Effect of urgency level on prehospital emergency transport times: a natural experiment.

Accurate estimation of ambulance transport time from the scene of incident to arrival at the emergency department (ED) is important for effective resource management and emergency care system planning. Further, differences in transport times between different urgency levels highlight the benefits of ambulance transports with highest urgency level in a setting where ambulances are allowed to not follow standard traffic rules. The objective of the study is to compare ambulance urgency level on the differences in estimates of ambulance transport times generated by Google Maps and the observed transport times in a prehospital setting where emergency vehicles have their own traffic laws. The study was designed as a natural experiment and register study. Ambulance transports dispatched with different levels of urgency (Level A and B) were included in the Central Denmark Region (a mixed urban and rural area) from March 10 to June 11, 2021. Ambulance transports for highest urgency level were compared to lowest urgency level with Google Maps estimated transport times as reference. We analyzed 1981 highest urgency level and 8.958 lowest urgency level ambulance transports. Google Maps significantly overestimated the duration of transports operating at highest level of urgency (Level A) by 1.9 min/10 km (95% CI 1.8; 2.0) in average and 4.8 min/10 km (95% CI 3.9; 5.6) for the first driven 10 km. Contrary, Google Maps significantly underestimated the duration of transports operating at lowest level of urgency (Level B) by -1.8 min/10 km (95% CI -2.1; -1.5) in average and -4.4 min/10 km (95% CI -5.4; -3.5) for the first driven 10 km. Google Maps systematically overestimates transport times of ambulance transports driven with Level A, the highest level of urgency in a setting where ambulances are allowed to not follow standard traffic rules. The results highlight the benefit of using urgency Level A and provide valuable information for emergency care management.

A systematic review on risk and protective factors for suicide and suicidal behaviour among Greenland Inuit.

Since the 1970s, suicide has been a major public health issue in Greenland. The World Health Organization has emphasised the importance of the identification of both risk and protective factors in relation to suicide. The aim of this paper was to identify scientific literature on risk and protective factors for suicide and suicidal behaviour among Greenland Inuit. Searches in PubMed and PsycInfo resulted in 420 studies that were screened by three of the authors. After screening, the authors included 15 studies that were subject to quality assessment and data extraction. All 15 studies reported on risk factors, and only three mentioned protective factors. Most reported risk factors were on an individual level and were related to socioeconomic status, mental health, alcohol and substance use, and life stress. Risk factors related to the family mainly related to adverse childhood experiences, while the community level concerned access to education, work, and conflicts. The results indicate a large knowledge gap about protective factors for suicide and suicidal behaviour. The few protective factors reported were related to men having a family, high socioeconomic status, and being born between 1901 and 1950.

Complications in hepatic vein catheterisation and transjugular liver biopsy.

INTRODUCTION: Portal pressure predicts the occurrence of decompensations in cirrhosis. Portal pressure is primarily measured via hepatic vein catheterisation (HVC), to which a transjugular liver biopsy (TJLB) may be added. Indications for HVC are mainly therapy control and prognosis. TJLB is performed when a percutaneous liver biopsy is contraindicated or for other diagnostic reasons. Both procedures have reported low complication rates. The aim of this study was to identify indications and 30-day postprocedural complications. METHODS: Based on procedure codes, a list was generated in the report database compromising procedures from 1 January 2018 to 31 January 2022. Procedures were identified in electronic charts (Cosmic Arkiv). A total of 209 patients undergoing 277 procedures were included. Information regarding indications, complications, age, sex, diagnosis, comorbidity and blood tests was also analysed. RESULTS: The more frequently reported indications for HVC were control of betablockers and diagnosis. Indications for TJLB were diagnostic and research purposes. Complications after HVC included pain and transient supraventricular arrythmias. Four major complications after TJLB were found, which led to admission due to various causes of bleeding. CONCLUSION: HVC and TJLB are safe procedures. The complication rate for HVC and TJLB was 3.3% and 6.8%, respectively. Complications were minor; only four major complications after TJLB were found - none of which were mortal. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Patient healthcare experiences in the Northwest Territories, Canada: an analysis of news media articles.

