The use of tramadol and other opioids for pain management has been accompanied by a multitude of challenges and concerns worldwide. The use of tramadol saw a decline in Denmark during 2017-2019 accompanied by a slight increase in the use of morphine and oxycodone. Using the Danish National Prescription Registry and utilizing data until and including 2023, we aimed to provide updated data on the utilization patterns of tramadol and other opioids in Denmark. We found a 35% decline in the use of tramadol from 2017 to 2023 most likely due to media attention, regulatory actions, health campaigns and targeted education of physicians and patients by the Danish health authorities. This decline was accompanied by an increase in the number of new (+90%) and current users of morphine (+57%), which surpassed those of tramadol, oxycodone and other opioids in 2023.

Antibodies targeting folate receptor 1 (FOLR1) induce autophagic cell death in addition to antibody-dependent cytotoxicity, but the biological relevance of anti-FOLR1 antibody-induced autophagy for clinical applications remains unclear. Here, we investigated the role of autophagic cell death triggered by IMGN853 (mirvetuximab soravtansine), a FOLR1-targeted antibody-drug conjugate, and explored potential combinations of IMGN853 with chemotherapeutic drugs used for ovarian cancer treatment. We discovered that FOLR1 was predominantly expressed in epithelial ovarian cancer cells, with similar expression levels observed in both primary ovarian tumors and metastatic omental tumors from patients with high-grade serous ovarian cancer (HGSC). Treatment with IMGN853 improved survival in mice bearing HGSC patient-derived xenografts, enhanced autophagy flux, and induced cell death in HGSC cells. Additionally, it increased expression of the autophagy-related marker LC3B-II and cell death as marked by activated caspase-3, in a manner dependent on beclin-1, in HGSC models. Notably, combinations of IMGN853 with topotecan or the anti-VEGF-A antibody B20 significantly reduced tumor growth compared to IMGN853 alone, while no significant effect was observed with olaparib. Our findings indicate that IMGN853 induces autophagic cell death, which contributes to its tumor-inhibiting effects. The identification of these effective combination therapies and the mechanisms behind FOLR1-mediated autophagic cell death could facilitate further clinical development of IMGN853.

With the growing evidence of cardiovascular risks associated with diclofenac use, regulatory measures governing its application and sales have intensified since 2008. We evaluated the association between central regulatory actions and trends in diclofenac use in Denmark from 1999 to 2023, according to different dosage forms and routes of administration.

Mitochondria play an essential role in the life cycle of eukaryotic cells. However, we still don't know how their ultrastructure, like the cristae of the inner membrane, dynamically evolves to regulate these fundamental functions, in response to external conditions or during interaction with other cell components. Although high-resolution fluorescent microscopy coupled with recently developed innovative probes can reveal this structural organization, their long-term, fast and live 3D imaging remains challenging. To address this problem, we have developed a CNN, called DeepCristae, to restore mitochondria cristae in low spatial resolution microscopy images. Our network is trained from 2D STED images using a novel loss specifically designed for cristae restoration. To efficiently increase the size of the training set, we also developed a random image patch sampling centered on mitochondrial areas. To evaluate DeepCristae, quantitative assessments are carried out using metrics we derived by focusing on the mitochondria and cristae pixels rather than on the whole image as usual. Depending on the conditions of use indicated, DeepCristae works well on broad microscopy modalities (Stimulated Emission Depletion (STED), Live-SR, AiryScan and LLSM). It is ultimately applied in the context of mitochondrial network dynamics during interaction with endo/lysosome membranes.

Bilateral lesions of the basal ganglia using termocoagulation or radiation for improving tremor, bradykinesia, and rigidity in people with Parkinson's disease (PD) have been performed starting several decades ago, especially when levodopa and deep brain stimulation (DBS) surgery were not available. However, because of unclear additional benefit compared to unilateral lesion, and particularly to the evidence of increased adverse events occurrence, bilateral lesions were basically abandoned at the end of the 20th century. Therefore, bilateral DBS has become the standard procedure to treat PD. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is an emerging incisionless technique used to produce therapeutic brain ablation. The positive experiences of unilateral MRgFUS ablation for PD, along with the preliminary favorable outcomes of bilateral thalamic MRgFUS for essential tremor, raise the possibility to eventually reintroduce bilateral lesioning in the management of PD motor features. This possibility has so far only been tested in a few small studies. This article reviews the evidence of bilateral lesioning of the basal ganglia to treat PD, and elaborates on current gaps, controversies, and perspectives of the different available neurosurgical procedures and specifically of MRgFUS ablation. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Intraductal papillary mucinous neoplasms (IPMN) occur in 5-10% of the population, but only a small minority progress to pancreatic ductal adenocarcinoma (PDAC). The lack of accurate predictors of high-risk disease leads both to unnecessary operations for indolent neoplasms as well as missed diagnoses of PDAC. Digital spatial RNA profiling (DSP-RNA) provides an opportunity to define and associate transcriptomic states with cancer risk.

