Pain trajectories over 12 months following conservative care consultation in patients with lumbar spinal stenosis.

OBJECTIVE: To investigate symptom trajectories in chiropractic patients with lumbar spinal stenosis (LSS). METHODS: Patients diagnosed with LSS were recruited from chiropractic clinics and self-reported questionnaires were collected at baseline and 1-year follow-up. Patients received weekly text messages about low back pain (LBP) and leg symptoms for 1 year. Group-based trajectory modelling was performed to identify symptom trajectory groups. The groups were compared based on patient characteristics, LBP and leg pain intensity, Oswestry Disability Index (ODI) and Zurich Claudication Questionnaire (ZCQ). RESULTS: A total of 90 patients were included in the analysis. A three-group trajectory model was chosen: 'improving' (16%), 'fluctuating/improving' (30%), and 'persistent' (54%). The 'persistent' group had a higher proportion of women [71% (95% CI 57-82%)] than the 'improving' group 29% (95% CI 11-56%), and a higher ODI score at both baseline [34.2 (95% CI 29.7-38.8) vs. 22.8 (16.4-29.1)] and 1-year follow-up [28.1 (95% CI 23.2-33.0) vs. 4.8 (0.1-9.4)]. Similar differences were observed for ZCQ symptom and function scores. CONCLUSIONS: Pain symptoms in people with LSS followed distinctly different trajectories. Half of the sample had a pattern of consistently severe symptoms over a year, while the other half either improved rapidly or experienced fluctuating symptoms with some improvement.

Serum Concentrations of Inhibin B in Healthy Females and Males Throughout Life.

OBJECTIVE: To describe the natural history of inhibin B throughout life according to sex, age, and pubertal development. METHODS: Based on serum samples from 2707 healthy controls aged 0 to 80 years, sex- and age-specific reference ranges of inhibin B concentrations were constructed. Concentrations were evaluated according to pubertal development and use of oral contraceptives (OCs). Also, measurements from 42 patients with Klinefelter syndrome were included. RESULTS: In both sexes, inhibin B concentrations were high during minipuberty, decreased in childhood, and increased significantly from Tanner stages B1 to B3 (peak: B4) in females and from G1 to G3 (peak: G3) in males. Despite variations in menstruating females, inhibin B concentrations remained relatively constant after puberty, until becoming unmeasurable at menopause. Despite a modest decrease, the inhibin B concentration in males remained relatively high from puberty onwards. At any age, males had highest concentrations. Inhibin B standard deviation (SD) scores were lower in OC-users (median SD score = -0.88) than in non-users (SD score = 0.35), p < 0.001. In patients with Klinefelter syndrome, inhibin B concentrations spanned the reference range until around 15 years of age, where they decreased to subnormal or unmeasurable levels. CONCLUSION: Valuable sex- and age-specific reference data for inhibin B concentrations were provided. In OC-users, decreased concentrations of inhibin B underlined the ovaries as the only place of inhibin B production. In patients with Klinefelter syndrome, the decline in inhibin B concentrations at puberty underlined the shift in regulation of inhibin B production at pubertal onset.

Blood pressure and lipid profiles in children born after ART with frozen embryo transfer.

