Multiple back fractures as a result of the first seizure.

Non-traumatic fractures due to seizures are an overlooked diagnostic group. It is well known that patients with generalized tonic-clonic seizures have an increased trauma risk. However, the cause of fracture is rarely due to the violent forces of muscle contractions. Usually, the primary patient examination focuses on the aetiology of the seizure, which sometimes delays the diagnosis of fractures. This is a case report of a 19-year-old woman who sustained three compression fractures of the thoracic spine due to a generalized tonic-clonic seizure, and a discussion of the diagnostic challenges in such a rare case.

Late Pleistocene stickleback environmental genomes reveal the chronology of freshwater adaptation.

Directly observing the chronology and tempo of adaptation in response to ecological change is rarely possible in natural ecosystems. Sedimentary ancient DNA (sedaDNA) has been shown to be a tractable source of genome-scale data of long-dead organisms1,2,3 and to thereby potentially provide an understanding of the evolutionary histories of past populations.4,5 To date, time series of ecosystem biodiversity have been reconstructed from sedaDNA, typically using DNA metabarcoding or shotgun sequence data generated from less than 1 g of sediment.6,7 Here, we maximize sequence coverage by extracting DNA from ∼50× more sediment per sample than the majority of previous studies1,2,3 to achieve genotype resolution. From a time series of Late Pleistocene sediments spanning from a marine to freshwater ecosystem, we compare adaptive genotypes reconstructed from the environmental genomes of three-spined stickleback at key time points of this transition. We find a staggered temporal dynamic in which freshwater alleles at known loci of large effect in marine-freshwater divergence of three-spined stickleback (e.g., EDA)8 were already established during the brackish phase of the formation of the isolation basin. However, marine alleles were still detected across the majority of marine-freshwater divergence-associated loci, even after the complete isolation of the lake from marine ingression. Our retrospective approach to studying adaptation from environmental genomes of three-spined sticklebacks at the end of the last glacial period complements contemporary experimental approaches9,10,11 and highlights the untapped potential for retrospective "evolve and resequence" natural experiments using sedaDNA.

The disease burden of paroxysmal nocturnal hemoglobinuria in Denmark: Epidemiology, survival, healthcare resource utilization, costs, treatment gaps, and labor market attachment.

OBJECTIVES: To establish epidemiology, healthcare costs, and labor market attachment in patients with paroxysmal nocturnal hemoglobinuria (Pt-PNH) in Denmark. METHODS: Data were from Statistics Denmark and the Danish Health Data Authority national population registers (2005-2021). Descriptive baseline statistics characterized the Pt-PNH analytic population; ordinary least squares and adjusted Cox proportional hazards regressions measured outcomes in the Pt-PNH versus Danish general population matched comparators. RESULTS: Overall PNH incidence in Denmark was n = 11 during 2007-2009, n = 25 during 2016-2018 and n = 7 during 2019-2020; prevalence increased from n = 13 in 2006 to n = 62 in 2021. Of the overall n = 85 Pt-PNH; n = 24 were treated with complement-5 inhibitors (Pt-C5i) and n = 61 not treated with C5i (Pt-nC5i). Versus respective comparators, all patients had significantly greater annual per-patient costs (from inpatient hospital admissions, outpatient contacts, PNH treatments; indirect costs from lost earnings + transfer payments; post-diagnosis for Pt-PNH and Pt-nC5i, post-treatment initiation for Pt-C5i). The Pt-C5i incurred the greatest healthcare and indirect cost differences (€709 119; €152 832, respectively) followed by the Pt-PNH (€189 323; €29 159, respectively) and Pt-nC5i (€95 548; €4713, respectively). The Pt-PNH versus comparators also had an increased hazard of death (2.71 [95% CI, 1.63 - 4.51]). CONCLUSION: Although a rare disease, PNH is associated with significant patient, healthcare system, and societal burdens in Denmark.

Quantifying the benefits of early sublingual allergen immunotherapy tablet initiation in children.