The factors that influence patient healthcare experiences are complex and connected to place. In northern Canada, the socio-historical context and the inequitable distribution of health services are unique influences on patients. The objective of this study was to examine the characteristics of patient healthcare experiences as reported through news media in the Northwest Territories. We used a case series design to examine patient healthcare experiences reported in news media articles. We conducted a systematic search for articles published between 2008 and 2017 in the online database of a media outlet in the Northwest Territories. We used descriptive statistics to summarise the article characteristics and thematic analysis to understand patient experiences in 128 articles related to 71 cases. Most often, cases involved women, concerned mental health, suicidality, or chronic diseases, and were predominantly negative. Patient experiences included problems associated with medical travel, communication difficulties with providers, lack of cultural safety, and barriers in accessing care resulting in poor-quality care, particularly for Indigenous patients. Broadly, these experiences are rooted in the colonial history in the North. Understanding patient experiences and including Indigenous patients in health system decision-making can help focus policies and clinical care on cultural safety and equity.

Patient experience studies in the circumpolar region: a scoping review.

OBJECTIVES: Patient experiences with health systems constitute a crucial pillar of quality care. Across the Arctic, patients' interactions with the healthcare system are influenced by challenges of access, historical inequities and social determinants. This scoping review sought to describe the range and nature of peer-reviewed literature on patient experience studies conducted within the circumpolar region. DESIGN: In a partnership between Danish/Greenlandic, Canadian and American research teams, a scoping review of published research exploring patient experiences in circumpolar regions was undertaken. DATA SOURCES: Seven electronic databases were queried: MEDLINE, Embase, Scopus, 'Global Health 1910 to 2019 Week 11', CINAHL, PsycINFO and SveMed+. ELIGIBILITY CRITERIA: Articles were eligible for inclusion if they (a) took place in the circumpolar region, (b) reported patients' perspective and (c) were focussed primarily on patient experiences with care, rather than satisfaction with treatment outcome. DATA EXTRACTION AND SYNTHESIS: Title and abstract screening, full-text review and data extraction was conducted by four researchers. Bibliometric information such as publication date and country of origin was extracted, as was information regarding study design and whether or not the article contained results relevant to the themes of Indigenous values, rural and remote context, telehealth and climate change. Two researchers then synthesised and characterised results relevant to these themes. RESULTS: Of the 2824 articles initially found through systematic searches in seven databases, 96 articles were included for data extraction. Findings from the review included unique features related to Indigenous values, rural and remote health, telehealth and climate change. CONCLUSIONS: The review findings provide an overview of patient experiences measures used in circumpolar nations. These findings can be used to inform health system improvement based on patient needs in the circumpolar context, as well as in other regions that share common features. This work can be further contextualized through Indigenous methodologies such as sharing circles and community based participatory methods.

Comorbidity Clusters and Healthcare Use in Individuals With COPD.

BACKGROUND: Individuals who share the same comorbidity profile are usually similar with regard to their disease severity, use of health care, and clinical outcomes. The identification of comorbidity clusters therefore bears prognostic information. The objective of this study was to identify and characterize comorbidity clusters in individuals with COPD in Denmark. METHODS: Data from the Danish national registers were used. The study population included all individuals ≥16 y old who lived in the Danish Capital Region on January 1, 2012, and were diagnosed with COPD (N = 70,274). Comorbid chronic conditions were identified using diagnostic algorithms. A 2-step cluster analysis was performed. RESULTS: 81% of subjects with COPD had chronic comorbidities; the most common was hypertension (47.6%), and the least common was anxiety (0.1%). Three comorbidity clusters were identified. Cluster 1 contained 16% of the studied individuals with COPD, with all having heart disease in addition to the remaining comorbidities. Cluster 2 contained 30% of the studied individuals with COPD, of whom approximately 1 in 3 suffered from allergies, while the rest had no comorbidities. Cluster 3 contained 54% of the studied individuals with COPD, where all comorbidities but heart disease were represented. Cluster 1 contained the highest proportion of individuals over the age of 65 y, as well as the individuals with the lowest education. After adjusting for sociodemographic characteristics, individuals in Cluster 1 had the highest rates of hospitalizations and bed days. CONCLUSIONS: The presence of heart disease in individuals with COPD is a strong prognostic factor for socioeconomic and health vulnerability.

The IFNL4 Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation.

Interferon lambda 4 (IFN-λ4) is a recently identified enigmatic member of the interferon (IFN) lambda family. Genetic data suggest that the IFNL4 gene acts in a proviral and anti-inflammatory manner in patients. However, the protein is indistinguishable in vitro from the other members of the interferon lambda family. We have investigated the gene regulation of IFNL4 in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of IFNL4 This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the IFNL4 promoter. Thus, the regulation of the IFNL4 gene is radically different and might explain some of the atypical phenotypes associated with the IFNL4 gene in humans.IMPORTANCE Recent genetic evidence has highlighted how the IFNL4 gene acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the IFNL4 gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the IFNL4 gene and its gene product, interferon lambda 4 (IFN-λ4). We have investigated the expression of the IFNL4 gene and found it to be poorly induced by viral infections. A thorough investigation of the IFNL4 promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of interferons (IFNs), i.e., the ability to be effectively induced by viral infections. We suggest that the unique function of the IFNL4 gene is related to its noncanonical transcriptional regulation.