STUDY QUESTION: Are blood pressure (BP) and lipid profiles different between children conceived after ART with frozen embryo transfer (FET), fresh embryo transfer (fresh-ET), and natural conception (NC)? SUMMARY ANSWER: Girls conceived after FET had significantly higher systolic BP and heart rate compared with girls born after fresh-ET; boys conceived after FET had a slightly more favourable lipid profile compared with boys born after fresh-ET and NC. WHAT IS KNOWN ALREADY: Children conceived after ART with FET are more often born large for gestational age (LGA). LGA in general increases the risk of obesity, diabetes, and cardiovascular disease later in life. Studies on mice and humans on the whole ART population have raised concerns about premature vascular ageing and higher BP. The cardiovascular health of children born after FET is scarcely explored and the results are diverging. STUDY DESIGN SIZE DURATION: This study was part of the cohort study 'Health in Childhood following Assisted Reproductive Technology' (HiCART), which included 606 singletons (292 boys) born between December 2009 and December 2013: 200 children were conceived after FET; 203 children were conceived after fresh-ET; and 203 children were conceived naturally and matched for birth year and sex. The study period lasted from January 2019 to September 2021. PARTICIPANTS/MATERIALS SETTING METHODS: The included children were 7-10 years of age at examination and underwent a clinical examination with anthropometric measurements, pubertal staging, and BP measurement. Additionally, a fasting blood sample was collected and analysed for cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides. Systolic and diastolic BP were converted to standard deviation scores (SDS) using an appropriate reference and accounting for height (SDS) of the child. The three study groups were compared pairwise using a univariate linear regression model. Mean differences were adjusted for confounders using multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Girls and boys conceived after FET had significantly higher birthweight (SDS) compared with naturally conceived peers (mean difference: girls: 0.35, 95% CI (0.06-0.64), boys: 0.35, 95% CI (0.03-0.68)). Girls conceived after FET had significantly higher systolic BP (SDS) and heart rate compared with girls conceived after fresh-ET (adjusted mean difference: systolic BP (SDS): 0.25 SDS, 95% CI (0.03-0.47), heart rate: 4.53, 95% CI (0.94-8.13)). Regarding lipid profile, no significant differences were found between the three groups of girls. For the boys, no significant differences were found for BP and heart rate. Lipid profiles were more favourable in boys born after FET compared with both boys conceived after fresh-ET and NC. All outcomes were adjusted for parity, maternal BMI at early pregnancy, smoking during pregnancy, educational level, birthweight, breastfeeding, child age at examination, and onset of puberty. LIMITATIONS REASONS FOR CAUTION: The participation rate varied from 18 to 42% in the three groups, and therefore selection bias cannot be excluded. However, extensive non-participant analyses were performed that showed almost no differences in background characteristics between participants and non-participants in the three groups, making selection bias less likely. WIDER IMPLICATIONS OF THE FINDINGS: The higher birthweight in children conceived after FET was associated with increased systolic BP (SDS) and heart rate in girls conceived after FET compared with fresh-ET. This may be an early indicator of compromised long-term cardiovascular health in this group. The study was not powered to investigate these outcomes and further studies are therefore warranted to confirm the findings. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Forskningsfond. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Girls with idiopathic central precocious puberty did not display substatial changes in body mass index after treatment with gonadotropin-releasing hormone analogues.

AIM: To evaluate changes in body mass index (BMI) in girls during and after treatment for idiopathic central precocious puberty (iCPP). METHODS: We studied 123 girls receiving gonadotropin-releasing hormone analogue (GnRHa)treatment for iCPP from 2009 to 2019. Pubertal and anthropometric measurements were monitored at routine clinical visits. BMI standard deviation scores (SDS) were estimated at baseline and followed in two stages from baseline to end of treatment (median 18.9 months) and from end of treatment to end of follow-up (median 18.2 months). The influence of baseline BMI SDS and the frequency and dose of treatment was evaluated using BMI trajectories and latent class mixed models. RESULTS: The median age at treatment initiation was 8.5 years. The median BMI SDS at baseline was 0.7, corresponding to a median BMI of 17.4 kg/m2. Overall, no changes in BMI SDS were observed during treatment. According to baseline BMI subgroups, an increasing trend in BMI trajectories during treatment was observed for girls in the lowest BMI group. After treatment, most girls maintained stable BMI levels. CONCLUSION: Our retrospective study did not provide evidence that GnRHa treatment for iCPP had a significant impact on BMI trajectories in girls.

MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch.

The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC directly regulates enhancer activity to promote cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNA polymerase II (RNAPII), rather than regulating RNAPII pause-release, as is the case at promoters. This process is mediated by MYC-induced H3K9 demethylation and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. We propose that MYC drives prognostic cancer type-specific gene programs through induction of an enhancer-specific epigenetic switch, which can be targeted by BET and GCN5 inhibitors.

