Retrospective, Observational Analysis on the Impact of SARS-CoV-2 Variant Omicron in Hospitalized Immunocompromised Patients in a German Hospital Network-The VISAGE Study.

AIMS: Endemic SARS-CoV-2 infections still burden the healthcare system and represent a considerable threat to vulnerable patient cohorts, in particular immunocompromised (IC) patients. This study aimed to analyze the in-hospital outcome of IC patients with severe SARS-CoV-2 infection in Germany. METHODS: This retrospective, observational study, analyzed administrative data from inpatient cases (n = 146,324) in 84 German Helios hospitals between 1 January 2022 and 31 December 2022 with regard to in-hospital outcome and health care burden in IC patients during the first 12 months of Omicron dominance. As the primary objective, in-hospital outcomes of patients with COVID-19-related severe acute respiratory infection (SARI) were analyzed by comparing patients with (n = 2037) and without IC diagnoses (n = 14,772). Secondary analyses were conducted on IC patients with (n = 2037) and without COVID-19-related SARI (n = 129,515). A severe in-hospital outcome as a composite endpoint was defined per the WHO definition if one of the following criteria were met: intensive care unit (ICU) treatment, mechanical ventilation (MV), or in-hospital death. RESULTS: In total, 12% of COVID-related SARI cases were IC patients, accounting for 15% of ICU admissions, 15% of MV use, and 16% of deaths, resulting in a higher prevalence of severe in-hospital courses in IC patients developing COVID-19-related SARI compared to non-IC patients (Odds Ratio, OR = 1.4, p < 0.001), based on higher in-hospital mortality (OR = 1.4, p < 0.001), increased need for ICU treatment (OR = 1.3, p < 0.001) and mechanical ventilation (OR = 1.2, p < 0.001). Among IC patients, COVID-19-related SARI profoundly increased the risk for severe courses (OR = 4.0, p < 0.001). CONCLUSIONS: Our findings highlight the vulnerability of IC patients to severe COVID-19. The persistently high prevalence of severe outcomes in these patients in the Omicron era emphasizes the necessity for continuous in-hospital risk assessment and monitoring of IC patients.

Participatory Action Research Among People With Serious Mental Illness: A Scoping Review.

Participatory action research (PAR) is a research approach that creates spaces for marginalized individuals and communities to be co-researchers to guide relevant social change. While working toward social transformation, all members of the PAR team often experience personal transformation. Engaging people with serious mental illness (PSMI) in PAR helps them to develop skills and build relationships with stakeholders in their communities. It supports positive changes that persist after the completion of the formal research project. With the increasing recognition of PAR's value in PSMI, it is helpful to consider the challenges and advantages of this approach to research with this population. This review aimed at determining how PAR has been conducted with PSMI and at summarizing strategies used to empower PSMI as co-researchers by engaging them in research. This scoping review followed five steps Arkesy and O'Malley (2005) outlined. We charted, collated, and summarized relevant information from 87 studies that met the inclusion criteria. We identified five strategies to empower PSMI through PAR. These are to build capacity, balance power distribution, create collaborative environments, promote peer support, and enhance their engagement as co-researchers. In conclusion, PAR is an efficient research approach to engage PSMI. Further, PSMI who engage in PAR may benefit from strategies for empowerment that meet their unique needs as co-researchers.

Understanding Intracellular Biology to Improve mRNA Delivery by Lipid Nanoparticles.

Poor understanding of intracellular delivery and targeting hinders development of nucleic acid-based therapeutics transported by nanoparticles. Utilizing a siRNA-targeting and small molecule profiling approach with advanced imaging and machine learning biological insights is generated into the mechanism of lipid nanoparticle (MC3-LNP) delivery of mRNA. This workflow is termed Advanced Cellular and Endocytic profiling for Intracellular Delivery (ACE-ID). A cell-based imaging assay and perturbation of 178 targets relevant to intracellular trafficking is used to identify corresponding effects on functional mRNA delivery. Targets improving delivery are analyzed by extracting data-rich phenotypic fingerprints from images using advanced image analysis algorithms. Machine learning is used to determine key features correlating with enhanced delivery, identifying fluid-phase endocytosis as a productive cellular entry route. With this new knowledge, MC3-LNP is re-engineered to target macropinocytosis, and this significantly improves mRNA delivery in vitro and in vivo. The ACE-ID approach can be broadly applicable for optimizing nanomedicine-based intracellular delivery systems and has the potential to accelerate the development of delivery systems for nucleic acid-based therapeutics.

