The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population.

OBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV. METHODS: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively. RESULTS: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. CONCLUSIONS: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects.

Orofacial dysfunction after stroke-A multidisciplinary approach.

OBJECTIVE: This paper describes the study protocol in an ongoing clinical trial evaluating oral screen training as part of a post-stroke rehabilitation programme. Baseline data were related to four domains: dysphagia, lip function, masticatory performance and patient-related outcome measures (PROM). BACKGROUND: Stroke is one of the most common causes of disability-adjusted life years, and dysphagia is a common remaining problem after stroke. Rehabilitation using oral screen training has been suggested to improve swallowing, but evidence is still insufficient. MATERIALS AND METHODS: Patients diagnosed with stroke with persisting objective and/or subjective swallowing dysfunction after primary rehabilitation were assessed for eligibility. In total, 25 patients were included. Objective function was assessed by swallowing capacity test (SCT), lip force and masticatory performance, subjective function by EAT-10 and NOT-S and PROM by LiSat-11 and ESAS. RESULTS: Baseline data presented a heterogeneous pattern with no significant association between objective and subjective dysfunction. Most of the participants (20/25) showed impaired swallowing capacity in SCT, and 23/24 revealed orofacial dysfunction according to NOT-S. The most common subjective item reported was chewing and swallowing problems (19/24). CONCLUSION: The heterogenous findings in the included tests and the lack of correlations emphasise the importance of multidisciplinary approaches to identify objective and subjective orofacial post-stroke dysfunction in clinical practice to be able to offer evidence-based individualised care. The included participants were representative of stroke patients with dysphagia, which supports proceeding with the planned intervention.

Mutations in the CYP27B1 gene cause vitamin D dependent rickets in pugs.

Rickets is a disorder of bone development and can be the result of either dietary or genetic causes. Here, related pugs from 2 litters were included. Three pugs had clinical signs including, lameness, bone deformities, and dyspnea. One other pug was found dead. Radiographs of 2 affected pugs, 5 and 6 months old, showed generalized widening, and irregular margination of the physes of both the appendicular and the axial skeleton with generalized decrease in bone opacity and bulbous swelling of the costochondral junctions. Two pugs had low serum calcium and 1,25 (OH)2 D3 concentrations. Test results further indicated secondary hyperparathyroidism with adequate concentrations of 25-hydroxyvitamin D. Necropsy revealed tongue-like projections of cartilage extending into the metaphysis consistent with rickets, loss of metaphyseal mineralization and lung pathology. Vitamin D-dependent rickets was diagnosed. A truncating mutation in the 1α-hydroxylase gene (CYP27B1) was identified by genome sequence analysis of the pugs with VDDR type 1A. Vitamin D-dependent rickets type 1A can occur in young pugs, and if left untreated is a life-threatening condition. Early medical intervention can reverse clinical signs and should be instituted as soon as possible.

Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis.

OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

Bayesian mixed model analysis uncovered 21 risk loci for chronic kidney disease in boxer dogs.

Chronic kidney disease (CKD) affects 10% of the human population, with only a small fraction genetically defined. CKD is also common in dogs and has been diagnosed in nearly all breeds, but its genetic basis remains unclear. Here, we performed a Bayesian mixed model genome-wide association analysis for canine CKD in a boxer population of 117 canine cases and 137 controls, and identified 21 genetic regions associated with the disease. At the top markers from each CKD region, the cases carried an average of 20.2 risk alleles, significantly higher than controls (15.6 risk alleles). An ANOVA test showed that the 21 CKD regions together explained 57% of CKD phenotypic variation in the population. Based on whole genome sequencing data of 20 boxers, we identified 5,206 variants in LD with the top 50 BayesR markers. Following comparative analysis with human regulatory data, 17 putative regulatory variants were identified and tested with electrophoretic mobility shift assays. In total four variants, three intronic variants from the MAGI2 and GALNT18 genes, and one variant in an intergenic region on chr28, showed alternative binding ability for the risk and protective alleles in kidney cell lines. Many genes from the 21 CKD regions, RELN, MAGI2, FGFR2 and others, have been implicated in human kidney development or disease. The results from this study provide new information that may enlighten the etiology of CKD in both dogs and humans.

Bayesian model and selection signature analyses reveal risk factors for canine atopic dermatitis.