Pancreas-related persisting sequelae in ALL survivors with a history of asparaginase-associated pancreatitis: A part of the ALL-STAR study.

OBJECTIVES: Asparaginase-associated pancreatitis (AAP) occurs in up to 18% of patients treated for acute lymphoblastic leukemia (ALL); however, long-term sequelae are largely unexplored. We aimed to explore pancreatic sequelae among ALL survivors with and without AAP. METHODS: We investigated pancreatic sequelae in a national cohort of ALL survivors, aged 1-45 years at ALL diagnosis treated according to the NOPHO-ALL2008 protocol and included sex- and age-matched community controls. RESULTS: We included 368 survivors (median follow-up 6.9 years), including 47 survivors with AAP and 369 controls. The p-lipase and p-pancreas-type amylase levels were lower in AAP survivors compared with both non-AAP survivors (Medians: 23 U/L [IQR 14-32] and 18 U/L [IQR 10-25] versus 29 [IQR 24-35] and 22 [17-28], p < .001 and p = .002) and community controls (28 U/L [IQR 22-33] and 21 U/L [IQR 17-26], both p < .006). Fecal-elastase was more frequently reduced in AAP survivors compared with non-AAP survivors (7/31 vs. 4/144, p = .001). Persisting pancreatic sequelae were found in 15/47 of AAP survivors and 20/323 of non-AAP survivors (p < .001), including diabetes mellitus in 2/39 of AAP survivors and 2/273 of non-AAP survivors. CONCLUSIONS: ALL survivors with AAP are at increased risk of persisting pancreatic dysfunction and require special attention during follow-up.

Differentiation of Idiopathic Central Precocious Puberty From Premature Thelarche Using Principal Component Analysis.

CONTEXT: Nonprogressive premature thelarche (PT) is a self-limiting variant of early puberty, while idiopathic central precocious puberty (ICPP) is a disorder that causes progressive development of secondary sexual characteristics and often requires treatment. The diagnostic differentiation between these conditions is important but can be challenging since they often both initially present clinically with isolated breast development. OBJECTIVE: To describe relevant clinical variables in a large cohort of girls referred for early puberty, and to evaluate clinical and biochemical parameters to distinguish between girls with ICPP and PT. METHODS: This retrospective study included 1361 girls referred with signs of early puberty to a single, tertiary center from 2009 to 2019. We evaluated clinical presentation, medical history, growth velocity, bone age, hormonal serum concentrations, and gonadotropin-releasing hormone (GnRH) test results. RESULTS: Central precocious puberty was diagnosed in 11% (ICPP: n = 143, organic CPP: n = 11) girls, whereas 8% (n = 91 girls) presented with PT. Receiver operating characteristic (ROC) analysis showed several biochemical and anthropometric markers as potential parameters to differentiate between ICPP and PT; however, none were individually adequate. Principal component analysis (PCA)-derived clinical and hormone profiles could predict girls with ICPP from girls with PT with a specificity of 90% and sensitivity of 84%, outperforming any single marker. CONCLUSION: Differentiation of girls with ICPP and PT can be supported by individual clinical and biochemical parameters. However, dimension reduction of clinical and hormonal profiles by PCA improved the diagnostic value, which in the future may support the diagnostic process as a supplement to the GnRH test in evaluation of pubertal disorders.

Cardiovascular autonomic nervous function in children conceived by assisted reproductive technology with frozen or fresh embryo transfer.

As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had ∼17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; ∼22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and ∼37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases.NEW & NOTEWORTHY We observed that children conceived by assisted reproductive technology (both frozen and fresh embryo transfer) had lowered heart rate variability during rest as compared with children conceived naturally. During physiological stress maneuvers, however, the cardiovascular autonomic nervous regulation was comparable between children conceived by assisted reproductive technologies and naturally. Our findings highlight the potential that lowered heart rate variability during rest in children conceived by assisted reproductive technologies may precede premature hypertension.