The cytoplasmic tail of the mechanosensitive channel Pkd2 regulates its internalization and clustering in eisosomes.

Polycystins are a family of conserved ion channels, mutations of which lead to one of the most common human genetic disorders, namely, autosomal dominant polycystic kidney disease. Schizosacchromyces pombe possesses an essential polycystin homologue, Pkd2, which directs Ca2+ influx on the cell surface in response to membrane tension, but its structure remains unsolved. Here, we analyzed the structure-function relationship of Pkd2 based on its AlphaFold-predicted structure. Pkd2 consists of three domains, the extracellular lipid-binding domain (LBD), nine-helix transmembrane domain (TMD) and C-terminal cytoplasmic domain (CCD). Our genetic and microscopy data revealed that LBD and TMD are essential for targeting Pkd2 to the plasma membrane from the endoplasmic reticulum. In comparison, CCD ensures the polarized distribution of Pkd2 by promoting its internalization and preventing its clustering in the eisosome, a caveolae-like membrane compartment. The domains of Pkd2 and their functions are conserved in other fission yeast species. We conclude that both extracellular and cytoplasmic domains of Pkd2 are crucial for its intracellular trafficking and function. We propose that mechanosensitive channels can be desensitized through either internalization or clustering in low-tension membrane compartments.

The structural basis of the talin-KANK1 interaction that coordinates the actin and microtubule cytoskeletons at focal adhesions.

Adhesion between cells and the extracellular matrix is mediated by heterodimeric (αß) integrin receptors that are intracellularly linked to the contractile actomyosin machinery. One of the proteins that control this link is talin, which organizes cytosolic signalling proteins into discrete complexes on ß-integrin tails referred to as focal adhesions (FAs). The adapter protein KANK1 binds to talin in the region of FAs known as the adhesion belt. Here, we adapted a non-covalent crystallographic chaperone to resolve the talin-KANK1 complex. This structure revealed that the talin binding KN region of KANK1 contains a novel motif where a ß-hairpin stabilizes the α-helical region, explaining both its specific interaction with talin R7 and high affinity. Single point mutants in KANK1 identified from the structure abolished the interaction and enabled us to examine KANK1 enrichment in the adhesion belt. Strikingly, in cells expressing a constitutively active form of vinculin that keeps the FA structure intact even in the presence of myosin inhibitors, KANK1 localizes throughout the entire FA structure even when actomyosin tension is released. We propose a model whereby actomyosin forces on talin eliminate KANK1 from talin binding in the centre of FAs while retaining it at the adhesion periphery.

Designing a neuroclinical assessment of empathy deficits in psychopathy based on the Zipper Model of Empathy.

The heterogeneity of the literature on empathy highlights its multidimensional and dynamic nature and affects unclear descriptions of empathy in the context of psychopathology. The Zipper Model of Empathy integrates current theories of empathy and proposes that empathy maturity is dependent on whether contextual and personal factors push affective and cognitive processes together or apart. This concept paper therefore proposes a comprehensive battery of physiological and behavioral measures to empirically assess empathy processing according to this model with an application for psychopathic personality. We propose using the following measures to assess each component of this model: (1) facial electromyography; (2) the Emotion Recognition Task; (3) the Empathy Accuracy task and physiological measures (e.g., heart rate); (4) a selection of Theory of Mind tasks and an adapted Dot Perspective Task, and; (5) an adjusted Charity Task. Ultimately, we hope this paper serves as a starting point for discussion and debate on defining and assessing empathy processing, to encourage research to falsify and update this model to improve our understanding of empathy.

TLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity.

Talin-1 is the core mechanosensitive adapter protein linking integrins to the cytoskeleton. The TLN1 gene is comprised of 57 exons that encode the 2,541 amino acid TLN1 protein. TLN1 was previously considered to be expressed as a single isoform. However, through differential pre-mRNA splicing analysis, we discovered a cancer-enriched, non-annotated 51-nucleotide exon in TLN1 between exons 17 and 18, which we refer to as exon 17b. TLN1 is comprised of an N-terminal FERM domain, linked to 13 force-dependent switch domains, R1-R13. Inclusion of exon 17b introduces an in-frame insertion of 17 amino acids immediately after Gln665 in the region between R1 and R2 which lowers the force required to open the R1-R2 switches potentially altering downstream mechanotransduction. Biochemical analysis of this isoform revealed enhanced vinculin binding, and cells expressing this variant show altered adhesion dynamics and motility. Finally, we showed that the TGF-ß/SMAD3 signaling pathway regulates this isoform switch. Future studies will need to consider the balance of these two TLN1 isoforms.