BACKGROUND: Allergic rhinitis (AR) is a chronic inflammatory disease of the upper airway, which progresses into allergic asthma (AA) in up to 45% of children. This analysis aimed to investigate clinical and economic benefits of sublingual allergen immunotherapy (SLIT tablets) initiated early in childhood for the treatment of AR by quantifying the long-term reduction in new cases of AA. METHODS: A Markov model was developed to estimate the long-term effects of SLIT tablets on the risk of developing asthma. Key parameters were primarily based on data from the GRAZAX® Asthma Prevention trial and included the age- and treatment-dependent risk of developing AA as well as annual probabilities of progression/remission in AR severity. Healthcare costs were estimated using data from the REACT study. RESULTS: In a modelled cohort of children with moderate-to-severe seasonal AR initiated on SLIT tablets at ages 7 and 12, 24% and 29%, respectively, develop AA during a 20-year period. In comparison, when initiated at age 5, 19% develop AA. Additionally, initiation of SLIT tablets at age 5 is associated with a total healthcare cost of EUR 20,429 per patient, whereas initiation at ages 7 and 12 is associated with, respectively, EUR 21,050 and EUR 22,379 per patient 20 years after AR diagnosis. CONCLUSION: Initiation of SLIT tablets in early childhood is associated with a clinically meaningful and permanent reduction in new cases of AA and lower healthcare costs among children with AR. This finding supports the clinical relevance of initiating SLIT tablets early for children with AR to obtain long-term clinical benefits.

A novel SARS-CoV-2 Beta RBD DNA vaccine directly targeted to antigen-presenting cells induces strong humoral and T cell responses.

Throughout the COVID-19 pandemic, several variants of concern (VoC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have evolved, affecting the efficacy of the approved COVID-19 vaccines. To address the need for vaccines that induce strong and persistent cross-reactive neutralizing antibodies and T cell responses, we developed a prophylactic SARS-CoV-2 vaccine candidate based on our easily and rapidly adaptable plasmid DNA vaccine platform. The vaccine candidate, referred to here as VB2129, encodes a protein homodimer consisting of the receptor binding domain (RBD) from lineage B.1.351 (Beta) of SARS-CoV-2, a VoC with a severe immune profile, linked to a targeting unit (human LD78ß/CCL3L1) that binds chemokine receptors on antigen-presenting cells (APCs) and a dimerization unit (derived from the hinge and CH3 exons of human IgG3). Immunogenicity studies in mice demonstrated that the APC-targeted vaccine induced strong antibody responses to both homologous Beta RBD and heterologous RBDs derived from Wuhan, Alpha, Gamma, Delta, and Omicron BA.1 variants, as well as cross-neutralizing antibodies against these VoC. Overall, preclinical data justify the exploration of VB2129 as a potential booster vaccine that induces broader antibody- and T cell-based protection against current and future SARS-CoV-2 VoC.

Impact of new cancer medicine - real-world evidence from Danish register study of lung cancer patients.

BACKGROUND: Lung cancer (LC) is the leading cause of cancer deaths worldwide. Several new treatments have become available in recent decades, but little research exists on the impact of these on productivity, early retirement and survival for LC patients and their spouses. This study evaluates the effect of new medicines on productivity, early retirement and survival for LC patients and their spouses. METHODS: Data from the period 1 January 2004-31 December 2018 were collected from complete Danish registers. LC cases diagnosed before approval of first targeted therapy (19 June 2006, Before patients) were compared with those who received at least one new cancer treatment, diagnosed after this date (After patients). Subgroup analyses based on cancer stage, and epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation were conducted. Linear regression and cox regression were used to estimate the outcomes including productivity, unemployment, early retirement, and mortality. Spouses of Before and After patients were compared on earnings, sick leave, early retirement, and healthcare utilisation. RESULTS: The study population comprised of 4,350 patient (2,175 After/2,175 Before). Patients who received new treatments had a significantly reduced risk of death (Hazard ratio = 0.76, Confidence interval: 0.71 - 0.82) and reduced risk of early retirement (Hazard ratio: 0.54, Confidence interval: 0.38 - 0.79). No significant differences in earnings, unemployment, or sick leave were found. Spouses of Before patients had a higher cost of healthcare services after diagnosis compared to spouses of After patients. For productivity, early retirement and sick leave, no significant differences were found between the spouse groups. CONCLUSION: Patients who received innovative new treatments had reduced risk of death and reduced risk of early retirement. Spouses of LC patients who received new treatments had lower healthcare costs in the years following diagnosis. All findings indicate that recipients of new treatments had reduced burden of illness.