Virtual patients in undergraduate psychiatry education: a systematic review and synthesis.

Virtual patients are increasingly used in undergraduate psychiatry education. This article reports on a systematic review aimed at providing an overview of different approaches in this context, describing their effectiveness, and thematically comparing learning outcomes across different undergraduate programs. The authors searched PubMed, PsycInfo, CINAHL, and Scopus databases for articles published between 2000 and January 2021. Quantitative and qualitative studies that reported on outcomes related to learners' knowledge, skills, and attitudes following an intervention with virtual patients in undergraduate psychiatry education were reviewed. Outcomes were thematically compared, and a narrative synthesis of the different outcomes and effectiveness was provided. Of 7856 records identified, 240 articles were retrieved for full-text review and 46 articles met all inclusion criteria. There were four broad types of virtual patient interventions: case-based presentation (n = 17), interactive virtual patient scenarios (n = 14), standardized virtual patients (n = 10), and virtual patient videogames (n = 5). The thematic analysis revealed that virtual patients in psychiatry education have been used for learners to construe knowledge about symptomatology and psychopathology, develop interpersonal and clinical communicative skills, and to increase self-efficacy and decrease stigmatizing attitudes towards psychiatric patients. In comparison with no intervention, traditional teaching, and text-based interventions, virtual patients were associated with higher learning outcomes. However, the results did not indicate any superiority of virtual patients over non-technological simulation. Virtual patients in psychiatry education offer opportunities for students from different health disciplines to build knowledge, practice skills, and improve their attitudes towards individuals with mental illness. The article discusses methodological shortcomings in the reviewed literature. Future interventions should consider the mediating effects of the quality of the learning environment, psychological safety, and level of authenticity of the simulation.

The effect of clinical guidelines on the utilisation of radiographs in chiropractic clinics in Denmark - an interrupted time series analysis.

BACKGROUND: In Denmark, chiropractors have a statutory right to use radiography and the government-funded national Health Insurance provides partial reimbursement. Danish National Clinical Guidelines recommends against routine use of imaging for uncomplicated spinal pain; however, it is not clear if clinical imaging guidelines recommendations have had an effect on the utilisation of spinal radiography. This study aimed to describe the utilisation rate of radiographs in Danish chiropractic clinics in the period from 2010 to 2020 and to assess the impact of clinical guidelines and policy changes on the utilisation of radiographs in Danish chiropractic clinics. METHODS: Anonymised data from January 1st, 2010, to December 31st, 2020, were extracted from the Danish Regions register on health contacts in primary care. Data consisted of the total number of patients consulting one of 254 chiropractic clinics and the total number of patients having or being referred for radiography. Data were used to investigate the radiography utilisation per month from 2010 to 2020. An 'interrupted time series' analysis was conducted to determine if two interventions, the dissemination of 1) Danish clinical imaging guidelines recommendations and policy changes related to referral for advanced imaging for chiropractors in 2013 and 2) four Danish clinical guidelines recommendations in 2016, were associated with an immediate change in the level and/or slope of radiography utilisation. RESULTS: In total, 336,128 unique patients consulted a chiropractor in 2010 of which 55,449 (15.4%) had radiography. In 2020, the number of patients consulting a chiropractor had increased to 366,732 of which 29,244 (8.0%) had radiography. The pre-intervention utilisation decreased by two radiographs per 10,000 patients per month. Little absolute change, but still statistically significant for Intervention 1, in the utilisation was found after the dissemination of the clinical guidelines and policy changes in 2013 or 2016. CONCLUSIONS: The proportion of Danish chiropractic patients undergoing radiography was halved in the period from 2010 to 2020. However, the dissemination of clinical imaging guidelines recommendations and policy changes related to referrals for advanced imaging showed little meaningful change in the monthly utilisation of radiographs in the same period.

Mapping Mammalian 3D Genome Interactions with Micro-C-XL.