A comprehensive model of nitrogen-free ordered carbon quantum dots.

We propose and demonstrate a novel range of models to accurately determine the optical properties of nitrogen-free carbon quantum dots (CQDs) with ordered graphene layered structures. We confirm the results of our models against the full range of experimental results for CQDs available from an extensive review of the literature. The models can be equally applied to CQDs with varied sizes and with different oxygen contents in the basal planes of the constituent graphenic sheets. We demonstrate that the experimentally observed blue fluorescent emission of nitrogen-free CQDs can be associated with either small oxidised areas on the periphery of the graphenic sheets, or with sub-nanometre non-functionalised islands of sp2-hybridised carbon with high symmetry confined in the centres of oxidised graphene sheets. Larger and/or less symmetric non-functionalised regions in the centre of functionalised graphene sheet are found to be sources of green and even red fluorescent emission from nitrogen-free CQDs. We also demonstrate an approach to simplify the modelling of the discussed sp2-islands by substitution with equivalent strained polycyclic aromatic hydrocarbons. Additionally, we show that the bandgaps (and photoluminescence) of CQDs are not dependent on either out-of-plane corrugation of the graphene sheet or the spacing between sp2-islands. Advantageously, our proposed models show that there is no need to involve light-emitting polycyclic aromatic molecules (nanographenes) with arbitrary structures grafted to the particle periphery to explain the plethora of optical phenomena observed for CQDs across the full range of experimental works.

The importance of perioperative optimisation to facilitate safe regional anaesthesia and their improved outcomes in fracture neck of femur patients.

BACKGROUND: Hip fractures are common presentations to orthopaedic departments, and their surgical management often results in blood transfusions. Compared with general anaesthesia, regional anaesthesia reduces the need for transfusions and mortality in the wider surgical population. AIMS: In hip fracture patients, our primary outcome measure was to examine any relationship between anaesthetic modality and transfusion rates. The secondary outcome measure was to assess the relationship between anaesthetic modality and one-year mortality. METHODS: A retrospective cohort study of 280 patients was carried out in 2017 and 2018. Data were collected from patient records, local transfusion laboratory and the national hip fracture database. RESULTS: A total of 59.6% had regional and 40.4% general anaesthesia. Regional anaesthesia patients were younger with fewer comorbidities (p < .05). About 19.8% regional and 34.5% general anaesthesia patients received transfusions (odds ratio (OR) = 0.47, p < .05); 13.6% were taking anticoagulants and were less likely to receive a regional anaesthetic (31.6% versus 64%, OR = 0.26, p < .05). One-year mortality was 27% for regional and 37% for general anaesthetic patients (OR = 0.64, p = .09). CONCLUSION: Regional anaesthesia halved the risk of blood transfusion. Anticoagulated patients were 74% less likely to receive regional anaesthetics, but had no additional transfusion risk. With optimisation, a larger proportion of patients could have regional anaesthesia.

Modelling Neurological Diseases in Large Animals: Criteria for Model Selection and Clinical Assessment.

Issue: The impact of neurological disorders is recognised globally, with one in six people affected in their lifetime and few treatments to slow or halt disease progression. This is due in part to the increasing ageing population, and is confounded by the high failure rate of translation from rodent-derived therapeutics to clinically effective human neurological interventions. Improved translation is demonstrated using higher order mammals with more complex/comparable neuroanatomy. These animals effectually span this translational disparity and increase confidence in factors including routes of administration/dosing and ability to scale, such that potential therapeutics will have successful outcomes when moving to patients. Coupled with advancements in genetic engineering to produce genetically tailored models, livestock are increasingly being used to bridge this translational gap. Approach: In order to aid in standardising characterisation of such models, we provide comprehensive neurological assessment protocols designed to inform on neuroanatomical dysfunction and/or lesion(s) for large animal species. We also describe the applicability of these exams in different large animals to help provide a better understanding of the practicalities of cross species neurological disease modelling. Recommendation: We would encourage the use of these assessments as a reference framework to help standardise neurological clinical scoring of large animal models.

What do we mean by critical and ethical global engagement? Questions from a research partnership between universities in Canada and Rwanda.