Proton exchange membrane water electrolysis (PEMWE) technology commercialization strongly relies on developing efficient and cost-effective anode catalysts. One key challenge is the high cost associated with IrO, which can be mitigated by reducing iridium (Ir) loading. A promising approach to achieving this is using a conductive support material to anchor Ir/IrO. In this study, we explored depositing metallic Ir on antimony-doped tin oxide (ATO) using a solid-state method. This approach is straightforward and time-efficient. Among four samples with 50 wt % Ir loading, one prepared with NaOH in 100% ethanol (Ir/ATO-NE) exhibited the highest specific oxygen evolution reaction (OER) performance. The Ir/ATO-NE catalyst achieved 340 A g at 1.6 V (versus RHE), surpassing a commercial IrO catalyst, which showed 282 A g. Additionally, Ir/ATO-NE demonstrated the lowest Tafel slope, indicating enhanced oxygen evolution kinetics and long-term durability comparable to commercial catalysts. Electron microscopy revealed uniform Ir nanoparticle (NP) sizes and a complete layer of Ir NPs on the support, in contrast to other samples. This study introduces a synthesis protocol for Ir catalysts that is efficient, simple, and effective for oxygen evolution in acidic media.

Changes in psychotropic drug use relative to suicidal behavior could potentially inform the timing of preventive efforts. We aimed to describe the initiation and discontinuation of psychotropic drugs relative to suicide and suicide attempts.

The syndrome "bassess richesses" is a vector-borne disease of sugar beet in Germany. The gammaproteobacterium ' Arsenophonus phytopathogenicus' causes reduced sugar content and biomass, growth abnormalities, and yellowing. Co-infection with the 16SrXII-P stolbur phytoplasmas often leads to more severe symptoms and a risk of complete economic loss. This yellowing agent of the Mollicutes class had not been described before, so its differences from other stolbur phytoplasmas remained unanswered. The genome of strain GOE was sequenced, providing a resource to analyze its characteristics. Phylogenetic position was revised, genome organization was compared, and functional reconstructions of metabolic and virulence factors were performed. Average nucleotide identity analysis indicates that GOE represents a new ' Phytoplasma' species. Our results show that GOE is also distinct from other stolbur phytoplasmas in terms of smaller genome size and G+C content. Its reductive evolution is reflected in conserved membrane protein repertoire and minimal metabolism. The encoding of a riboflavin kinase indicates a lost pathway of phytoplasmas outside the groups 16SrXII and 16SrXIII. GOE shows a complete transposon harboring orthologs of SAP11, SAP54, and SAP05 effectors indicating an original phytoplasma pathogenicity island. Our results deepen the understanding of phytoplasma evolution and reaffirm the heterogeneity of stolbur phytoplasmas.

Chronic exposure to manganese (Mn) induces manganism and has been widely implicated as a contributing environmental factor to Parkinson's disease (PD), featuring notable overlaps between the two in motor symptoms and clinical hallmarks. Here, we developed an adult model of Mn toxicity that recapitulated key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. Metabolomics analysis of the brain and body tissues of these flies at an early stage of toxicity identified systemic changes in the metabolism of biotin (also known as vitamin B) in Mn-treated groups. Biotinidase-deficient flies showed exacerbated Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction. Supplementing the diet of wild-type flies with biotin ameliorated the pathological phenotypes of concurrent exposure to Mn. Biotin supplementation also ameliorated the pathological phenotypes of three standard fly models of PD. Furthermore, supplementing the culture media of human induced stem cells (iPSCs) differentiated midbrain dopaminergic neurons with biotin protected against Mn-induced mitochondrial dysregulation, cytotoxicity, and neuronal loss. Last, analysis of the expression of genes encoding biotin-related proteins in patients with PD revealed increased amounts of biotin transporters in the substantia nigra compared with healthy controls, suggesting a potential role of altered biotin metabolism in PD. Together, our findings identified changes in biotin metabolism as underlying Mn neurotoxicity and parkinsonian pathology in flies, for which dietary biotin supplementation was preventative.

