The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease.

Truncating genetic variants of SORL1, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in SORL1 are missense variants, for which it is complicated to determine the pathogenicity level because carriers come from pedigrees too small to be informative for penetrance estimations. Here, we describe three unrelated families in which the SORL1 coding missense variant rs772677709, that leads to a p.Y1816C substitution, segregates with Alzheimer's disease. Further, we investigate the effect of SORLA p.Y1816C on receptor maturation, cellular localization, and trafficking in cell-based assays. Under physiological circumstances, SORLA dimerizes within the endosome, allowing retromer-dependent trafficking from the endosome to the cell surface, where the luminal part is shed into the extracellular space (sSORLA). Our results showed that the p.Y1816C mutant impairs SORLA homodimerization in the endosome, leading to decreased trafficking to the cell surface and less sSORLA shedding. These trafficking defects of the mutant receptor can be rescued by the expression of the SORLA 3Fn-minireceptor. Finally, we find that iPSC-derived neurons with the engineered p.Y1816C mutation have enlarged endosomes, a defining cytopathology of AD. Our studies provide genetic as well as functional evidence that the SORL1 p.Y1816C variant is causal for AD. The partial penetrance of the mutation suggests this mutation should be considered in clinical genetic screening of multiplex early-onset AD families.

SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment.

SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.

Epitope mapping of nanobodies binding the Alzheimer's disease receptor SORLA.

Reduced levels of the Sortilin-related receptor with A-type repeats (SORLA) in different brain regions as well as in the cerebrospinal fluid have been associated with Alzheimer's disease. Methods and reagents to develop reliable detection assays to quantify SORLA and its specific isoforms are therefore much needed. Nanobodies (Nbs) are unique biomolecules derived from the blood of camelids that display advantageous physicochemical and antigen affinity properties, making them attractive tools with great relevance to both diagnostic and therapeutic applications. Here, we purified and characterized eight Nbs that were isolated from the blood of an alpaca immunized with the recombinant extracellular domain of SORLA. The selected Nbs showed high affinity to SORLA in the low nanomolar range as observed by surface plasmon resonance. For mapping of the Nbs' epitopes within the antigen, we transiently transfected HEK293 cells with a panel of SORLA deletion constructs, and developed a protocol of immunostaining by applying fluorescent dye conjugated Nbs. With this method, we showed that the selected Nbs specifically recognize a part of SORLA containing Fibronectin-type III domains, representing promising tools not only for disease clarifying research, but also for translational medicine as candidates for clinical diagnostic purposes.

Breast cancer, breast cancer-directed radiation therapy and risk of hypothyroidism: A systematic review and meta-analysis.

OBJECTIVE: Breast cancer and breast cancer-directed radiation therapy (RT) may increase the risk of late effects, such as hypothyroidism. We conducted a systematic review and meta-analysis to investigate the association between breast cancer, RT, and risk of hypothyroidism in breast cancer survivors. METHODS: Through February 2022, we searched PubMed, EMBASE, and references of relevant articles, to identify papers on breast cancer and breast cancer-directed RT and subsequent risk of hypothyroidism. Articles were screened by title and abstract and reviewed for eligibility. We used a pre-formed data extraction sheet and identified key design elements that could potentially introduce bias. The main outcome was the confounder-adjusted relative risk (RR) of hypothyroidism in breast cancer survivors versus women without breast cancer, and in breast cancer survivors according to the receipt of RT to the supraclavicular lymph nodes. We used a random-effects model to calculate pooled RRs and associated 95% confidence intervals (95% CI). RESULTS: From 951 papers screened by title and abstract, 34 full-text papers were reviewed for eligibility. We included 20 studies published between 1985 and 2021-19 were cohort studies. Compared with women without breast cancer, the pooled RR of hypothyroidism in breast cancer survivors was 1.48 (95% CI: 1.17, 1.87), with highest risk associated with RT to the supraclavicular region (RR = 1.69, 95% CI: 1.16, 2.46). The most important limitations of the studies were small sample size yielding estimates with low precision, and lack of data on potential confounders. CONCLUSION: Breast cancer and radiation therapy to the supraclavicular lymph nodes is associated with an increased risk of hypothyroidism.

Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer.

SORL1, the gene encoding the large multidomain SORLA protein, has emerged as only the fourth gene that when mutated can by itself cause Alzheimer's disease (AD), and as a gene reliably linked to both the early- and late-onset forms of the disease. SORLA is known to interact with the endosomal trafficking regulatory complex called retromer in regulating the recycling of endosomal cargo, including the amyloid precursor protein (APP) and the glutamate receptor GluA1. Nevertheless, SORLA's precise structural-functional relationship in endosomal recycling tubules remains unknown. Here, we address these outstanding questions by relying on crystallographic and artificial-intelligence evidence to generate a structural model for how SORLA folds and fits into retromer-positive endosomal tubules, where it is found to dimerize via both SORLA's fibronectin-type-III (3Fn)- and VPS10p-domains. Moreover, we identify a SORLA fragment comprising the 3Fn-, transmembrane, and cytoplasmic domains that has the capacity to form a dimer, and to enhance retromer-dependent recycling of APP by decreasing its amyloidogenic processing. Collectively, these observations generate a model for how SORLA dimer (and possibly polymer) formation can function in stabilizing and enhancing retromer function at endosome tubules. These findings can inform investigation of the many AD-associated SORL1 variants for evidence of pathogenicity and can guide discovery of novel drugs for the disease.

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.

The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%-3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of ß-amyloid (Aß) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD.

Accreditation and clinical outcomes: shorter length of stay after first-time hospital accreditation in the Faroe Islands.

BACKGROUND: The aim of accreditation is to improve quality of care and patient safety. However, studies on the effectiveness of accreditation on clinical outcomes are limited and inconsistent. Comparative studies have contrasted accredited with non-accredited hospitals or hospitals without a benchmark, but assessments of clinical outcomes of patients treated at hospitals undergoing accreditation are sparse. The Faroe Islands hospitals were accredited for the first time in 2017, making them an ideal place to study the impact of accreditation. OBJECTIVE: We aimed to investigate the association between first-time hospital accreditation and length of stay (LOS), acute readmission (AR) and 30-day mortality in the unique situation of the Faroe Islands. METHODS: We conducted a before and after study based on medical record reviews in relation to first-time accreditation. All three Faroese hospitals were voluntarily accredited using a modified second version of the Danish Healthcare Quality Programme encompassing 76 standards. We included inpatients 18 years or older treated at a Faroese hospital with one of six clinical conditions (stroke/transient ischemic attack (TIA), bleeding gastic ulcer, chronic obstructive pulmonary disease (COPD), childbirth, heart failure and hip fracture) in 2012-2013 designated 'before accreditation'or 2017-2018' after accreditation'. The main outcome measures were LOS, all-cause AR and all-cause 30-day mortality. We computed adjusted cause-specific hazard rate (HR) ratios using Cox Proportional Hazard regression with before accreditation as reference. The analyses were controlled for age, sex, cohabitant status, in-hospital rehabilitation, type of admission, diagnosis and cluster effect at patient and hospital levels. RESULTS: The mean LOS was 13.4 days [95% confidence interval (95% CI): 10.8, 15.9] before accreditation and 7.5 days (95% CI: 6.10, 8.89) after accreditation. LOS of patients hospitalized after accreditation was significantly shorter [overall, adjusted HR = 1.23 (95% CI: 1.04, 1.46)]. By medical condition, only women in childbirth had a significantly shorter LOS [adjusted HR = 1.30 (95% CI: 1.04, 1.62)]. In total, 12.3% of inpatients before and 9.5% after accreditation were readmitted acutely within 30 days of discharge, and 30-day mortality was 3.3% among inpatients before and 2.8% after accreditation, respectively. No associations were found overall or by medical condition for AR [overall, adjusted HR = 1.34 (95% CI: 0.82, 2.18)] or 30-day mortality [overall, adjusted HR = 1.33 (95% CI: 0.55, 3.21)]) after adjustment for potential confounding factors. CONCLUSION: First-time hospital accreditation in the Faroe Islands was associated with a significant reduction in LOS, especially of women in childbirth. Notably, shorter LOS was not followed by increased AR. There was no evidence that first-time accreditation lowered the risk of AR or 30-day mortality.