No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R) brain availability, which has recently become possible to image with Positron Emission Tomography (PET). This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17) or the latent construct of global 5-HT4R levels (all p-values > .37). Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits.

Enhanced Muscle Insulin Sensitivity After Contraction/Exercise Is Mediated by AMPK.

Earlier studies have demonstrated that muscle insulin sensitivity to stimulate glucose uptake is enhanced several hours after an acute bout of exercise. Using AICAR, we recently demonstrated that prior activation of AMPK is sufficient to increase insulin sensitivity in mouse skeletal muscle. Here we aimed to determine whether activation of AMPK is also a prerequisite for the ability of muscle contraction to increase insulin sensitivity. We found that prior in situ contraction of m. extensor digitorum longus (EDL) and treadmill exercise increased muscle and whole-body insulin sensitivity in wild-type (WT) mice, respectively. These effects were not found in AMPKα1α2 muscle-specific knockout mice. Prior in situ contraction did not increase insulin sensitivity in m. soleus from either genotype. Improvement in muscle insulin sensitivity was not associated with enhanced glycogen synthase activity or proximal insulin signaling. However, in WT EDL muscle, prior in situ contraction enhanced insulin-stimulated phosphorylation of TBC1D4 Thr649 and Ser711 Such findings are also evident in prior exercised and insulin-sensitized human skeletal muscle. Collectively, our data suggest that the AMPK-TBC1D4 signaling axis is likely mediating the improved muscle insulin sensitivity after contraction/exercise and illuminates an important and physiologically relevant role of AMPK in skeletal muscle.

Combined venetoclax and alvocidib in acute myeloid leukemia.

More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo. Alvocidib decreased MCL-1, and/or increased pro-apoptotic proteins such as BIM or NOXA, often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy, while knock-down of BIM almost entirely abrogated synergy, demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization, while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined, venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary, yet variable mechanisms favoring apoptosis, highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.

Vorinostat differentially alters 3D nuclear structure of cancer and non-cancerous esophageal cells.

The histone deacetylase (HDAC) inhibitor vorinostat has received significant attention in recent years as an 'epigenetic' drug used to treat solid tumors. However, its mechanisms of action are not entirely understood, particularly with regard to its interaction with the aberrations in 3D nuclear structure that accompany neoplastic progression. We investigated the impact of vorinostat on human esophageal epithelial cell lines derived from normal, metaplastic (pre-cancerous), and malignant tissue. Using a combination of novel optical computed tomography (CT)-based quantitative 3D absorption microscopy and conventional confocal fluorescence microscopy, we show that subjecting malignant cells to vorinostat preferentially alters their 3D nuclear architecture relative to non-cancerous cells. Optical CT (cell CT) imaging of fixed single cells showed that drug-treated cancer cells exhibit significant alterations in nuclear morphometry. Confocal microscopy revealed that vorinostat caused changes in the distribution of H3K9ac-marked euchromatin and H3K9me3-marked constitutive heterochromatin. Additionally, 3D immuno-FISH showed that drug-induced expression of the DNA repair gene MGMT was accompanied by spatial relocation toward the center of the nucleus in the nuclei of metaplastic but not in non-neoplastic cells. Our data suggest that vorinostat's differential modulation of 3D nuclear architecture in normal and abnormal cells could play a functional role in its anti-cancer action.

The Hedgehog pathway as targetable vulnerability with 5-azacytidine in myelodysplastic syndrome and acute myeloid leukemia.