Canine atopic dermatitis is an inflammatory skin disease with clinical similarities to human atopic dermatitis. Several dog breeds are at increased risk for developing this disease but previous genetic associations are poorly defined. To identify additional genetic risk factors for canine atopic dermatitis, we here apply a Bayesian mixture model adapted for mapping complex traits and a cross-population extended haplotype test to search for disease-associated loci and selective sweeps in four dog breeds at risk for atopic dermatitis. We define 15 associated loci and eight candidate regions under selection by comparing cases with controls. One associated locus is syntenic to the major genetic risk locus (Filaggrin locus) in human atopic dermatitis. One selection signal in common type Labrador retriever cases positions across the TBC1D1 gene (body weight) and one signal of selection in working type German shepherd controls overlaps the LRP1B gene (brain), near the KYNU gene (psoriasis). In conclusion, we identify candidate genes, including genes belonging to the same biological pathways across multiple loci, with potential relevance to the pathogenesis of canine atopic dermatitis. The results show genetic similarities between dog and human atopic dermatitis, and future across-species genetic comparisons are hereby further motivated.

Older adults' perspectives on rehabilitation and recovery one year after a hip fracture - a qualitative study.

BACKGROUND: In order to improve quality of care and recovery after hip fracture we need to include the perspectives of the individual older adults when evaluating different rehabilitation interventions. The aim of this study was therefore to explore older adults' experiences of their rehabilitation after a hip fracture and of the recovery process during the 12 months following the fracture. METHODS: Qualitative interviews were conducted with 20 older adults (70-91 years of age) who had participated in a randomised controlled trial evaluating the effects of early discharge followed by geriatric interdisciplinary home rehabilitation compared to in-hospital care according to a multifactorial rehabilitation program. Ten participants from each group were interviewed shortly after the one-year follow-up when the study was completed. Data were analysed with qualitative content analysis. RESULTS: The analysis resulted in four themes: Moving towards recovery with the help of others; Getting to know a new me; Striving for independence despite obstacles; and Adapting to an altered but acceptable life. The participants emphasised the importance of having access to rehabilitation that was provided by skilled staff, and support from family members and friends for well-being and recovery. They experienced a change in their self-image but strove for independence despite struggling with complications and functional limitations and used adaptive strategies to find contentment in their lives. CONCLUSIONS: Rehabilitation interventions provided by competent health care professionals, as well as support from family members and friends, were emphasised as crucial for satisfactory recovery. Participants' experiences further highlight the importance of targeting both physical and psychological impacts after a hip fracture. To improve recovery, rehabilitation providers should customise future interventions to suit each individual´s wishes and needs and provide rehabilitation in various settings throughout the recovery process. TRIAL REGISTRATION: The trial is registered at Current Controlled Trials Ltd, ICRCTN 15738119 . Date of registration 16/06/2008, retrospectively registered.

Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA.

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). METHODS: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. RESULTS: PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs. METHODS: Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case-control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant- and gene-level enrichment analyses, was implemented to explore genotype-phenotype relations. RESULTS: Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle-specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants. CONCLUSION: Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.

Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis.

OBJECTIVES: To further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease. METHODS: High-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined. RESULTS: Twenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2-0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4-3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations. CONCLUSION: Population stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.

The ABCC4 gene is associated with pyometra in golden retriever dogs.

Pyometra is one of the most common diseases in female dogs, presenting as purulent inflammation and bacterial infection of the uterus. On average 20% of intact female dogs are affected before 10 years of age, a proportion that varies greatly between breeds (3-66%). The clear breed predisposition suggests that genetic risk factors are involved in disease development. To identify genetic risk factors associated with the disease, we performed a genome-wide association study (GWAS) in golden retrievers, a breed with increased risk of developing pyometra (risk ratio: 3.3). We applied a mixed model approach comparing 98 cases, and 96 healthy controls and identified an associated locus on chromosome 22 (p = 1.2 × 10-6, passing Bonferroni corrected significance). This locus contained five significantly associated SNPs positioned within introns of the ATP-binding cassette transporter 4 (ABCC4) gene. This gene encodes a transmembrane transporter that is important for prostaglandin transport. Next generation sequencing and genotyping of cases and controls subsequently identified four missense SNPs within the ABCC4 gene. One missense SNP at chr22:45,893,198 (p.Met787Val) showed complete linkage disequilibrium with the associated GWAS SNPs suggesting a potential role in disease development. Another locus on chromosome 18 overlapping the TESMIN gene, is also potentially implicated in the development of the disease.

A novel canine reference genome resolves genomic architecture and uncovers transcript complexity.