Economic benefits of remimazolam compared to midazolam and propofol for procedural sedation in colonoscopies and bronchoscopies.

BACKGROUND: Sedation is common practice in endoscopic procedures to suppress a patient's level of consciousness while maintaining the cardio-respiratory function. Midazolam and propofol are the sedatives most frequently used for procedural sedation at hospitals in Scandinavia. Remimazolam is a new ultra-short-acting benzodiazepine sedative and the present analysis aimed at estimating the economic benefits of introducing remimazolam for procedural sedation in colonoscopies and bronchoscopies in hospitals in Scandinavia. METHOD: We developed a cost model applying a micro-costing approach that comprised the cost components that are affected by differences in the efficacy of remimazolam, midazolam, and propofol, and the model estimated the cost per successful colonoscopy and bronchoscopy when using remimazolam, midazolam or propofol as sedation. A micro-costing approach was applied, and the model consisted of six stages representing the journey for patients undergoing endoscopies and was informed primarily by data from clinical studies on remimazolam. RESULTS: We found a total cost of DKK 1200 per successful colonoscopy procedure when using remimazolam, a total cost of DKK 1320 when using midazolam, and a total cost of DKK 1255 when using propofol. Hence, the incremental saving per successful colonoscopy procedure of using remimazolam was estimated to be DKK 120 compared to midazolam and DKK 55 compared to propofol. The total cost per successful bronchoscopy procedure when using remimazolam was DKK 1353 and DKK 1724 for midazolam, resulting in an incremental saving per bronchoscopy of DKK 372 when using remimazolam. Performed sensitivity analyses identified the time in recovery as the largest contributor to uncertainty in the analyses of remimazolam compared to midazolam in colonoscopies and bronchoscopies. In the comparison of remimazolam and propofol in colonoscopies, procedure time was the largest contributor to uncertainty. CONCLUSION: We found that procedural sedation with remimazolam was associated with economically meaningful savings compared to procedural sedation with midazolam and propofol in colonoscopies and to midazolam in bronchoscopies.

A 2-million-year-old ecosystem in Greenland uncovered by environmental DNA.

Late Pliocene and Early Pleistocene epochs 3.6 to 0.8 million years ago1 had climates resembling those forecasted under future warming2. Palaeoclimatic records show strong polar amplification with mean annual temperatures of 11-19 °C above contemporary values3,4. The biological communities inhabiting the Arctic during this time remain poorly known because fossils are rare5. Here we report an ancient environmental DNA6 (eDNA) record describing the rich plant and animal assemblages of the Kap København Formation in North Greenland, dated to around two million years ago. The record shows an open boreal forest ecosystem with mixed vegetation of poplar, birch and thuja trees, as well as a variety of Arctic and boreal shrubs and herbs, many of which had not previously been detected at the site from macrofossil and pollen records. The DNA record confirms the presence of hare and mitochondrial DNA from animals including mastodons, reindeer, rodents and geese, all ancestral to their present-day and late Pleistocene relatives. The presence of marine species including horseshoe crab and green algae support a warmer climate than today. The reconstructed ecosystem has no modern analogue. The survival of such ancient eDNA probably relates to its binding to mineral surfaces. Our findings open new areas of genetic research, demonstrating that it is possible to track the ecology and evolution of biological communities from two million years ago using ancient eDNA.

Genomic ancestry, diet and microbiomes of Upper Palaeolithic hunter-gatherers from San Teodoro cave.