Patients experience more support, information and involvement after first-time hospital accreditation: a before and after study in the Faroe Islands.

BACKGROUND: The impact of hospital accreditation on the experiences of patients remains a weak point in quality improvement research. This is surprising given the time and cost of accreditation and the fact that patient experiences influence outcomes. We investigated the impact of first-time hospital accreditation on patients' experience of support from health-care professionals, information and involvement in decisions. OBJECTIVE: We aimed to examine the association between first-time hospital accreditation and patient experiences. METHODS: We conducted a longitudinal study in the three Faroese hospitals that, unlike hospitals on the Danish mainland and elsewhere internationally, had no prior exposure to systematic quality improvement. The hospitals were accredited in 2017 according to a modified second version of the Danish Healthcare Quality program. Study participants were 18 years or older and hospitalized for at least 24 h in 2016 before or 2018 after accreditation. We administered the National Danish Survey of Patient Experiences for acute and scheduled hospitalization. Patients rated their experiences of support, information and involvement in decision-making on a 5-point Likert scale. We calculated individual and grouped mean item scores, the percentages of scores ≥4, the mean score difference, the relative risk (RR) for high/very high scores (≥4) using Poisson regression and the risk difference. Patient experience ratings were compared using mixed effects linear regression. RESULTS: In total, 400 patients before and 400 after accreditation completed the survey. After accreditation patients reported increased support from health professionals; adjusted mean score difference (adj. mean diff.) = 1.99 (95% confidence interval (CI): 1.89, 2.10), feeling better informed before and during the hospitalization; adj. mean diff. = 1.14 (95% CI: 1.07; 1.20) and more involved in decision-making; adj. mean diff. = 1.79 (95% CI: 1.76; 1.82). Additionally, the RR for a high/very high score (≥4) was significantly greater on 15 of the 16 questionnaire items. The greatest RR for a high/very high score (≥4) after accreditation, was found for the item 'Have you had a dialogue with the staff about the advantages and disadvantages of the examination/treatment options available?'; RR= 5.73 (95% CI: 4.51, 7.27). CONCLUSION: Hospitalized patients experienced significantly more support from health professionals, information and involvement in decision-making after accreditation. Future research on accreditation should include the patients' perspective.

The association between first-time accreditation and the delivery of recommended care: a before and after study in the Faroe Islands.

BACKGROUND: Significant resources are spent on hospital accreditation worldwide. However, documentation of the effects of accreditation on processes, quality of care and outcomes in healthcare remain scarce. This study aimed to examine changes in the delivery of patient care in accordance with clinical guidelines (recommended care) after first-time accreditation in a care setting not previously exposed to systematic quality improvement initiatives. METHODS: We conducted a before and after study based on medical record reviews in connection with introducing first-time accreditation. We included patients with stroke/transient ischemic attack, bleeding gastric ulcer, diabetes, chronic obstructive pulmonary disease (COPD), childbirth, heart failure and hip fracture treated at public, non-psychiatric Faroese hospitals during 2012-2013 (before accreditation) or 2017-2018 (after accreditation). The intervention was the implementation of a modified second version of The Danish Healthcare Quality Program (DDKM) from 2014 to 2016 including an on-site accreditation survey in the Faroese hospitals. Recommended care was assessed using 63 disease specific patient level process performance measures in seven clinical conditions. We calculated the fulfillment and changes in the opportunity-based composite score and the all-or-none score. RESULTS: We included 867 patient pathways (536 before and 331 after). After accreditation, the total opportunity-based composite score was marginally higher though the change did not reach statistical significance (adjusted percentage point difference (%): 4.4%; 95% CI: - 0.7 to 9.6). At disease level, patients with stroke/transient ischemic attack, bleeding gastric ulcer, COPD and childbirth received a higher proportion of recommended care after accreditation. No difference was found for heart failure and diabetes. Hip fracture received less recommended care after accreditation. The total all-or-none score, which is the probability of a patient receiving all recommended care, was significantly higher after accreditation (adjusted relative risk (RR): 2.32; 95% CI: 2.03 to 2.67). The improvement was particularly strong for patients with COPD (RR: 16.22; 95% CI: 14.54 to 18.10). CONCLUSION: Hospitals were in general more likely to provide recommended care after first-time accreditation.