We present GSD_1.0, a high-quality domestic dog reference genome with chromosome length scaffolds and contiguity increased 55-fold over CanFam3.1. Annotation with generated and existing long and short read RNA-seq, miRNA-seq and ATAC-seq, revealed that 32.1% of lifted over CanFam3.1 gaps harboured previously hidden functional elements, including promoters, genes and miRNAs in GSD_1.0. A catalogue of canine "dark" regions was made to facilitate mapping rescue. Alignment in these regions is difficult, but we demonstrate that they harbour trait-associated variation. Key genomic regions were completed, including the Dog Leucocyte Antigen (DLA), T Cell Receptor (TCR) and 366 COSMIC cancer genes. 10x linked-read sequencing of 27 dogs (19 breeds) uncovered 22.1 million SNPs, indels and larger structural variants. Subsequent intersection with protein coding genes showed that 1.4% of these could directly influence gene products, and so provide a source of normal or aberrant phenotypic modifications.

Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort.

Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC (n = 765). The selected genes were either from human BC studies (n = 294) or from within canine mammary tumor associated regions (n = 471). A set of predominantly estrogen receptor positive tumors (ER + 85%) and their normal tissue counterparts (n = 61) were sequenced to ~ 140 × and 85 × mean target coverage, respectively. MuTect2 and VarScan2 were employed to detect single nucleotide variants (SNVs) and copy number aberrations (CNAs), while MutSigCV (SNVs) and GISTIC (CNAs) algorithms estimated the significance of recurrent somatic events. The significantly mutated genes (q ≤ 0.01) were PIK3CA (28% of patients), TP53 (21%) and CDH1 (11%). However, histone modifying genes contained the largest number of variants (KMT2C and ARID1A, together 28%). Mutations in KMT2C were mutually exclusive with PI3KCA mutations (p ≤ 0. 001) and half of these affect the formation of a functional PHD domain. The tumor suppressor CDK10 was deleted in 80% of the cohort while the oncogene MDM4 was amplified. Mutational signature analyses pointed towards APOBEC deaminase activity (COSMIC signature 2) and DNA mismatch repair (COSMIC signature 6). We noticed two significantly distinct patterns related to patient age; TP53 being more mutated in the younger group (29% vs 9% of patients) and CDH23 mutations were absent from the older group. The increased somatic mutation prevalence in the histone modifying genes KMT2C and ARID1A distinguishes the Swedish cohort from previous studies. KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age-diverse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.

Geriatric Interdisciplinary Home Rehabilitation After Hip Fracture in People with Dementia - A Subgroup Analysis of a Randomized Controlled Trial.

PURPOSE: To investigate if the effects of geriatric interdisciplinary home rehabilitation after hip fracture were different among people with dementia compared to those without dementia and to describe the overall outcome after hip fracture in people with dementia. PATIENTS AND METHODS: A post hoc subgroup analysis of a randomized controlled trial was conducted including 205 people with hip fracture, aged ≥70, living in ordinary housing or residential care facilities. Early discharge followed by individually designed interdisciplinary home rehabilitation for a maximum of 10 weeks was compared to in-hospital geriatric care according to a multifactorial rehabilitation program. Outcomes were hospital length of stay (LOS), readmissions, falls, mortality, performance in activities of daily living (ADL), and walking ability. RESULTS: Interdisciplinary home rehabilitation vs in-hospital care had comparable effects on falls and mortality between discharge and 12 months and on ADL and walking ability at 3 and 12 months regardless of whether the participants had dementia or not (P≥0.05 for all). Among participants with dementia, postoperative LOS was a median of 18 days (interquartile range [IQR] 14-30) in the home rehabilitation group vs 23 days (IQR 15-30) in the control group (P=0.254) with comparable numbers of readmissions after discharge. Dementia was associated with increased risk of falling (odds ratio [OR] 3.86; 95% confidence interval [CI]: 2.05-7.27; P<0.001) and increased mortality (OR 4.20; 95% CI 1.79-9.92, P=0.001) between discharge and 12 months and with greater dependence in ADL and walking at 3 and 12 months compared to participants without dementia (P<0.001 for all). CONCLUSION: The effects of geriatric interdisciplinary home rehabilitation vs in-hospital geriatric care did not differ in participants with and without dementia. However, the statistical power of this subgroup analysis was likely insufficient to detect differences between the groups. Dementia was associated with a substantial negative impact on the outcomes following the hip fracture. Our findings support offering interdisciplinary home rehabilitation after hip fracture to people with dementia.