Distinguishing grade 3 pancreatic neuroendocrine tumors (PanNETs) from neuroendocrine carcinomas (PanNECs) is sometimes challenging. Recently, a diffuse p16-positive pattern was reported in PanNECs but not in grade 3 PanNETs, suggesting that p16 could help differentiate these entities. This study aimed to investigate p16 expression in PanNETs of various grades and its association with clinicopathologic features.

is one of the closest relatives of the highly host-adapted and uncultivable hemotrophic mycoplasma. The complete genome of strain 117C was constructed from long-reads derived from Pacific Biosciences single-molecule, real-time sequencing technology. The genome is organized into one circular, gapless chromosome with a length of 1,034 kb.

Ionizing radiation induces various types of DNA damage, and the reparability and lethal effects of DNA damage differ depending on its spatial density. Elucidating the structure of radiation-induced clustered DNA damage and its repair processes will enhance our understanding of the lethal impact of ionizing radiation and advance progress toward precise therapeutics. Previously, we developed a method to directly visualize DNA damage using atomic force microscopy (AFM) and classified clustered DNA damage into simple base damage clusters (BDCs), complex BDCs and complex double-strand breaks (DSBs). This study investigated the repair of each type of damage in DNA-repair-deficient human TK6 cells and elucidated the association between each type of clustered DNA damage and the pathway responsible for its repair postirradiation with low linear energy transfer (LET) radiation (X-rays) and high-LET radiation (Fe-ion beams) in cells. We found that base excision repair and, surprisingly, nucleotide excision repair restored simple and complex BDCs. In addition, the number of complex DSBs in wild-type cells increases 1 h postirradiation, which was most likely caused by BDC cleavage initiated with DNA glycosylases. Furthermore, complex DSBs, which are likely associated with lethality, are repaired by homologous recombination with little contribution from nonhomologous-end joining.

The number of orthotopic lung transplants (OLT) has skyrocketed since the 1960s, generating an ever-increasing cohort of post-OLT patients. Many challenges exist in the post-OLT timeframe, including donor graft dysfunction, infection, malignancy, and immunosuppression-related conditions. A rather elusive topic in the posttransplant setting remains the impact of the underlying disease process and donor lungs on other organ systems and the complications arising from the complex physiologic interactions. The liver represents a vital organ often impacted in many ways by the lung transplant procedure. Also, there is a higher likelihood of adverse outcomes in OLT recipients who have significant liver pathology. Yet little is known about the morphologic changes in liver after patients have received an OLT. In this study we retrospectively reviewed liver pathology cases obtained after the patient received an OLT.

Tissue regeneration is a complex process involving large changes in cell proliferation, fate determination, and differentiation. Mitochondrial dynamics and metabolism play a crucial role in development and wound repair, but their function in large-scale regeneration remains poorly understood. Planarians offer an excellent model to investigate this process due to their remarkable regenerative abilities. In this study, we examine mitochondrial dynamics during planarian regeneration. We find that knockdown of the mitochondrial fusion gene, opa1, impairs both tissue regeneration and stem cell pluripotency. Interestingly, the regeneration defects caused by opa1 knockdown are rescued by simultaneous knockdown of the mitochondrial fission gene, drp1, which partially restores mitochondrial dynamics. Furthermore, we discover that Mito stem cells exhibit an enrichment of pluripotency due to their fate choices at earlier stages. Transcriptomic analysis reveals the delicate mitonuclear balance in metabolism and mitochondrial proteins in regeneration, controlled by mitochondrial dynamics. These findings highlight the importance of maintaining mitochondrial dynamics in large-scale tissue regeneration and suggest the potential for manipulating these dynamics to enhance stem cell functionality and regenerative processes.