Three-dimensional (3D) chromosome organization is a major factor in genome regulation and cell-type specification. For example, cis-regulatory elements, known as enhancers, are thought to regulate the activity of distal promoters via interaction in 3D space. Genome-wide chromosome conformation capture (3C)-technologies, such as Hi-C, have transformed our understanding of how genomes are organized in cells. The current understanding of 3D genome organization is limited by the resolution with which the topological organization of chromosomes in 3D space can be resolved. Micro-C-XL measures chromosome folding with resolution at the level of the nucleosome, the basic unit of chromatin, by utilizing micrococcal nuclease (MNase) to fragment genomes during the chromosome conformation capture protocol. This results in an improved signal-to-noise ratio in the measurements, thus facilitating the better detection of insulation sites and chromosome loops compared to other genome-wide 3D technologies. A visually supported, detailed, step-by-step protocol for preparing high-quality Micro-C-XL samples from mammalian cells is presented in this article.

Similar improvements in patient-reported outcomes for non-specific low back pain patients with and without lumbar spinal stenosis symptoms following a structured education and exercise therapy program.

BACKGROUND: People with nonspecific low back pain (NSLBP) can also experience overlapping symptoms of lumbar spinal stenosis (LSS), but the impact on treatment outcomes is unknown. This study investigated differences in treatment outcomes for disability, back pain intensity, and leg pain intensity following an education and exercise therapy program for NSLBP patients with and without comorbid LSS symptoms. METHODS: This was a longitudinal analysis of 655 Danish participants in the GLA:D® Back program; an education and exercise therapy program for people with persistent NSLBP. Participants were classified as having comorbid LSS symptoms based on self-report. Linear mixed models were used to assess differences in change in disability (Oswestry Disability Index [0-100]) and back and leg pain intensity (Numeric Rating Scale [0-10]) at 3-, 6-, and 12-months between those with and without LSS symptoms. RESULTS: 28% of participants reported LSS symptoms. No certain differences in change in disability or back pain intensity improvement were observed at any time-point between those with and without LSS symptoms. Participants with LSS symptoms had slightly greater improvement in leg pain intensity at 6- (-0.7, 95% CI -1.2 to -0.2) and 12-months (-0.6, 95% CI -1.2 to -0.1). CONCLUSION: Compared to those without LSS symptoms, patients with persistent NSLBP and LSS symptoms can expect similar improvements in disability and back pain intensity, and slightly greater improvements in leg pain intensity with treatment. Therefore, education and exercise therapy programs designed for NSLBP are likely helpful for those also experiencing LSS symptoms.

The association between cervical degenerative MRI findings and self-reported neck pain, disability and headache: a cross-sectional exploratory study.

BACKGROUND: Neck pain and headache are highly prevalent conditions and leading causes of disability worldwide. Although MRI is widely used in the management of these conditions, there is uncertainty about the clinical significance of cervical MRI findings in patients with neck pain or headache. Therefore, this study aims to investigate the association between cervical degenerative MRI findings and self-reported neck pain, neck disability, and headache. METHODS: This study was a secondary analysis of a cohort of patients with low back pain aged 18-40 years recruited from a non-surgical outpatient spine clinic. The cervical MRI and outcome measures used in this analysis were collected at a four-year follow-up (2014-2017). Self-reported outcome measures included neck pain intensity, neck disability as measured by the Neck Disability Index, and headache as measured by a single NDI item. Cervical MRI findings included disc degeneration, disc contour changes, and vertebral endplate signal changes (VESC). Multivariable logistic regression analyses, adjusted for age and sex, were used to analyse the associations between MRI findings and neck pain, neck disability, and headache. RESULTS: A total of 600 participants who underwent MRI and completed the relevant questionnaires at follow-up were included. The median age was 37 years (interquartile range 31-41) and 325 (54%) were female. Of the included participants, 181 (31%) had moderate or severe neck pain, 274 (59%) had moderate or severe neck disability, 193 (42%) reported headaches, and 211 (35%) had one or more cervical degenerative MRI findings. Cervical disc degeneration and disc contour changes were positively associated with moderate or severe neck pain with odds ratio 1.6 (95% CI 1.1-2.4) and 1.6 (1.1-2.3), respectively. VESC was associated with moderate or severe neck disability with odds ratio 3.3 (1.3-8.4). No statistically significant associations were found between the MRI findings assessed and headache. CONCLUSIONS: In this cross-sectional exploratory study, we found that cervical disc degeneration and disc contour changes were associated with neck pain, and VESC was associated with neck disability. None of the MRI findings were associated with headache. The results suggest that cervical degenerative changes may contribute to the aetiology of neck symptoms, but the associations are modest and cannot guide clinical decisions.