Whole-genome genotyping and resequencing reveal the association of a deletion in the complex interferon alpha gene cluster with hypothyroidism in dogs.

BACKGROUND: Hypothyroidism is a common complex endocrinopathy that typically has an autoimmune etiology, and it affects both humans and dogs. Genetic and environmental factors are both known to play important roles in the disease development. In this study, we sought to identify the genetic risk factors potentially involved in the susceptibility to the disease in the high-risk Giant Schnauzer dog breed. RESULTS: By employing genome-wide association followed by fine-mapping (top variant p-value = 5.7 × 10- 6), integrated with whole-genome resequencing and copy number variation analysis, we detected a ~ 8.9 kbp deletion strongly associated (p-value = 0.0001) with protection against development of hypothyroidism. The deletion is located between two predicted Interferon alpha (IFNA) genes and it may eliminate functional elements potentially involved in the transcriptional regulation of these genes. Remarkably, type I IFNs have been extensively associated to human autoimmune hypothyroidism and general autoimmunity. Nonetheless, the extreme genomic complexity of the associated region on CFA11 warrants further long-read sequencing and annotation efforts in order to ascribe functions to the identified deletion and to characterize the canine IFNA gene cluster in more detail. CONCLUSIONS: Our results expand the current knowledge on genetic determinants of canine hypothyroidism by revealing a significant link with the human counterpart disease, potentially translating into better diagnostic tools across species, and may contribute to improved canine breeding strategies.

Effects of Geriatric Interdisciplinary Home Rehabilitation on Independence in Activities of Daily Living in Older People With Hip Fracture: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effects of early discharge followed by geriatric interdisciplinary home rehabilitation for older people with hip fracture on independence in activities of daily living (ADL) compared with inhospital geriatric care according to a multifactorial rehabilitation program. DESIGN: Planned analysis of a randomized controlled trial with 3- and 12-month follow-ups. SETTING: Geriatric ward, ordinary housing, and residential care facilities. PARTICIPANTS: Of 466 people screened for eligibility, participants (N=205) with acute hip fracture, aged 70 years or older, including those with cognitive impairment and those living in residential care facilities, were randomized to intervention or control groups. INTERVENTION: Individually designed interdisciplinary home rehabilitation for a maximum of 10 weeks. The intervention aimed at early hospital discharge and focused on prevention of falls, independence in daily activities, and walking ability indoors and outdoors. MAIN OUTCOME MEASURES: Independence in ADL was measured using the Barthel ADL Index, and the ADL Staircase including the Katz ADL Index during hospital stay (prefracture performance) and at the follow-up visits in the participants' homes. RESULTS: There were no significant differences in ADL performance between the groups, and they recovered their prefracture level of independence in personal and instrumental ADL comparably. At 12 months, 33 (41.3%) in the intervention group vs 33 (41.8%) in the control group (P=.99) had regained or improved their prefracture ADL performance according to the Barthel ADL Index, and 27 (37.0%) vs 36 (48.6%) according to the ADL Staircase (P=.207). CONCLUSIONS: In older people with hip fracture, early discharge followed by geriatric interdisciplinary home rehabilitation resulted in a comparable recovery of independence in ADL at 3 and 12 months as inhospital geriatric care and rehabilitation.

Effects of geriatric interdisciplinary home rehabilitation on complications and readmissions after hip fracture: a randomized controlled trial.

OBJECTIVE:: This pre-planned secondary analysis of geriatric interdisciplinary home rehabilitation, which was initially found to shorten the postoperative length of stay in hospital for older individuals following hip fracture, investigated whether such rehabilitation reduced the numbers of complications, readmissions, and total days spent in hospital after discharge during a 12-month follow-up period compared with conventional geriatric care and rehabilitation. DESIGN:: Randomized controlled trial. SETTING:: Geriatric department, participants' residential care facilities, and ordinary housing. SUBJECTS:: Individuals aged ⩾70 years with acute hip fracture ( n = 205) were included. INTERVENTION:: Geriatric interdisciplinary home rehabilitation was individually designed and aimed at early discharge with the intention to prevent, detect, and treat complications after discharge. MAIN MEASURES:: Complications, readmissions, and days spent in hospital were registered from patients' digital records and interviews conducted during hospitalization and at 3- and 12-month follow-up visits. RESULTS:: No significant difference in outcomes was observed. Between discharge and the 12-month follow-up, among participants in the geriatric interdisciplinary home rehabilitation group ( n = 106) and control group ( n = 93), 57 (53.8%) and 44 (47.3%) had complications ( P = 0.443), 46 (43.4%) and 38 (40.9%) fell ( P = 0.828), and 38 (35.8%) and 27 (29.0%) were readmitted to hospital ( P = 0.383); the median total days spent in hospital were 11.5 and 11.0 ( P = 0.353), respectively. CONCLUSION:: Geriatric interdisciplinary home rehabilitation for older individuals following hip fracture resulted in similar proportions of complications, readmissions, and total days spent in hospital after discharge compared with conventional geriatric care and rehabilitation.