Language - the words we use - can play a key role in enabling or limiting transformation of inequalities in the field of global health. At the same time, given the interdisciplinary, intersectoral, and international nature of much global health work, intended meanings, commitments, and underlying values for words used cannot be taken for granted. This commentary sets out to clarify, and in this manner render available for further discussion and debate, the phrase 'critical and ethical global engagement' (CEGE). It derives from discussions between scholars and partners in research, education, and healthcare practice based at one Canadian and two Rwanda institutions. Initially, our aim was to conceptualise the term 'critical and ethical global engagement' in order to guide our own practices. As the complexity of the values, commitments, and considerations underlying our use of this phrase emerged, however, we realised these discussions merited being captured and shared, to facilitate further exploration and exchange on this phrase.

Smart sensor implant technology in total knee arthroplasty.

Innovations in computer technology and implant design have paved the way for the development of smart instruments and intelligent implants in trauma and orthopaedics to improve patient-related functional outcomes. Sensor technology uses embedded devices that detect physical, chemical and biological signals and provide a way for these signals to be measured and recorded. Sensor technology applications have been introduced in various fields of medicine in the diagnosis, treatment and monitoring of diseases. Intelligent 'Smart' implants are devices that can provide diagnostic capabilities along with therapeutic benefits. In trauma and orthopaedics, applications of sensors is increasing because of the advances in microchip technologies for implant devices and research designs. It offers real-time monitoring from the signals transmitted by the embedded sensors and thus provides early management solutions. Smart orthopaedic implants have applications in total knee arthroplasty, hip arthroplasty, spine surgery, fracture healing, early detection of infection and implant loosening. Here we have explored the role of Smart sensor implant technology in total knee arthroplasty. Smart sensor assisted can be used intraoperatively to provide objective assessment of ligament and soft tissue balancing whilst maintaining the sagittal and coronal alignment to achieve desired kinematic targets following total knee arthroplasty. It can also provide post-implantation data to monitor implant performance in natural conditions and patient's clinical recovery during rehabilitation. The use of Smart Sensor implant technology in total knee arthroplasty appears to provide superior patient satisfaction rates and improved functional outcomes.

Blood transfusions and hip fracture mortality - A retrospective cohort study.

BACKGROUND: Hip fractures are associated with serious morbidity and mortality. Low haemoglobin at presentation has been shown to be associated with increased mortality in hip fracture patients. This comorbid patient group commonly receives packed red cell blood transfusions during their hospital admission, the impact of which is less clear. AIMS AND OBJECTIVES: We aim to assess the rate, appropriateness and impact of blood transfusions on one-year mortality in hip fracture patients. We also aim to assess the impact of patients taking anticoagulant medications at presentation on the rates of blood transfusions in this patient group. METHODS: A retrospective cohort study of 324 consecutive hip fracture patients. Data was collected from the national hip fracture database, electronic patient records and PACS. RESULTS: 75 patients received a blood transfusion. Receiving a blood transfusion increased absolute risk of one-year mortality by 2.466 (p < 0.05). Adjusted for age, sex, comorbidities, residence prior to admission and time from presentation to surgery increased the risk of one-year mortality was 2.790 (p < 0.05).28% of patients who went on to receive a transfusion had a haemoglobin of less than 100 g/L at presentation. 94.6% of transfused patients had a pre-transfusion haemoglobin of less than 90 g/L. There was no increased risk of requiring a blood transfusion if anticoagulant medication was being taken at presentation. CONCLUSION: Receiving a blood transfusion during an admission for hip fracture carried an increased risk of one-year mortality of almost two and a half times. With appropriate preoperative optimisation, taking an anticoagulant medication at presentation did not increase the risk of requiring a transfusion. Most blood transfusions were administered appropriately using thresholds. Just over a quarter of patients who received a transfusion had an admission haemoglobin of less than 100 g/L, showing it as a poor predictor of blood transfusion requirement during admission.

Comparison of irrigant activation devices and conventional needle irrigation on smear layer and debris removal in curved canals. (Smear layer removal from irrigant activation using SEM).