Recent improvements in the analysis of ancient biomolecules from human remains and associated dental calculus have provided new insights into the prehistoric diet and genetic diversity of our species. Here we present a multi-omics study, integrating metagenomic and proteomic analyses of dental calculus, and human ancient DNA analysis of the petrous bones of two post-Last Glacial Maximum (LGM) individuals from San Teodoro cave (Italy), to reconstruct their lifestyle and the post-LGM resettlement of Europe. Our analyses show genetic homogeneity in Sicily during the Palaeolithic, representing a hitherto unknown Italian genetic lineage within the previously identified Villabruna cluster. We argue that this lineage took refuge in Italy during the LGM, followed by a subsequent spread to central-western Europe. Analysis of dental calculus showed a diet rich in animal proteins which is also reflected on the oral microbiome composition. Our results demonstrate the power of this approach in the study of prehistoric humans and will enable future research to reach a more holistic understanding of the population dynamics and ecology.

Atomistic structure search using local surrogate model.

We describe a local surrogate model for use in conjunction with global structure search methods. The model follows the Gaussian approximation potential formalism and is based on the smooth overlap of atomic positions descriptor with sparsification in terms of a reduced number of local environments using mini-batch k-means. The model is implemented in the Atomistic Global Optimization X framework and used as a partial replacement of the local relaxations in basin hopping structure search. The approach is shown to be robust for a wide range of atomistic systems, including molecules, nanoparticles, surface supported clusters, and surface thin films. The benefits in a structure search context of a local surrogate model are demonstrated. This includes the ability to benefit from transfer learning from smaller systems as well as the possibility to perform concurrent multi-stoichiometry searches.

Administration and patient-incurred costs associated with opioid agonist treatment in Norway.

OBJECTIVES: Opioid use disorder is associated with high rates of mortality and has become an escalating global health issue. Opioid agonist treatment (OAT) with oral methadone or daily sublingual buprenorphine hydrochloride, either administered separately or in combination with naloxone hydrochloride (SL-BPN, SL-BPN/NX), is supervised by a healthcare professional experienced in treating opioid use disorder to ensure proper dosing and prevent misuse. For that reason, there may be substantial direct and indirect costs associated with OAT. Recently, weekly and monthly subcutaneous depot formulations of buprenorphine (SC-BPN) have been approved. This study aimed to estimate management and patient-incurred costs associated with the most commonly used OATs compared to the cost of weekly and monthly SC-BPN. METHODS: We conducted a cost-minimisation analysis comparing the monthly costs of OAT treatment with oral formulations, i.e. oral methadone, SL-BPN, SL-BPN/NX and SC-BPN. The analysis assessed treatment acquisition costs and costs associated with management, supervision and administration of therapy, patients' transportation costs and the indirect costs associated with patients' time-use. The model was set up to reflect the Norwegian medically assisted rehabilitation system and considered the costs of a stable maintenance OAT regimen given continuously to patients already initiated and titrated on the therapy. RESULTS: OAT management with monthly formulation of SC-BPN was associated with a reduction in monthly costs of €605, €586, and €411 per month compared to SL-BPN, SL-BPN/NX and oral methadone, respectively. Similar results were estimated when comparing to the weekly formulation of SC-BPN. CONCLUSION: The analysis showed that the monthly formulation of SC-BPN was the cost-minimising alternative, followed by the weekly formulation, when considering all cost components.

The prevalence of comorbidities in Danish patients with obesity - A Danish register-based study based on data from 2002 to 2018.

We used the Danish National Health Registers to conduct a study on the prevalence of obesity-related comorbidities in Danish citizens who have been diagnosed with obesity at a Danish hospital. This was a retrospective observational study with a population comprising all Danish citizens (≥18 years) who have been registered with a specific obesity class diagnosis in the Danish National Patient Register between 2002 and 2018. A total of 86 980 persons with hospital-diagnosed obesity were included in the study population. To investigate how the risk of having comorbidities varies with the degree of obesity, we applied adjusted logistic regression to estimate the odds ratio of having one of the following predefined comorbidities for people with a BMI in obesity classes II and III compared with people with a BMI in obesity class I: type 2 diabetes, ischaemic heart disease, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease, hip and knee osteoarthritis, obstructive sleep apnoea and asthma. Comorbidities were defined from ICD-10 diagnosis codes and prescription medication utilization. The odds ratio for obstructive sleep apnoea (OR 1.86 and OR 3.0), type 2 diabetes (OR 1.68 and OR 2.26), hip and knee osteoarthritis (OR 1.29 and OR 1.54) and asthma (OR1.13 and OR 1.25) increased significantly with obesity class (obesity class II relative to I and III relative to I, respectively). The odds ratio of having had at least one comorbidity was estimated to be 1.52 for people with a BMI in obesity class II and 2.10 for people with a BMI in obesity class III compared with people in obesity class I. The risk of obstructive sleep apnoea, type 2 diabetes, hip and knee osteoarthritis, and asthma increased significantly with increasing BMI, highlighting the importance of preventing further weight gain even in individuals who are already living with obesity.