Body Mass Index Trajectories in Children Exposed to Gestational Diabetes in Utero: A Nationwide Register-based Study.

CONTEXT: Children exposed to gestational diabetes mellitus (GDM) in utero are at high risk of developing overweight and obesity, but their postnatal growth trajectories and risk profiles remain unclear. OBJECTIVE: We aimed to identify distinct body mass index (BMI) trajectories from birth to 10 years of age in children exposed to GDM and to explore their associations with infant and maternal characteristics. METHODS: This nationwide cohort study linked data from Danish registries on 15 509 children exposed to GDM in utero, born in Denmark from January 2008 to October 2019. We applied latent class trajectory modeling to identify distinct BMI trajectories. Associations of BMI trajectories with infant and maternal characteristics were analyzed using multiple linear regression. RESULTS: We identified 3 distinct BMI trajectories characterized by a "normal" (60%), a "late accelerating" (28%) and an "early accelerating" (12%) BMI trajectory, the 2 latter at risk of overweight and obesity, respectively, at age 10 years, relative to World Health Organization child growth standards. Children in the "late accelerating" BMI trajectory were more often born large for gestational age (P < .001). More children in the "early accelerating" BMI trajectory were boys, born small for gestational age, and had mothers with a higher pre-pregnancy BMI compared to the other groups (P < .001). CONCLUSION: Children exposed to GDM in utero differ widely in their BMI trajectory. The detection of risk profiles based on early BMI growth and infant and maternal characteristics provides an opportunity for future targeted care and prevention.

Surgical trends and regional variation in Danish patients diagnosed with lumbar spinal stenosis between 2002 and 2018: a retrospective registry-based study of 83,783 patients.

BACKGROUND: Lumbar spinal stenosis (LSS) is the most common reason for spine surgery in older people. However, surgery rates vary widely both internationally and nationally. This study compared patient and sociodemographic characteristics, geographical location and comorbidity between surgically and non-surgically treated Danish patients diagnosed with LSS from 2002 to 2018 and described variations over time. METHODS: Diagnostic ICD-10 codes identifying patients with LSS and surgical procedure codes for decompression with or without fusion were retrieved from the Danish National Patient Register. Patients ≥ 18 years who had been admitted to private or public hospitals in Denmark between 2002 and 2018 were included. Data on age, sex, income, retirement status, geographical region and comorbidity were extracted. A multivariable logistic regression model was used to calculate the relative risk for surgically versus non-surgically treated LSS patients using the total population and subsequently divided into three time periods. Variations over time were displayed graphically. RESULTS: A total of 83,783 unique patients with an LSS diagnosis were identified, and of these, 38,362 (46%) underwent decompression surgery. Compared to those who did not receive surgery, the surgically treated patients were more likely to be aged 65-74 years, were less likely to have comorbidities, had higher income and were more likely to reside in the northern part of Denmark. Patients aged 65-74 years remained more likely to receive surgery over time, although the difference between age groups eventually diminished, as older patients (aged ≥ 75) were increasingly more likely to undergo surgery. Large variations and differences in the relative risk of surgery were observed within and between the geographical regions. The likelihood of receiving surgery varied up to threefold between regions. CONCLUSION: Danish patients with LSS who receive surgery differ in a number of respects from those not receiving surgery. Patients aged 65 to 74 years were more likely to receive surgery than other age groups, and LSS surgical patients were healthier, more often retired and had higher incomes than those not undergoing surgery. There were considerable variations in the relative risk of surgery between and within geographical regions.

