In Operando Imaging Electrostatic-Driven Disassembly and Reassembly of Collagen Nanostructures.

Collagen is the most abundant protein in tissue scaffolds in live organisms. Collagen can self-assemble in vitro, which has led to a number of biotechnological and biomedical applications. To understand the dominant factors that participate in the formation of collagen nanostructures, here we study in real time and with nanoscale resolution the disassembly and reassembly of collagens.

Synthetic polypeptides using a biologic as a reference medicinal product - the European landscape of regulatory approvals.

Recent advances in synthetic drug manufacturing have introduced a new dynamic to the European regulatory system, with chemically synthesized polypeptide products using biological originator products as their reference medicine. Whereas biosimilars are subject to a dedicated regulatory framework in the EU, synthetically produced follow-on products are not eligible for assessment through this pathway, requiring approval via the traditional generic pathway under Article 10 (1), or via the hybrid pathway under Article 10 (3). This review presents an overview of recent developments in the field of synthetic peptides referencing biological originators in the EU.

Elucidating the role of water in collagen self-assembly by isotopically modulating collagen hydration.

Water is known to play an important role in collagen self-assembly, but it is still largely unclear how water-collagen interactions influence the assembly process and determine the fibril network properties. Here, we use the H[Formula: see text]O/D[Formula: see text]O isotope effect on the hydrogen-bond strength in water to investigate the role of hydration in collagen self-assembly. We dissolve collagen in H[Formula: see text]O and D[Formula: see text]O and compare the growth kinetics and the structure of the collagen assemblies formed in these water isotopomers.

Biological and substitute parents in Beaker period adult-child graves.

Joint inhumations of adults and children are an intriguing aspect of the shift from collective to single burial rites in third millennium BC Western Eurasia. Here, we revisit two exceptional Beaker period adult-child graves using ancient DNA: Altwies in Luxembourg and Dunstable Downs in Britain. Ancestry modelling and patterns of shared IBD segments between the individuals examined, and contemporary genomes from Central and Northwest Europe, highlight the continental connections of British Beakers.

The Global Landscape of Manufacturers of Follow-on Biologics: An Overview of Five Major Biosimilar Markets and 15 Countries.

Background: Current knowledge is limited about which manufacturers are active in the global field of biopharmaceutical product development and how many unique follow-on biologics are approved in global markets.

Objective: This study aimed to provide a cross-sectional overview of manufacturers of follow-on biologics approved in 15 large countries from different regions of the world, as well as in five major biosimilar markets with long established biosimilar frameworks.

Methods: We screened national drug databases to identify follow-on biologics and their manufacturers approved in 15 countries in Asia, Africa, Latin America and the rest of the world, as well as five major biosimilar markets: the European Union (including the UK), USA, Canada, Australia and Japan.

Four scenarios for the future of medicines and social policy in 2030.

The future of medicines is likely determined by an array of scientific, socioeconomic, policy, medical need, and geopolitical factors, with many uncertainties ahead. Here, we report from a scenario project, analyzing various trends, crucial and complex developments in the medicines' space. From a range of 'critical uncertainties' we derived two scenario drivers: global convergence, ranging from very high (trust and solidarity), to very low (fragmented ecosystems); and disease orientation, ranging from public health first to interceptive medicine.

Regulatory Flexibilities and Guidances for Addressing the Challenges of COVID-19 in the EU: What Can We Learn from Company Experiences?

The COVID-19 pandemic required urgency in the development and delivery of effective vaccines and therapeutics; meanwhile, ongoing clinical research, regulation and supply for other much-needed therapeutics and vaccines needed to be sustained. In Europe, the European Commission, the European Medicines Agency (EMA) and the national regulatory agencies (NRAs) responded by issuing guidance outlining regulatory flexibilities mainly directed at COVID-19 vaccines and, belatedly, therapeutics. Using a survey methodology, this study gathered the views of the R&D based pharmaceutical industry in May-June 2021 on the value of these flexibilities for continued use in the post-pandemic era as well as for future use in health emergency situations.

Sensitivity of Laségue Sign and Slump Test in Hernia and Disc Bulging Diagnoses Compared with Magnetic Resonance Imaging.

 To show the accuracy of the most used maneuvers in the clinical diagnosis of lumbosciatalgia, the slump test and the Laségue sign.  In order to perform the present study, 101 patients with magnetic resonance imaging (MRI) discopathy (gold standard) were selected and had their medical records reviewed to identify which had the positive maneuvers on the initial physical examination.  The sensitivity found for the slump test and the Laségue sign in the diagnosis of disc herniation was 55.