Although alcohol use disorder (AUD) is highly prevalent, only a few medications are approved for its treatment leaving much room for improvement. Cannabidiol (CBD) might be a particularly promising candidate, with preclinical data suggesting that CBD is effective in targeting AUD symptoms and disease processes that drive alcohol use and relapse, due to its anti-craving, stress-reducing, and anti-compulsive effects. Here we report data from the double-blind randomized controlled ICONIC trial that compared the effects of a single dose of 800 mg cannabidiol against placebo (PLC) in N = 28 individuals with AUD. Cue-induced nucleus accumbens (NAc) activation, alcohol craving during a combined stress- and alcohol cue exposure session, as well as craving during an fMRI alcohol cue-reactivity task and CBD plasma levels served as outcomes. Individuals receiving CBD showed lower bilateral cue-induced NAc activation (t = 4.906, p < 0.001, d = 1.15; t = 4.873, p < 0.001, d = 1.13) and reported significantly lower alcohol craving after a combined stress- and alcohol cue exposure session (F = 4.516, p = 0.043, eta = 0.15) and during the fMRI cue-reactivity task (F = 6.665, p = 0.015, eta = 0.23). CBD levels were significantly higher in the CBD group (t = 3.808, p < 0.001, d = 1.47) and showed a significant negative association with alcohol craving during the cue exposure experiment (r = -0.394, p = 0.030) and during fMRI (r = -0.389, p = 0.030), and with left and right NAc activation (r_ = -0.459, p = 0.030; r_ = -0.405, p = 0.030). CBD's capacity to reduce stress- and cue-induced alcohol craving and to normalize NAc activation - a region critical to the pathophysiology of AUD - contribute to understanding the neurobiological basis of its clinical effects and support its potential as a treatment option for AUD. Clinical Trials Registry: DRKS00029993.

 The aim of the present study was to detect atypical Scheuermann's disease through computed tomography scans and estimate its prevalence.  This cross-sectional observational study involved 1,287 computed tomography scans from patients aged 18 to 40 years of both genders. The criteria for diagnosing atypical Scheuermann's disease included wedging of 5° in 3 consecutive vertebrae, combined with a total Cobb angle of 10° or more within the thoracolumbar interval from T8 to L2. Positive cases were assessed for kyphosis severity, presence of Schmorl's nodes, and scoliosis. Prevalence estimation and correlation analysis with age and sex were performed.  The study identified 28 cases of atypical Scheuermann's kyphosis, indicating a prevalence of 2.8%.  The current research, utilizing abdominal tomography, offers valuable insights into the prevalence of Scheuermann's disease in its atypical form within the sampled population.

Neurochemical signals like dopamine (DA) play a crucial role in a variety of brain functions through intricate interactions with other neuromodulators and intracellular signaling pathways. However, studying these complex networks has been hindered by the challenge of detecting multiple neurochemicals simultaneously. To overcome this limitation, we developed a single-protein chemigenetic DA sensor, HaloDA1.0, which combines a cpHaloTag-chemical dye approach with the G protein-coupled receptor activation-based (GRAB) strategy, providing high sensitivity for DA, sub-second response kinetics, and an extensive spectral range from far-red to near-infrared. When used together with existing green and red fluorescent neuromodulator sensors, Ca indicators, cAMP sensors, and optogenetic tools, HaloDA1.0 provides high versatility for multiplex imaging in cultured neurons, brain slices, and behaving animals, facilitating in-depth studies of dynamic neurochemical networks.

Silicotuberculosis, the combination of silicosis and pulmonary tuberculosis (TB), remains a substantial clinical and public health problem in high TB burden countries with silica-exposed workforces. The objectives of this narrative review are to propose a definition of silicotuberculosis which includes post-tuberculous lung disease, to emphasise the importance of understanding how the two diseases modify each other, and to identify as yet unanswered questions relevant to clinical practice and disease control and mitigation. The unique aetiological relationship between silica exposure and TB is now firmly established, as is the accelerated impairment and mortality imposed by TB on individuals with silicosis. However, the rich clinical, pathology and laboratory literature on combined disease from the pre-TB treatment era appears to have been largely forgotten. The close clinical and pathological appearance of the two diseases continues to pose a challenge to imaging, diagnosis and pathological description, while inconsistent evidence regarding TB treatment and TB preventive treatment prevails. Many other topics raise questions to be answered, : the range of phenotypes of combined disease; the rates and determinants of disease progression; the role of computed tomography in identifying and characterising combined disease; appropriate screening practice; acceptable policies of management of workers that combine risk reduction with social security; and the workplace respirable silica concentration that protects against the excess TB attributable to inhaled silica.

To describe the clinical and radiological parameters of spine malignant tumors.

Capacity-building interventions for health extension workers (HEWs) are key to providing quality health services to the community. Since Ethiopia's Health Extension Program was established, several types of capacity-building interventions have been developed to build HEW competencies. However, no comprehensive study has mapped the types of capacity-building interventions being used or the competencies targeted.