A theoretical analysis of taxonomic binning accuracy.

Many metagenomic and environmental DNA studies require the taxonomic assignment of individual reads or sequences by aligning reads to a reference database, known as taxonomic binning. When a read aligns to more than one reference sequence, it is often classified based on sequence similarity. This step can assign reads to incorrect taxa, at a rate which depends both on the assignment algorithm and on underlying population genetic and database parameters. In particular, as we move towards using environmental DNA to study eukaryotic taxa subject to regular recombination, we must take into account issues concerning gene tree discordance. Though accuracy is often compared across algorithms using a fixed data set, the relative impact of these population genetic and database parameters on accuracy has not yet been quantified. Here, we develop both a theoretical and simulation framework in the simplified case of two reference species, and compute binning accuracy over a wide range of parameters, including sequence length, species-query divergence time, divergence times of the reference species, reference database completeness, sample age and effective population size. We consider two assignment methods and contextualize our results using parameters from a recent ancient environmental DNA study, comparing them to the commonly used discriminative k-mer-based method Clark (Current Biology, 31, 2021, 2728; BMC Genomics, 16, 2015, 1). Our results quantify the degradation in assignment accuracy as the samples diverge from their closest reference sequence, and with incompleteness of reference sequences. We also provide a framework in which others can compute expected accuracy for their particular method or parameter set. Code is available at https://github.com/bdesanctis/binning-accuracy.

The substantial costs to society associated with obesity - a Danish register-based study based on 2002-2018 data.

INTRODUCTION: The Danish national health registers were used to investigate the economic burden of obesity, associated costs of comorbidities and a breakdown into direct and indirect costs. METHODS: The study population comprised all Danish adult citizens registered with a hospital diagnosis of obesity in the Danish National Patient Register between 2002 and 2018. Cases were matched with five controls via the Danish Civil Registration System. We estimated the difference in total healthcare costs and indirect costs between cases and controls and the difference in healthcare resource utilization. In a sub-analysis, we estimated total healthcare costs for persons who had been registered with one or more of 11 predefined comorbidities. RESULTS: People with obesity experienced a statistically significant twofold increase in average direct healthcare costs per year (EUR 5,934), compared with controls (EUR 2,788) and had statistically significantly higher indirect costs compared to controls. Total healthcare costs for people with obesity and one or more of the 11 comorbidities were 91.7%-342.8% higher than total healthcare costs of the population with obesity but none of the 11 comorbidities. CONCLUSION: Obesity was associated with an increase in both direct and indirect costs. The presence of comorbidities was associated with additional healthcare costs. KEY POINTS: Obesity is associated with an increase in direct and indirect costs in Denmark.Comorbidities are associated with additional healthcare costs.

First-in-human trial exploring safety, antitumor activity, and pharmacokinetics of Sym013, a recombinant pan-HER antibody mixture, in advanced epithelial malignancies.