AIM: To compare the effectiveness of smear layer and debris removal in the final rinse of curved canals of permanent molars using different commercially available irrigant activation devices. METHODS: The mesial roots of 74 extracted maxillary and mandibular molars were instrumented using the Mtwo nickel-titanium rotary system (VDW GmbH, Munich, Germany). They were then randomly assigned to one of three groups, varying in their final rinse protocol. Group 1 (n = 15) - conventional needle irrigation with 4% NaOCl; Group 2 (n = 19) - EndoActivator® (Dentsply Tulsa Dental Specialties, Tulsa, OK, USA) with 4% NaOCl; Group 3 (n = 17) - XP-endo® Finisher (FKG Dentaire SA, La Chaux-de-Fonds, Switzerland) with 4% NaOCl. After the final rinse, all canals were flushed with 1 mL 15% EDTA for 60 s and then flushed with saline. The roots were split longitudinally and prepared for scanning electron microscope imaging. ImageJ for Windows was utilised to assess the images for smear layer removal, while two blinded investigators assessed debris presence in the middle and apical thirds using a 5-point scale. RESULTS: There was no significant difference in smear layer and debris removal between treatment and control groups in the same canal zones. A significant difference was noted across different canal zones both within and across the groups. CONCLUSION: There is no statistically significant difference in effectiveness between activated irrigation techniques and manual activation. Further investigations are required to evaluate all methods available and determine the most efficient technique to irrigate successfully.

Weaponizing mutual aid: Can a pandemic or biological attack turn our strongest emergency management tool against us?

A functional mutual aid system allows the effective cost sharing of resources and the swift mitigation of loss of life and property. COVID-19 has illuminated weaknesses in our mutual aid framework. Weaknesses could potentially allow abuse and the misuse of these unifying instruments. By designing our response system in an insightful and nuanced fashion, we are able to affectively lend aid to those in need. Our mutual aid systems allow us to be forward thinking-it -challenges us to anticipate what could happen and how we should respond. This article will articulate challenges COVID-19 has posed in our mutual aid system and will propose potential improvements to better enhance our aid agreements for future pandemics.

Developing a core outcome set for paediatric wrist fractures: a systematic review of prior outcomes.

OBJECTIVES: This review aims to summarize the outcomes used to describe effectiveness of treatments for paediatric wrist fractures within existing literature. METHOD: We searched the Cochrane Library, Scopus, and Ovid Medline for studies pertaining to paediatric wrist fractures. Three authors independently identified and reviewed eligible studies. This resulted in a list of outcome domains and outcomes measures used within clinical research. Outcomes were mapped onto domains defined by the COMET collaborative. RESULTS: Our search terms identified 4,262 different papers. Screening of titles excluded 2,975, leaving 1,287 papers to be assessed for eligibility. Of this 1,287, 30 studies were included for full analysis. Overall, five outcome domains, 16 outcome measures, and 28 measurement instruments were identified as outcomes within these studies. 24 studies used at least one measurement pertaining to the physiological/clinical outcome domain. The technical, life impact, and adverse effect domains were recorded in 23, 20, and 11 of the studies respectively. Within each domain it was common for different measurement instruments to be used to assess each outcome measure. The most commonly reported outcome measures were range of movement, a broad array of "radiological measures" and pain intensity, which were used in 24, 23, and 12 of the 30 studies. CONCLUSION: This study highlights the heterogeneity in outcomes reported within clinical effectiveness studies of paediatric wrist fractures. We provided an overview of the types of outcomes reported in paediatric wrist fracture studies and identified a list of potentially relevant outcomes required for the development of a core outcome set.

Spatial tracking of individual fluid dispersed particles via Raman spectroscopy.

We demonstrate a method for the spatial tracking of individual particles, dispersed in a fluid host, via Raman spectroscopy. The effect of moving a particle upon the intensity of different bands within its Raman spectrum is first established computationally through a scattering matrix method. By comparing an experimental spectrum to the computational analysis, we show that the position of the particle can be obtained. We apply this method to the specific cases of molybdenum disulfide and graphene oxide particles, dispersed in a nematic liquid crystal, and contained within a microfluidic channel. By considering the ratio and difference between the intensities of the two Raman bands of molybdenum disulfide and graphene oxide, we demonstrate that an accurate position can be obtained in two dimensions.

Prevention of Unintentional Childhood Injury.