COpenhagen Neuroplastic TRaining Against Contractures in Toddlers (CONTRACT): protocol of an open-label randomised clinical trial with blinded assessment for prevention of contractures in infants with high risk of cerebral palsy.

INTRODUCTION: Contractures are frequent causes of reduced mobility in children with cerebral palsy (CP) already at the age of 2-3 years. Reduced muscle use and muscle growth have been suggested as key factors in the development of contractures, suggesting that effective early prevention may have to involve stimuli that can facilitate muscle growth before the age of 1 year. The present study protocol was developed to assess the effectiveness of an early multicomponent intervention, CONTRACT, involving family-oriented and supervised home-based training, diet and electrical muscle stimulation directed at facilitating muscle growth and thus reduce the risk of contractures in children at high risk of CP compared with standard care. METHODS AND ANALYSIS: A two-group, parallel, open-label randomised clinical trial with blinded assessment (n=50) will be conducted. Infants diagnosed with CP or designated at high risk of CP based on abnormal neuroimaging or absent fidgety movement determined as part of General Movement Assessment, age 9-17 weeks corrected age (CA) will be recruited. A balanced 1:1 randomisation will be made by a computer. The intervention will last for 6 months aiming to support parents in providing daily individualised, goal-directed activities and primarily in lower legs that may stimulate their child to move more and increase muscle growth. Guidance and education of the parents regarding the nutritional benefits of docosahexaenic acid (DHA) and vitamin D for the developing brain and muscle growth will be provided. Infants will receive DHA drops as nutritional supplements and neuromuscular stimulation to facilitate muscle growth. The control group will receive standard care as offered by their local hospital or community. Outcome measures will be taken at 9, 12, 18, 24, 36 and 48 months CA. Primary and secondary outcome measure will be lower leg muscle volume and stiffness of the triceps surae musculotendinous unit together with infant motor profile, respectively. ETHICS AND DISSEMINATION: Full approval from the local ethics committee, Danish Committee System on Health Research Ethics, Region H (H-19041562). Experimental procedures conform with the Declaration of Helsinki. TRIAL REGISTRATION NUMBER: NCT04250454. EXPECTED RECRUITMENT PERIOD: 1 January 2021-1 January 2025.

Impact of fate properties, groundwater fluctuations and the presence of worm burrows on pesticide leaching assessments through golf areas.

The risk of pesticide leaching from recreational areas such as golf course turfs is not distinguished in a regulative framework within the EU where the focus is on agricultural soils. But with increasing popularity of golf, and thus, increasing number of golf courses leading to potentially increasing use of pesticides, understanding the processes determining pesticide leaching are critical to ensure optimal quality of both groundwater and golf turf. This study input the measured variation in fate properties of tebuconazole (TBZ) and MCPA as pure active ingredients and commercial products in simulations with realistic hydrological conceptualizations to investigate their implication in leaching assessments. Scenarios with (i) fluctuating and fixed groundwater levels and (ii) preferential flows including fluctuating and fixed groundwater levels were evaluated. The results showed that mobile MCPA leached in higher concentrations by a factor of 1.3 with fluctuating groundwater levels than with fixed groundwater levels. When preferential flow paths were incorporated in the models, the leaching was substantial for MCPA regardless of its formulation as active ingredient or commercial product, while in multiple simulations without preferential pathways there was no leaching of MCPA. Compared to MCPA leaching without preferential flow paths, the leaching concentrations increased up to a factor of 13.9 when preferential flows were included. With preferential flow paths, the increase in leaching concentration from fixed groundwater levels to fluctuating groundwater levels was up to a factor of 2.3 depending on the formulation of MCPA. This study demonstrated that it is imperative to assess fate parameters in the topsoil of golf courses and consider realistic groundwater BC (boundary condition) and the presence of preferential flow paths to obtain representative pesticide leaching risk assessments.

