single combined procedure of epicardial (EPI) pacemaker implantation and system extraction may prevent this. OBJECTIVE: The purpose of this study was to evaluate the feasibility and safety of these 2 approaches by comparing clinical outcome for both strategies over 1 year. METHODS: In center 1, 80 consecutive pacemaker-dependent patients underwent extraction with an externalized pacemaker and delayed implantation on the contralateral side (ENDO group). In center 2, 80 consecutive patients had 2 epicardial ventricular leads surgically implanted with extraction of the infected pacemaker during the same procedure (EPI group). Patients were followed-up for 12 months. RESULTS: One hundred sixty pacing-dependent patients were successfully implanted and extracted (ENDO group 71 ± 13 years vs EPI group 73 ± 14, P = NS). In the EPI group, 2 patients developed significant pericardial bleeding. In-hospital mortality was 0% in the ENDO group and 2.5% in the EPI group. Total hospitalization time was 15 ± 7 days in the ENDO group vs 9 ± 6 days in the EPI group (P <.001). At 1 year, no infection recurrences occurred in either group, and mortality was equal (5% in each group). Median 1-year pacing thresholds were lower in the ENDO vs the EPI group (0.8 ± 0.6 V vs 1.1 ± 0.6 V, P = .02). CONCLUSION: The ENDO and EPI strategies had an excellent success rate and low risk of complications. A single procedure using surgical epicardial lead implantation was associated with a shorter duration of hospital stay.

Cardiac Resynchronization Therapy Delivered Via a Multipolar Left Ventricular Lead is Associated with Reduced Mortality and Elimination of Phrenic Nerve Stimulation: Long-Term Follow-Up from a Multicenter Registry.

INTRODUCTION: Cardiac resynchronization therapy (CRT) using quadripolar left ventricular (LV) leads provides more pacing vectors compared to bipolar leads. This may avoid phrenic nerve stimulation (PNS) and allow optimal lead placement to maximize biventricular pacing. However, a long-term improvement in patient outcome has yet to be demonstrated. METHODS: A total of 721 consecutive patients with conventional CRTD criteria implanted with quadripolar (n = 357) or bipolar (n = 364) LV leads were enrolled into a registry at 3 UK centers. Lead performance and mortality was analyzed over a 5-year period. RESULTS: Patients receiving a quadripolar lead were of similar age and sex to those receiving a bipolar lead, although a lower proportion had ischemic heart disease (62.6% vs. 54.1%, P = 0.02). Both groups had similar rates of procedural success, although lead threshold, impedance, and procedural radiation dose were significantly lower in those receiving a quadripolar lead. PNS was more common in those with quadripolar leads (16.0% vs. 11.6%, P = 0.08), but was eliminated by switching pacing vector in all cases compared with 60% in the bipolar group (P < 0.001). Furthermore, LV lead displacement (1.7% vs. 4.6%, P = 0.03) and repositioning (2.0% vs. 5.2%, P = 0.03) occurred significantly less often in those with a quadripolar lead. All-cause mortality was also significantly lower in the quadripolar compared to bipolar lead group in univariate and multivariate analysis (13.2% vs. 22.5%, P < 0.001). CONCLUSIONS: In a large, multicenter experience, the use of quadripolar LV leads for CRT was associated with elimination of PNS and lower overall mortality. This has important implications for LV pacing lead choice.

Localized decrease of beta-catenin contributes to the differentiation of human embryonic stem cells.

Human embryonic stem cells (hESC) are pluripotent, and can be directed to differentiate into different cell types for therapeutic applications. To expand hESCs, it is desirable to maintain hESC growth without differentiation. As hESC colonies grow, differentiated cells are often found at the periphery of the colonies, but the underlying mechanism is not well understood. Here, we utilized micropatterning techniques to pattern circular islands or strips of matrix proteins, and examined the spatial pattern of hESC renewal and differentiation. We found that micropatterned matrix restricted hESC differentiation at colony periphery but allowed hESC growth into multiple layers in the central region, which decreased hESC proliferation and induced hESC differentiation. In undifferentiated hESCs, beta-catenin primarily localized at cell-cell junctions but not in the nucleus. The amount of beta-catenin in differentiating hESCs at the periphery of colonies or in multiple layers decreased significantly at cell-cell junctions. Consistently, knocking down beta-catenin decreased Oct-4 expression in hESCs. These results indicate that localized decrease of beta-catenin contributes to the spatial pattern of differentiation in hESC colonies.