A pragmatic regulatory approach for complex generics through the U.S. FDA 505(j) or 505(b)(2) approval pathways.

The diverse nature of complex drug products poses challenges for the development of regulatory guidelines for generic versions. While complexity is not new in medicines, the technical capacity to measure and analyze data has increased. This requires a determination of which measurements and studies are relevant to demonstrate therapeutic equivalence.

Trigeminal Nerve Repair: Is the Trigeminocardiac Reflex a Concern?

Purpose: Our hypothesis is that direct manipulation of the third and second divisions of the trigeminal nerve during microneurosurgery does not affect the incidence of trigeminocardiac reflex (TCR). The purpose of this paper was to analyze the incidence of TCR events during microneurosurgery involving the second and third divisions of the trigeminal nerve.

Materials And Methods: This was a retrospective cohort study of 94 patients who underwent nerve repair of the second and third divisions of the trigeminal nerve, between July 2014 and February 2021 by a single surgeon (J.

Regulatory density as a means to refine current regulatory approaches for increasingly complex medicines.

The continuous scientific, societal, and technological advancements have shifted drug development toward increasingly complex and ever more targeted treatments. This creates new and unprecedented challenges for global regulatory systems. To address the increased risks and uncertainties of increasingly complex medicine, we advocate for a more tailored and flexible regulatory approach, which is explained here with the concept of 'regulatory density'.

Trigeminocardiac Reflex Induced by Maxillary Nerve Stimulation during Sphenopalatine Ganglion Implantation: A Case Series.

Background: The trigeminocardiac reflex (TCR) is a brainstem reflex following stimulation of the trigeminal nerve, resulting in bradycardia, asystole and hypotension. It has been described in maxillofacial and craniofacial surgeries. This case series highlights TCR events occurring during sphenopalatine ganglion (SPJ) neurostimulator implantation as part of the Pathway CH-2 clinical trial "Sphenopalatine ganglion Stimulation for Treatment of Chronic Cluster Headache".

Intravenous vs oral acetaminophen in sinus surgery: A randomized clinical trial.

Background: Multimodal perioperative analgesia including acetaminophen is recommended by current guidelines. The comparative efficacy of intravenous vs oral acetaminophen in sinus surgery is unknown. We aimed to determine whether intravenous or oral acetaminophen results in superior postoperative analgesia following sinus surgery.

The UK BIO-TRAC Study: A Cross-Sectional Study of Product and Batch Traceability for Biologics in Clinical Practice and Electronic Adverse Drug Reaction Reporting in the UK.

Introduction: Due to the complexity of biologics and the inherent challenges for manufacturing, it is important to know the specific brand name and batch number of suspected biologics in adverse drug reaction (ADR) reports.

Objective: The aim of this study was to assess the extent to which biologics are traceable by brand name and batch number in UK hospital practice and in ADRs reported by patients and healthcare professionals.

Methods: We performed an online hospital pharmacist survey to capture information on how specific product details are recorded during the processes of prescribing, dispensing and administration of biologics in routine UK hospital practice.

Cervical Spine Movement in a Cadaveric Model of Severe Spinal Instability: A Study Comparing Tracheal Intubation with 4 Different Laryngoscopes.

Background: This study compared the Macintosh blade direct laryngoscope, Glidescope, C-Mac d-Blade, and McGrath MAC X-blade video laryngoscopes in 2 cadaveric models with severe cervical spinal instability. We hypothesized that the Glidescope video laryngoscope would allow for intubation with the least amount of cervical spine movement. Our secondary endpoints were glottic visualization and intubation success.

The future of drug development: the paradigm shift towards systems therapeutics.

Progress in cell biology, genetics, molecular, and systems pharmacology is the driving force behind a current paradigm shift in drug research. This paradigm shift shapes new avenues for advanced treatments that are commonly referred to as 'systems therapeutics'. Systems therapeutics differ in many ways from current drugs because they target biological networks rather than single transduction pathways, and affect disease processes rather than physiological processes.

Challenges and Opportunities for the Traceability of (Biological) Medicinal Products.

This article provides an overview of the current situation regarding the traceability of medicinal products, with a focus on drug safety and biologics. Limited traceability of biologics, in particular with regard to the batch number, is associated with incomplete recording of exposure information in clinical practice. The current pharmaceutical barcode standards in the EU do not support the automatic recording of dynamic product information, such as batch numbers and expiry dates, by means of electronic barcode scanning in clinical practice.