Dynamic switching of transcriptional regulators between two distinct low-mobility chromatin states.

How chromatin dynamics relate to transcriptional activity remains poorly understood. Using single-molecule tracking, coupled with machine learning, we show that histone H2B and multiple chromatin-bound transcriptional regulators display two distinct low-mobility states. Ligand activation results in a marked increase in the propensity of steroid receptors to bind in the lowest-mobility state. Mutational analysis revealed that interactions with chromatin in the lowest-mobility state require an intact DNA binding domain and oligomerization domains. These states are not spatially separated as previously believed, but individual H2B and bound-TF molecules can dynamically switch between them on time scales of seconds. Single bound-TF molecules with different mobilities exhibit different dwell time distributions, suggesting that the mobility of TFs is intimately coupled with their binding dynamics. Together, our results identify two unique and distinct low-mobility states that appear to represent common pathways for transcription activation in mammalian cells.

Childhood BMI after ART with frozen embryo transfer.

STUDY QUESTION: Does BMI at 7-10 years of age differ in children conceived after frozen embryo transfer (FET) compared to children conceived after fresh embryo transfer (fresh-ET) or natural conception (NC)? SUMMARY ANSWER: BMI in childhood does not differ between children conceived after FET compared to children conceived after fresh-ET or NC. WHAT IS KNOWN ALREADY: High childhood BMI is strongly associated with obesity and cardiometabolic disease and mortality in adulthood. Children conceived after FET have a higher risk of being born large for gestational age (LGA) than children conceived after NC. It is well-documented that being born LGA is associated with an increased risk of obesity in childhood, and it has been hypothesized that ART induces epigenetic variations around fertilization, implantation, and early embryonic stages, which influence fetal size at birth as well as BMI and health later in life. STUDY DESIGN, SIZE, DURATION: The study 'Health in Childhood following Assisted Reproductive Technology' (HiCART) is a large retrospective cohort study with 606 singletons aged 7-10 years divided into three groups according to mode of conception: FET (n = 200), fresh-ET (n = 203), and NC (n = 203). All children were born in Eastern Denmark from 2009 to 2013 and the study was conducted from January 2019 to September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We anticipated that the participation rate would differ between the three study groups owing to variation in the motivation to engage. To reach the goal of 200 children in each group, we invited 478 in the FET-group, 661 in the fresh-ET-group, and 1175 in the NC-group. The children underwent clinical examinations including anthropometric measurements, whole-body dual-energy x-ray absorptiometry-scan, and pubertal staging. Standard deviation scores (SDS) were calculated for all anthropometric measurements using Danish reference values. Parents completed a questionnaire regarding the pregnancy and the current health of the child and themselves. Maternal, obstetric, and neonatal data were obtained from the Danish IVF Registry and Danish Medical Birth Registry. MAIN RESULTS AND THE ROLE OF CHANCE: As expected, children conceived after FET had a significantly higher birthweight (SDS) compared to both children born after fresh-ET (mean difference 0.42, 95% CI (0.21; 0.62)) and NC (mean difference 0.35, 95% CI (0.14; 0.57)). At follow-up (7-10 years), no differences were found in BMI (SDS) comparing FET to fresh-ET, FET to NC, and fresh-ET to NC. Similar results were also found regarding the secondary outcomes weight (SDS), height (SDS), sitting height, waist circumference, hip circumference, fat, and fat percentage. In the multivariate linear regression analyses, the effect of mode of conception remained non-significant after adjusting for multiple confounders. When stratified on sex, weight (SDS), and height (SDS) were significantly higher for girls born after FET compared to girls born after NC. Further, FET-girls also had significantly higher waist, hip, and fat measurements compared to girls born after fresh-ET. However, for the boys the differences remained insignificant after confounder adjustment. LIMITATIONS, REASONS FOR CAUTION: The sample size was decided in order to detect a difference of 0.3 SDS in childhood BMI (which corresponds to an adult cardiovascular mortality hazard ratio of 1.034). Thus, smaller differences in BMI SDS may be overlooked. As the overall participation rate was 26% (FET: 41%, fresh-ET: 31%, NC: 18%), selection bias cannot be excluded. Regarding the three study groups, many possible confounders have been included but there might be a small risk of selection bias as information regarding cause of infertility is not available in this study. WIDER IMPLICATIONS OF THE FINDINGS: The increased birthweight in children conceived after FET did not translate into differences in BMI, however, for the girls born after FET, we observed increased height (SDS) and weight (SDS) compared to the girls born after NC, while for the boys the results remained insignificant after confounder adjustment. Since body composition in childhood is a strong biomarker of cardiometabolic disease later in life, longitudinal studies of girls and boys born after FET are needed. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Novo Nordisk Foundation (grant number: NNF18OC0034092, NFF19OC0054340) and Rigshospitalets Research Foundation. There were no competing interests. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03719703.