Effectiveness and safety of oral anticoagulation treatment beyond 1 year after venous thromboembolism in patients at intermediate recurrence risk.

Effectiveness and safety of long-term anticoagulation treatment are uncertain in venous thromboembolism (VTE) patients at intermediate risk of recurrence. We examined the association between treatment beyond 1 year and outcomes in a Danish nationwide register-based study. VTE patients at intermediate risk of recurrence, that is, non-cancer patients with a first-time unprovoked VTE, who started oral anticoagulation treatment within 30 days and were alive 365 days after the index VTE were included and followed between 2007 and 2015. Exposure was extended (>365 days) or intermediate (91-365 days) treatment. Analyses were done using Cox regression on a propensity score weighted population. We included 18 609 patients with 7232 (38.9%) receiving extended treatment. Mean duration of follow-up was 2.6 years. Compared with intermediate treatment, treatment beyond 365 days was associated with a lower weighted risk of recurrent VTE (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.49-0.65) and all-cause mortality (HR 0.81, 95% CI 0.72-0.90) and an increased risk of major bleeding (HR 1.87, 95% CI 1.58-2.22). In conclusion, extended anticoagulation treatment (predominantly warfarin) beyond 1 year was in real-life settings associated with a lower risk of recurrent VTE and all-cause mortality among VTE patients with an intermediate risk of recurrence. However, an increased bleeding risk should be considered.

Finger orthoses for management of joint hypermobility disorders: Relative effects on hand function and cognitive load.

BACKGROUND: Joint hypermobility refers to joints that move beyond their normal limits. Individuals with hypermobility of the fingers experience difficulties in activities of daily living. Finger orthoses are available for managing hypermobility of the fingers, but their effectiveness has received little attention in scholarly literature. OBJECTIVES: To determine if use of custom fit finger orthoses leads to improvements in time needed to perform standardised hand function tests, and attentional demand required to perform these tests, in individuals with joint hypermobility syndrome, Hypermobile Ehlers-Danlos syndrome or Classical Ehlers-Danlos syndrome. STUDY DESIGN: Repeated-measures study. METHODS: Fourteen participants performed three different hand function tests (target box and block test, writing and picking up coins), with and without their finger orthoses. Time to complete each test was recorded as a measure of functional performance. Brain activity was recorded in the pre-frontal cortices as a measure of attentional demand. RESULTS: Functional performance significantly improved for all but one test (picking up coins with non-dominant hand) when participants wore finger orthoses (p < 0.05). Activity in the pre-frontal cortex was lower when using the orthosis to perform the coin test (dominant hand; p < 0.05). No differences were observed in other tests (p > 0.05). CONCLUSIONS: Results suggested that finger orthoses improved hand function and provided limited evidence to suggest that they may also affect attentional demand. While the limited sample does not provide conclusive evidence supporting the use of finger orthosis in this clinical population, results warrant further investigation in large scale longitudinal studies or randomised controlled trials.

Consecutive cycles of accreditation and quality of in-hospital care: a Danish population-based study.