Unintentional injury accounts for one-third of deaths in children and adolescents each year, primarily from motor vehicle crashes. Children younger than 13 years should be restrained in the back seat, and infants and toddlers should remain rear-facing until at least two years of age. Infants should be positioned on their backs in a crib, on a mattress with only a fitted sheet to avoid suffocation, and all items that could potentially entrap or entangle the child should be removed from the sleep environment. Fencing that isolates swimming pools from the house is effective in preventing drownings. Swimming lessons are recommended for all children by four years of age. Inducing vomiting after toxic ingestions is not recommended. Installing and maintaining smoke detectors, having a home escape plan, and teaching children how to respond during a fire are effective strategies for preventing fire-related injuries or death. The most effective way to prevent gun-related injuries in children and adolescents is the absence of guns from homes and communities. Family physicians should counsel patients with guns in the home to keep them locked, unloaded, and with ammunition stored in a separate locked location. Fall injuries can be reduced by avoiding walkers for infants and toddlers. Consistent helmet use while bicycling reduces head and brain injuries. Although direct counseling by physicians seems to improve some parental safety behaviors, its effect on reducing childhood injuries is unclear. Community-based interventions can be effective in high-risk populations.

The prevalence of adult de novo scoliosis: A systematic review and meta-analysis.

INTRODUCTION: Primary degenerative scoliosis represents a new scoliosis developing in patients with no prior history of spinal curvature. Researchers sought to determine the prevalence of this type of scoliosis. METHODS: MEDLINE, Embase, CINAHL, Web of Science and PubMed were searched from inception to 28th March, 2018. Studies that assessed adults from the general population for scoliosis using imaging techniques were included. Studies were included only if the study authors had excluded participants with previously diagnosed scoliosis and/or spinal disorders. Mixed-effects logistic-regression was used to establish an overall prevalence estimate with 95% confidence intervals (primary outcome) and to examine the effect of age and sex (secondary outcomes). RESULTS: Four cross-sectional studies and one cohort study, involving 4069 participants (66.6% Female), aged between 41 and 94 years, were eligible for inclusion. Reported prevalence figures ranged from 13 to 68%. The pooled prevalence estimate from the mixed-effects logistic regression analysis was 37.6% (95% CI 18.7-61.8). Females were more likely to suffer from scoliosis compared with males (p < 0.001), with prevalence figures of 41.2% (95% CI 20.7-65.8) versus 27.5% (95% CI 12.2-51.1), respectively. Individuals aged < 60 years had a prevalence of 13% (95% CI 5.2-30.2), whereas the prevalence estimates were substantially higher in the > 60 age group [36% (95% CI 17.4-60.6)]. CONCLUSION: Primary degenerative scoliosis is a highly prevalent condition, especially in females. Further research targeting this type of scoliosis is required to obtain more precise global prevalence estimates and to understand the influence of age and sex.

Transcription factor Creb3l1 regulates the synthesis of prohormone convertase enzyme PC1/3 in endocrine cells.

Transcription factor cAMP responsive element-binding protein 3 like 1 (Creb3l1) is a non-classical endoplasmic reticulum stress molecule that is emerging as an important component for cellular homeostasis, particularly within cell types with high peptide secretory capabilities. We have previously shown that Creb3l1 serves an important role in body fluid homeostasis through its transcriptional control of the gene coding for antidiuretic hormone arginine vasopressin in the neuropeptide-rich magnocellular neurones of the supraoptic nucleus. In response to osmotic stimuli such as dehydration, vasopressin magnocellular neurones undergo remarkable transcriptome changes, including increased Creb3l1 expression, to ensure that the supply of vasopressin meets demand. To determine where else Creb3l1 fits into the secretory cell supply chain, we performed RNA-sequencing of Creb3l1 knockdown anterior pituitary mouse corticotroph cell line AtT20. The target chosen for further investigation was Pcsk1, which encodes proprotein convertase enzyme 1 (PC1/3). PC1/3 is crucial for processing of neuropeptides and peptide hormones such as pro-opiomelanocortin (POMC), proinsulin, proglucagon, vasopressin and oxytocin. Viral manipulations in supraoptic nuclei by over-expression of Creb3l1 increased Pcsk1, whereas Creb3l1 knockdown decreased Pcsk1 expression. In vitro promoter activity and binding studies showed that Creb3l1 was a transcription factor of the Pcsk1 gene binding directly to a G-box motif in the promoter. In the dehydrated rat anterior pituitary, Creb3l1 and Pcsk1 expression decreased in parallel compared to control, supporting our findings from manipulations in AtT20 cells and the supraoptic nucleus. No relationship was observed between Creb3l1 and Pcsk1 expression in the neurointermediate lobe of the pituitary, indicating a different mechanism of PC1/3 synthesis by these POMC-synthesising cells. Therefore, Creb3l1, by regulating the expression of Pcsk1, does not control the processing of POMC peptides in the intermediate lobe.