Knocking on Doors - How Healthcare Workers Informally Develop Expertise in Biomedical and Health Informatics.

With digital systems permeating the healthcare sector, the healthcare workforce (clinical and administrative) need insight in biomedical health informatics (BMHI) to some degree. This study shows how novices in BMHI had to knock hard on several doors to find and become part of a community of practice to gain such expertise within BMHI. While it may be generally understood that gaining access to expertise is important, our findings suggest that more attention is needed to how such access is gained. The study exemplifies that the needed skills and competencies are difficult to identify in the individual projects and are highly situated - not least because it requires access to various experts in communities of practices. Therefore, there is a continued need to reframe the necessary education and training. Knowing when to knock on doors, which doors to knock on, and keeping doors open is central to becoming - and keep on being - a part of a community of practice centring on health information technology and BMHI.

Patient expectations and levels of satisfaction in chiropractic treatment for lumbar radiculopathy. A mixed methods study.

BACKGROUND: Chiropractic patients are generally satisfied with the care received. It is unclear if this also applies to Danish patients with lumbar radiculopathy included in a standardised chiropractic care package (SCCP). This study aimed to investigate patient satisfaction and explore perspectives on the SCCP for lumbar radiculopathy. METHODS: An explanatory sequential mixed methods design with three separate phases was used. Phase one was a quantitative analysis based on a survey in a prospective cohort of patients with lumbar radiculopathy in an SCCP from 2018 to 2020. Patients rated their satisfaction with the examination, information, treatment effect, and overall management of their problem on a 0-10 scale. In phase two, six semi-structured interviews conducted in 2021 were used to gain further explanatory insights into the findings from phase one. Data were analysed using systematic text condensation. In phase three, the quantitative and qualitative data were merged in a narrative joint display to obtain a deeper understanding of the overall results. RESULTS: Of 303 eligible patients, 238 responded to the survey. Of these, 80-90% were very satisfied (≥ 8) when asked about the examination, information, and overall management, whereas 50% were very satisfied with the treatment effect. The qualitative analysis led to the emergence of four themes: 'Understanding the standardised care packages', 'Expectations regarding consultation and treatment effect', 'Information about diagnosis and prognosis', and 'Interdisciplinary collaboration'. The joint display analysis showed that high patient satisfaction with the examination could be explained by the patients' feeling of being carefully and thoroughly examined by the chiropractor and by referrals to MRI. Advice and information given to patients on variations in symptoms and the expected prognosis were considered reassuring. Satisfaction with the chiropractor's coordination of care and with referral to other healthcare professionals was explained by the patients' positive experiences of coordinated care and their sense of alleviated responsibility. CONCLUSION: Overall, patients were satisfied with the SCCP for lumbar radiculopathy. From a patient's perspective, the consultation should include a thorough examination and a focus on communication and information relating to symptoms and prognosis, while expectations regarding the content and efficacy of the treatment should be addressed and aligned.