When More Is Less: An Exploratory Study of the Precautionary Reporting Bias and Its Impact on Safety Signal Detection.

Concerns have been expressed that large numbers of nonvalue-added reports have been accumulating in adverse drug reaction (ADR) databases, for example, via patient support programs. We performed an assessment of the impact of such reports, which we refer to as "precautionary reports," on safety signal detection in the Netherlands. The case narratives of ADR reports of three case products were screened with text-mining algorithms to identify those reports that lack a causal relationship with the suspected medicinal product.

Traceability of Biologics in The Netherlands: An Analysis of Information-Recording Systems in Clinical Practice and Spontaneous ADR Reports.

Introduction And Objective: Pharmacovigilance requirements for biologics mandate that EU Member States shall ensure that any biologic that is the subject of a suspected adverse drug reaction (ADR) is identifiable by brand name and batch number. Recent studies showed that brand name identification is well established, whereas batch numbers are (still) poorly reported. We evaluated information-recording systems and practices in the Dutch hospital setting to identify determinants for brand name and batch number recording as well as success factors and bottlenecks for traceability.

Classification of Recombinant Biologics in the EU: Divergence Between National Pharmacovigilance Centers.

Background And Objective: Biological medicinal products (biologics) are subject to specific pharmacovigilance requirements to ensure that biologics are identifiable by brand name and batch number in adverse drug reaction (ADR) reports. Since Member States collect ADR data at the national level before the data is aggregated at the European Union (EU) level, it is important that an unambiguous understanding of which medicinal products belong to the biological product category exists. This study aimed to identify the level of consistency between Member States regarding the classification of biologics by national authorities responsible for ADR reporting.

Save 100 Babies©: engaging communities for just and equitable birth outcomes through Photovoice and Appreciative Inquiry.

This paper presents a community engagement model designed to advance social justice and equity for African American birth outcomes through the combined techniques of Photovoice and Appreciative Inquiry. In response to the persistent racial disparities in birth outcomes, Save 100 Babies© was constructed as a 2-day summit where the emphasis was placed on individual and community assets rather than deficits. The engagement was designed to create a level of readiness among individuals working within and outside the field of Maternal and Child Health to envision strategies to attain equitable birth outcomes.

HIV-1 Gag co-opts a cellular complex containing DDX6, a helicase that facilitates capsid assembly.

To produce progeny virus, human immunodeficiency virus type I (HIV-1) Gag assembles into capsids that package the viral genome and bud from the infected cell. During assembly of immature capsids, Gag traffics through a pathway of assembly intermediates (AIs) that contain the cellular adenosine triphosphatase ABCE1 (ATP-binding cassette protein E1). In this paper, we showed by coimmunoprecipitation and immunoelectron microscopy (IEM) that these Gag-containing AIs also contain endogenous processing body (PB)-related proteins, including AGO2 and the ribonucleic acid (RNA) helicase DDX6.

Video laryngoscopy-assisted secondary tracheoesophageal puncture placement for the patient with severely limited neck extension.

Secondary tracheoesophageal puncture (TEP) placement in patients with severe limitations in neck extension is challenging. Visualization of the hypopharynx with traditional rigid endoscopy may not be possible. We report using the C-MAC (Karl Storz, Tuttlingen, Germany) video laryngoscope to successfully place a secondary TEP in patient with severe radiation fibrosis at a tertiary referral center.

HIV Gag-leucine zipper chimeras form ABCE1-containing intermediates and RNase-resistant immature capsids similar to those formed by wild-type HIV-1 Gag.

During HIV-1 assembly, Gag polypeptides multimerize to form an immature capsid and also package HIV-1 genomic RNA. Assembling Gag forms immature capsids by progressing through a stepwise pathway of assembly intermediates containing the cellular ATPase ABCE1, which facilitates capsid formation. The NC domain of Gag is required for ABCE1 binding, acting either directly or indirectly.

Innate immune signaling induces high levels of TC-specific deaminase activity in primary monocyte-derived cells through expression of APOBEC3A isoforms.

In HIV-1-infected individuals, G-to-A hypermutation is found in HIV-1 DNA isolated from peripheral blood mononuclear cells (PBMCs). These mutations are thought to result from editing by one or more host enzymes in the APOBEC3 (A3) family of cytidine deaminases, which act on CC (APOBEC3G) and TC (other A3 proteins) dinucleotide motifs in DNA (edited cytidine underlined). Although many A3 proteins display high levels of deaminase activity in model systems, only low levels of A3 deaminase activity have been found in primary cells examined to date.