PURPOSE: Sym013 contains six humanized monoclonal antibodies that bind to non-overlapping epitopes on three human epidermal growth factor receptors (HER1-3). Preclinical studies suggested Sym013 strongly suppresses growth of multiple epithelial tumors. This is a first-in-human study exploring safety and efficacy of Sym013 in patients with advanced epithelial malignancies. METHODS: Dose escalation used single-patient cohorts until the stopping rule was met, followed by 3 + 3 design. Dose levels planned were: 1, 2, 4, 6, 9, 12, 15, and 18 mg/kg. Treatment cycles were 28 days with imaging every eight weeks. Serum samples were collected at multiple time points for assessment of pharmacokinetics and development of anti-drug antibodies. RESULTS: Thirty-two patients were enrolled with multiple solid tumors, most common being colorectal cancer (CRC; 10/32, 31%). Due to mucositis, rash, and diarrhea at 4 mg/kg once-weekly, dosing was changed to biweekly (Q2W). Mandatory prophylaxis was added due to Grade 3 infusion-related reaction and oral mucositis at 9 mg/kg Q2W. The 15 mg/kg Q2W cohort was enrolling when the study was terminated for business reasons. Most common adverse events were skin (81%) and gastrointestinal (75%) disorders, including dermatitis/rash, stomatitis, and diarrhea. One patient with CRC achieved a partial response; 12 patients with varied malignancies had stable disease. CONCLUSION: During the conduct of the study, management of frequent infusion-related reactions, skin toxicities, and mucosal disorders, which are indicative of HER inhibition, necessitated multiple protocol amendments. The investigators, in concert with the Sponsor, agreed that achieving a tolerated regimen with acceptable target saturation was unlikely. TRIAL REGISTRY: www. CLINICALTRIALS: gov ; NCT02906670 (September 20, 2016).

Preference for sublingual immunotherapy with tablets in a Spanish population with allergic rhinitis.

BACKGROUND: This study investigated patients' preference for allergy immunotherapy (AIT) administered as either sublingual immunotherapy-tablets versus monthly or weekly subcutaneous immunotherapy (SCIT) from a Spanish patient perspective. METHODS: A discrete choice experiment (DCE) consisting of two blocks with eight choice sets in each was constructed to elicit the preferences for AIT. Three attributes were included in the DCE for the mode of administration, including the frequency of administration, the risk of systemic reactions and the co-payment. Adults and caregivers of children with moderate to severe allergic rhinitis (AR) were included if they were not currently receiving or had not previously received AIT. RESULTS: In total, 587 adults and 613 caregivers started the survey. Of those, 579 adults and 611 caregivers completed the survey and were included in the study. Both adults and caregivers had a significant preference for tablets compared with both monthly and weekly injections (p ≤ 0.0001). Furthermore, the respondents showed a significant preference for reducing the risk of systemic reactions. Subgroup analyses showed that caregivers of polyallergic children and female caregivers were significantly less price sensitive when choosing their preferred treatment. CONCLUSION: Our study demonstrated that both adults with AR and caregivers of children with AR prefer daily SLIT-tablets to SCIT with either a weekly or monthly dose schedule.

The Effect of Bariatric Surgery on Healthcare Costs and Labor Market Attachment.

PURPOSE: We aimed to estimate the total cost of bariatric surgery in Denmark. MATERIALS AND METHODS: The study population included all Danish citizens ≥ 18 years who had received bariatric surgery, identified in the Danish National Patient Register in the period from 2002 to 2018. Patients who had received bariatric surgery were matched with three controls on gender, year of birth, and region of residence. A difference-in-difference approach was used to estimate the healthcare costs attributable to bariatric surgery from 3 years before to 5 years after surgery. RESULTS: Total healthcare costs for cases receiving bariatric surgery during the first 5 years following surgery amounted to EUR 32,899, and EUR 16,651 for their matched controls. Thereby, the difference in total healthcare costs (EUR 16,248) between persons receiving bariatric surgery and their matched controls was 2.2 times the DRG rate for the surgery itself (EUR 7387). Moreover, the results suggest that receiving bariatric surgery led to a total increase in gross earnings of EUR 5970 (5%) and a total reduction in receipt of transfer payments of EUR 4488 (12%) in the period up until 5 years after surgery. CONCLUSION: The results showed a significant and persistent increase in healthcare costs for people with obesity receiving bariatric surgery during the first 5 years after surgery. We also found that bariatric surgery was associated with increased attachment to the labor market.