Clinical Effects of a Topically Applied Toll-like Receptor 9 Agonist in Active Moderate-to-Severe Ulcerative Colitis.

BACKGROUND AND AIMS: Toll-like receptors [TLRs] are potential drug targets for immunomodulation. We determined the safety and efficacy of the TLR-9 agonist DNA-based immunomodulatory sequence 0150 [DIMS0150] in ulcerative colitis [UC] patients refractory to standard therapy. METHODS: In this randomized, double-blind, placebo-controlled trial, 131 patients with moderate-to-severe active UC were randomized to receive two single doses of the oligonucleotide DIMS0150 [30 mg] or placebo administered topically during lower GI endoscopy at baseline and Week 4. The primary endpoint was clinical remission, defined as Clinical Activity Index [CAI] ≤4, at Week 12. Secondary endpoints included mucosal healing and symptomatic remission of key patient-reported outcomes [absence of blood in stool and weekly stool frequency <35]. RESULTS: There was no statistical significant difference between the groups in the induction of clinical remission at Week 12, with 44.4% in the DIMS0150 group vs. 46.5% in the placebo group. However, the proportion of patients who achieved symptomatic remission was 32.1% in the DIMS0150 group vs. 14.0% in the placebo group at Week 4 [p = 0.020], and 44.4% vs. 27.9% at Week 8 [p = 0.061]. More patients on DIMS0150 compared with those on placebo had mucosal healing [34.6% vs. 18.6%; p = 0.09] and histological improvement regarding the Geboes score [30.9% vs. 9.3%; p = 0.0073] at Week 4. Significantly more patients on DIMS0150 were in clinical remission with mucosal healing at Week 4: 21% vs. 4.7% in the placebo group [p = 0.02]. DIMS0150 was well tolerated, and no safety signals compared with placebo were evident. CONCLUSIONS: Therapy with the topically applied TLR-9 agonist DIMS0150 is a promising and well-tolerated novel therapeutic option for treatment-refractory, chronic active UC patients, warranting further clinical trials.

Effects of Geriatric Interdisciplinary Home Rehabilitation on Walking Ability and Length of Hospital Stay After Hip Fracture: A Randomized Controlled Trial.

OBJECTIVE: To evaluate if Geriatric Interdisciplinary Home Rehabilitation could improve walking ability for older people with hip fracture compared with conventional geriatric care and rehabilitation. A secondary aim was to investigate the postoperative length of hospital stay (LOS). DESIGN: Randomized controlled trial. SETTING: Geriatric ward, ordinary housing, and residential care facilities. PARTICIPANTS: People operated on for a hip fracture (n = 205), aged 70 or older, including those with cognitive impairment, and living in the north of Sweden. INTERVENTION: Home rehabilitation with the aim of early hospital discharge that was individually designed and carried out by an interdisciplinary team for a maximum of 10 weeks. Special priority was given to prevention of falls, independence in daily activities, and walking ability both indoors and outdoors. MEASUREMENTS: Walking ability and the use of walking device was assessed in an interview during the hospital stay. These assessments were repeated along with gait speed measurements at 3- and 12-month follow-up. The length of the hospital stay after the hip fracture was recorded. RESULTS: No significant differences were observed in walking ability, use of walking device, and gait speed at the 3- and 12-month follow-up between the groups. At 12 months, 56.3% of the intervention group and 57.7% of the control group had regained or improved their prefracture walking ability. The median postoperative LOS in the geriatric ward was 6 days shorter for the intervention group (P = .003). CONCLUSION: Participants receiving Geriatric Interdisciplinary Home Rehabilitation regained walking ability in the short- and long-term similar to those receiving conventional geriatric care and rehabilitation according to a multifactorial rehabilitation program. The intervention group had a significantly shorter postoperative LOS in the hospital.