BACKGROUND: Little is known about whether repeated cycles of hospital accreditation are a robust method to improve quality of care continuously. OBJECTIVE: We aimed to examine the association between compliance with consecutive cycles of accreditation and quality of in-hospital care. METHODS: We conducted a Danish nationwide population-based study including patients aged 18 years treated for acute stroke, chronic obstructive pulmonary disease, diabetes, heart failure or hip fracture at public, non-psychiatric hospitals. From 2012 to 2015, two cycles of national hospital accreditation were completed, resulting in 12 high and 14 low compliant hospitals (Low = partially accredited in both cycles). Our outcome measure was quality of in-hospital care measured by 39 process performance measures (PPMs), reflecting recommendations from the national clinical guidelines by adherence to (i) individual PPMs and (ii) the full bundle of PPMs (all-or-none). We computed adjusted odds ratios (ORs) using logistic regression based on robust standard error estimation for cluster sampling of data at hospital level. RESULTS: In total, 78 387 patient pathways covering 508 816 processes were included, of which 47% had been delivered at high compliant hospitals and 53% at low compliant hospitals, respectively. Compliance with consecutive cycles was not associated with improved quality of in-hospital care (individual: OR = 0.92, 95% confidence interval (CI): 0.77-1.10; All-or-none: OR = 0.87, 95% CI: 0.66-1.15). However, in the second cycle alone, patients treated at partially accredited hospitals had a lower adherence than patients treated at fully accredited hospitals (Individual: OR = 0.84, 95% CI: 0.71-0.99; All-or-none: OR = 0.78, 95% CI: 0.59-1.03). The association was particularly strong among patients treated at partially accredited hospitals required to submit additional documentation. CONCLUSION: Compliance with consecutive cycles of hospital accreditation in Denmark was not associated with improved quality of in-hospital care. However, compliance with the second cycle alone was associated with improved quality of in-hospital care.

Expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with Alzheimer's disease.

SORL1 is strongly associated with both sporadic and familial forms of Alzheimer's disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl. A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.

Safety of High-Volume Plasmapheresis in Children With Acute Liver Failure.

OBJECTIVES: Paediatric acute liver failure (P-ALF) is a rare condition and is associated with a high mortality rate. Management of P-ALF aims to stabilise vital organ functions and to remove circulating toxins and provide vital plasma factors that are lacking. High-volume plasmapheresis (HVP) removes protein-bound substances and improves survival in adult ALF. It is unknown if this effect can be extrapolated to P-ALF. The aim of this study is to report the safety and feasibility of HVP in P-ALF. METHODS: Children with P-ALF were offered HVP if bilirubin was higher than 200 µmol/L or if the aetiology was toxic hepatitis. HVP was performed with fresh frozen plasma corresponding to 10% of the body weight on a minimum of 3 consecutive days. Diagnostics, biochemical and clinical data during HVP as well as outcome data after 3 months were collected from 2012 to 2019 and retrospectively analysed. RESULTS: Sixteen children were treated by HVP and completed at least one series of three treatment sessions with HVP. The only complication seen was an increase in pH > 7.55 in three children within the first 12 hours and was corrected with hydrochloric acid. No bleeding or septic episodes were noted during HVP. Eight children survived without liver transplantation, two survived after successful grafting and a total of six children died. The liver injury unit score between survivors with their own liver and the rest, the two groups was significantly different (P = 0.005). CONCLUSION: HVP with fresh frozen plasma is feasible and well tolerated in children with P-ALF. No serious adverse events and no procedure-related mortality were observed.

[Malignant pertussis in a three-week-old girl].

Whooping cough is an infectious disease caused by Bordetella pertussis. Particularly children under the age of six months can be severely affected by the infection. Severe leukocytosis may lead to thrombosis and pulmonary hypertension and eventually circulatory failure and death. This a case report of a three-week-old girl with malignant pertussis, who due to respiratory insufficiency was mechanically ventilated, and her severe leucocytosis was treated with exchange blood transfusion. Whooping cough may partially be prevented with efficient vaccination programmes.

Patient-related healthcare disparities in the quality of acute hip fracture care: a 10-year nationwide population-based cohort study.