BACKGROUND: Therapy and outcome for elderly acute myeloid leukemia (AML) patients has not improved for many years. Similarly, there remains a clinical need to improve response rates in advanced myelodysplastic syndrome (MDS) patients treated with hypomethylating agents, and few combination regimens have shown clinical benefit. We conducted a 5-azacytidine (5-Aza) RNA-interference (RNAi) sensitizer screen to identify gene targets within the commonly deleted regions (CDRs) of chromosomes 5 and 7, whose silencing enhances the activity of 5-Aza. METHODS AND RESULTS: An RNAi silencing screen of 270 genes from the CDRs of chromosomes 5 and 7 was performed in combination with 5-Aza treatment in four AML cell lines (TF-1, THP-1, MDS-L, and HEL). Several genes within the hedgehog pathway (HhP), specifically SHH, SMO, and GLI3, were identified as 5-Aza sensitizing hits. The smoothened (SMO) inhibitors LDE225 (erismodegib) and GDC0449 (vismodegib) showed moderate single-agent activity in AML cell lines. Further studies with erismodegib in combination with 5-Aza demonstrated synergistic activity with combination index (CI) values of 0.48 to 0.71 in seven AML lines. Clonogenic growth of primary patient samples was inhibited to a greater extent in the combination than with single-agent erismodegib or 5-Aza in 55 % (6 of 11) primary patient samples examined. There was no association of the 5-Aza/erismodegib sensitization potential to clinical-cytogenetic features or common myeloid mutations. Activation of the HhP, as determined by greater expression of HhP-related genes, showed less responsiveness to single-agent SMO inhibition, while synergy between both agents was similar regardless of HhP gene expression. In vitro experiments suggested that concurrent dosing showed stronger synergy than sequential dosing. CONCLUSIONS: Inhibition of the HhP with SMO inhibitors in combination with the hypomethylating agent 5-Aza demonstrates synergy in vitro and inhibits long-term repopulation capacity ex vivo in AML and MDS. A clinical trial combining 5-Aza with LDE225 (erismodegib) in MDS and AML is ongoing based on these results as well as additional publications suggesting a role for HhP signaling in myeloid disease.

Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: a Danish nationwide cohort study.

BACKGROUND: The effect of peginterferon and ribavirin treatment on chronic hepatitis C virus (HCV) infection has been established in several controlled clinical studies. However, the effectiveness of treatment and predictors of treatment success in routine clinical practice remains to be established. Our aim was to estimate the effectiveness of peginterferon and ribavirin treatment in unselected HCV patients handled in routine clinical practice. The endpoint was sustained virological response (SVR), determined by the absence of HCV RNA 24 weeks after the end of treatment. METHODS: We determined the proportion of SVR in a nationwide, population-based cohort of 432 patients with chronic HCV infection who were starting treatment, and analyzed the impact of known covariates on SVR by using a logistic regression analysis. RESULTS: The majority of treated patients had genotype 1 (133 patients) and genotype 2/3 (285 patients) infections, with 44% and 72%, respectively, obtaining SVR. Other than genotype, the predictors of SVR were age≤45 years at the start of treatment, completion of unmodified treatment, the absence of cirrhosis and non-European origin. CONCLUSIONS: The effectiveness of peginterferon and ribavirin treatment for chronic hepatitis C in a routine clinical practice is comparable to that observed in controlled clinical trials, with a higher SVR rate in genotype 2 and 3 patients compared to genotype 1 patients. Our data further indicate that age at start of treatment is a strong predictor of SVR irrespective of HCV genotype, with patients 45 years or younger having a higher SVR rate.

[Reporting chronic hepatitis B and C in Denmark]. / Anmeldelse af kronisk hepatitis B og C i Danmark.

INTRODUCTION: It became mandatory to report cases of chronic hepatitis B and C in Denmark in May 2002. The "treating doctor" is obliged to make the report. The purpose of this study is to find out how many patients with chronic hepatitis B or C who are monitored in the Danish health care system are reported to the State Serum Institute (SSI) and to find out who makes the report and from these numbers to estimate the total number of patients in Denmark with chronic hepatitis B and C. MATERIALS AND METHODS: Patients with chronic hepatitis B or C who were reported to the SSI before June 20th 2006 were cross-referenced with patients included in the Danish Database of Hepatitis B and C (DANHEP) on the basis of their social security number. RESULTS: The study found that only 50% of patients monitored at Danish hospitals with chronic hepatitis B or C are registered with the SSI. Respectively 47% and 38% of these were registered by their general practitioner, a few percent by a doctor whose place of employment is not registered, and the rest by doctors working at hospitals. CONCLUSION: This study demonstrates that the reporting of patients with chronic hepatitis B and C in Denmark is considerably inadequate. It is important that general practitioners as well as doctors working at hospitals are aware of their duty to report these diseases. An optimal reporting rate could be achieved by making it mandatory to notify the laboratory diagnosis of chronic hepatitis B and C as well as establishing an electronic reporting system, where data from laboratories are cross-referenced with clinical and epidemiological data.