OBJECTIVES: To characterise and quantify possible patient-related disparities in hip fracture care including temporal changes. DESIGN: Population-based cohort study. SETTING: All Danish hospitals treating patients with hip fracture. PARTICIPANTS: 60 275 hip fracture patients from 2007 to 2016. INTERVENTIONS: Quality of care was defined as fulfilment of eligible care process measures for the individual patient recommended by an expert panel. Using yearly logistic regression models, we predicted the individual patient's probability for receiving high-quality care, resulting in a distribution of adjusted probabilities based on age, sex, comorbidity, fracture type, education, family mean income, migration status, cohabitation status, employment status, nursing home residence and type of municipality. Based on the distribution, we identified best-off patients (ie, the 10% of patients with the highest probability) and worst-off patients (ie, the 10% of patients with the lowest probability). We evaluated disparities in quality of care by measuring the distance in fulfilment of outcomes between the best-off and worst-off patients. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was fulfilment of all-or-none, defined as receiving all relevant process measures. Secondary outcomes were fulfilment of the individual process measures including preoperative optimisation, early surgery, early mobilisation, assessment of pain, basic mobility, nutritional risk and need for antiosteoporotic medication, fall prevention and a postdischarge rehabilitation programme. RESULTS: The proportion of patients receiving high-quality care varied over time for both best-off and worst-off patients. The absolute difference in percentage points between the best-off and worst-off patients for receiving all-or-none of the eligible process measures was 12 (95% CI 6 to 18) in 2007 and 23 (95% CI 19 to 28) in 2016. Disparities were consistent for a range of care processes, including assessment of pain, mobilisation within 24 hours, assessment of need for antiosteoporotic medication and nutritional risk assessment. CONCLUSIONS: Disparity of care between best-off and worst-off patients remained substantial over time.

Incidence of hypothyroidism after treatment for breast cancer-a Danish matched cohort study.

BACKGROUND: Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment. METHODS: Using nationwide registries, we identified all Danish women aged ≥ 35 years diagnosed with non-metastatic breast cancer (1996-2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities. RESULTS: We included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls [5-year cumulative incidence, 1.8% (95%CI = 1.7-1.9) and 1.6% (95%CI = 1.5-1.6), respectively]. The overall IR was 4.45 (95%CI = 4.25-4.67) and 3.81 (95%CI = 3.73-3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11-1.24). BCS who received RTn with chemotherapy (HR = 1.74, 95%CI = 1.50-2.02) or without chemotherapy (HR = 1.31, 95%CI = 1.14-1.51) had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone [HR = 1.71, 95%CI = 1.45-2.01 and HR = 1.36, 95%CI = 1.17-1.58, respectively]. CONCLUSIONS: BCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy.

Hypothyroidism and the risk of breast cancer recurrence and all-cause mortality - a Danish population-based study.

BACKGROUND: Hypothyroidism may occur as a late effect of breast cancer-directed treatment, particularly after radiotherapy, but little is known whether hypothyroidism affects the prognosis after breast cancer. We investigated the association between hypothyroidism and breast cancer recurrence, and all-cause mortality. METHODS: In this population-based cohort study, we used national medical registries to identify all Danish women 35 years or older diagnosed with stage I-III, operable breast cancer between 1996 and 2009. Hypothyroidism was defined as hospital diagnoses ascertained via diagnostic codes, or as prescriptions for levothyroxine. Two analytic models were used: (i) hypothyroidism present at the time of the breast cancer diagnosis (prevalent) and (ii) hypothyroidism diagnosed during follow-up as a time-varying exposure lagged by 1 year (incident). Breast cancer recurrence was defined as any local, regional, or distant recurrence or contralateral breast cancer. All-cause mortality included death from any cause in any setting. We used Cox regression models accounting for competing risks to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer recurrence and all-cause mortality. RESULTS: The study cohort included 35,463 women with breast cancer with 212,641 person-years of follow-up. At diagnosis, 1272 women had hypothyroidism and 859 women developed hypothyroidism during follow-up. In total, 5810 patients developed recurrent breast cancer. Neither prevalent nor incident hypothyroidism was associated with breast cancer recurrence (adjusted HRprevalent 1.01, 95% CI 0.87-1.19; adjusted HRincident 0.93, 95% CI 0.75-1.16, respectively). Furthermore, no differences were seen for all-cause mortality for prevalent or incident hypothyroidism (adjusted HRprevalent 1.02, 95% CI 0.92-1.14, and HRincident 1.08, 95% CI 0.95-1.23, respectively). Stratification by menopausal status, oestrogen receptor status, chemotherapy, or radiotherapy did not alter the estimates. CONCLUSIONS: Hypothyroidism present at diagnosis or during follow-up was not associated with breast cancer recurrence or all-cause mortality in women with breast cancer. Our findings provide reassurance to patients and their physicians that hypothyroidism is unlikely to impact on the clinical course of breast cancer or survival.