Return to work in persons with persistent postconcussion symptoms: a survey study examining the perspectives of employees and managers.

OBJECTIVE: To examine challenges in return to work (RTW) for persons with persistent postconcussion symptoms (PPCS) experienced by the affected employees and their managers. METHODS: A survey of employees (S-E) and two surveys of managers (S-M1, S-M2) executed 4 months apart to capture the time perspective. Inclusion: Adults aged 18-66 with PPCS > 4 weeks, employed at the time of mTBI who returned to work within the previous year. Managers involved in their RTW process. OUTCOME MEASURES: Work status, working hours, work functioning (Work Role Functioning Questionnaire, WRFQ), work productivity. RESULTS: Ninety-two employees and 66 managers were recruited. Three-fourths of the employees had returned to work but only one-third worked under similar conditions. Weekly working hours decreased from 36,3 hours (SD = 10,5) before mTBI to 17,6 hours (SD = 9,7). Employees had difficulties with tasks 43% of time (WRFQ). They needed more breaks, struggled with multitasking and work speed. About 65.9% experienced affected work productivity. Managers reported lack of knowledge and difficulties assessing the number of working hours and suitable tasks. CONCLUSIONS: Most employees returned to work but only a minority worked under similar conditions as before mTBI. Employees and managers struggled to estimate workload. The affected employees and their workplaces need a long-term RTW support.

Long-term stroke risk in Moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) is considered a progressive disease with an ongoing risk of recurrent stroke. However, there is a lack of long-term observational data to quantify the extent of the stroke risk. METHODS: This study aimed to provide insight into the long-term stroke risk in MMD and explore possible risk factors for stroke. Records from all patients diagnosed with MMD in 13 clinical departments from 6 different Danish hospitals between 1994 and 2017 were retrospectively reviewed until 2021. RESULTS: The cohort comprised 50 patients (33 females and 17 males). Patients were followed up for a median of 9.4 years, with more than 10 years of follow-up for 24 patients. Ten patients had 11 new stroke events-6 ischemic strokes and 5 brain hemorrhages. Events occurred at a median of 7 years and up to 25 years after diagnosis. The overall Kaplan-Meier 5-year stroke risk was 10%. Patients with bypass performed had significantly fewer events than conservatively treated patients (HR 0.25, 95% confidence interval (CI) 0.07-0.91, p < 0.05). All but one event occurred in females, a difference that reached statistical significance. CONCLUSIONS: The study provides data on the extent of the risk of recurrent stroke in MMD. Bypass surgery patients had fewer stroke events than those treated conservatively. There was a trend toward a higher stroke risk in females. DATA ACCESS STATEMENT: The data supporting this study's findings are available from the corresponding author upon reasonable request.

Whole-genome RNA sequencing identifies distinct transcriptomic profiles in impingement cartilage between patients with femoroacetabular impingement and hip osteoarthritis.

Femoroacetabular impingement (FAI) has a strong clinical association with the development of hip osteoarthritis (OA); however, the pathobiological mechanisms underlying the transition from focal impingement to global joint degeneration remain poorly understood. The purpose of this study is to use whole-genome RNA sequencing to identify and subsequently validate differentially expressed genes (DEGs) in femoral head articular cartilage samples from patients with FAI and hip OA secondary to FAI. Thirty-seven patients were included in the study with whole-genome RNA sequencing performed on 10 gender-matched patients in the FAI and OA cohorts and the remaining specimens were used for validation analyses. We identified a total of 3531 DEGs between the FAI and OA cohorts with multiple targets for genes implicated in canonical OA pathways. Quantitative reverse transcription-polymerase chain reaction validation confirmed increased expression of FGF18 and WNT16 in the FAI samples, while there was increased expression of MMP13 and ADAMTS4 in the OA samples. Expression levels of FGF18 and WNT16 were also higher in FAI samples with mild cartilage damage compared to FAI samples with severe cartilage damage or OA cartilage. Our study further expands the knowledge regarding distinct genetic reprogramming in the cartilage between FAI and hip OA patients. We independently validated the results of the sequencing analysis and found increased expression of anabolic markers in patients with FAI and minimal histologic cartilage damage, suggesting that anabolic signaling may be increased in early FAI with a transition to catabolic and inflammatory gene expression as FAI progresses towards more severe hip OA. Clinical significance:Cam-type FAI has a strong clinical association with hip OA; however, the cellular pathophysiology of disease progression remains poorly understood. Several previous studies have demonstrated increased expression of inflammatory markers in FAI cartilage samples, suggesting the involvement of these inflammatory pathways in the disease progression. Our study further expands the knowledge regarding distinct genetic reprogramming in the cartilage between FAI and hip OA patients. In addition to differences in inflammatory gene expression, we also identified differential expression in multiple pathways involved in hip OA progression.

Ultrasonographic features of the endometrium following successful medical termination of early pregnancy.

OBJECTIVE: Ultrasonographic features of the endometrium are often assessed when deciding the necessity of surgical intervention following early medical abortion. Knowledge is therefore needed on the ultrasonographic appearance of the endometrium following successful medical abortion in order to avoid unnecessary surgical interventions. We aimed to assess endometrial thickness and echogenicity at multiple time points following successful early medical abortion. STUDY DESIGN: We conducted a retrospective study in the largest office-based abortion providing clinic in Denmark. Using archived ultrasonographic images, we assessed endometrial thickness and echogenicity following all early medical abortions that did not need surgical intervention or repeated medication for completion during the years 2014-2017. RESULTS: Ultrasonographic endometrial features were assessed 1854 times following 1074 early medical abortions. Median endometrial thickness in the 1st week from induction was 13 milimeters (mm; lower-upper quartile 11-17 mm). For the 2nd, 3rd, 4th, and >4th week, the median endometrial thickness was found to be 11 mm (9-15 mm), 11 mm (8-14 mm), 12 mm (9-16 mm), and 11 mm (8-14 mm), respectively. Of the ultrasonographic examinations performed in the 1st week from medical induction, 24.7 % showed a heterogenous endometrium. For 2nd, 3rd, 4th, >4th week, the frequency of heterogeneity was 23.9 %, 16.3 %, 21.3 %, 18.9 %, respectively. A total of 151 abortions (14.1 %) were each examined three times, median time of examination being day 7, 15, and 26 following induction. Among these abortions, the three most common patterns of change in endometrial thickness were "decreasing" (37.7 %), "increasing-decreasing" (23.2 %), and "decreasing-increasing" (21.9 %). Further, 49.7 % of the 151 abortions showed a homogenous endometrium at all three examinations, 17.2 % showed a heterogenous endometrium at first examination and a homogenous endometrium the following two examinations, and 9.9 % showed a heterogenous endometrium at the first two examinations followed by a homogenous endometrium. CONCLUSION: In early medical abortions completed without secondary intervention, endometrial thickness and echogenicity varied clinically significantly for weeks following the medical induction. Every possible pattern of change in endometrial thickness and echogenicity was observed.

Comparison of Reptilian Genomes Reveals Deletions Associated with the Natural Loss of γδ T Cells in Squamates.

T lymphocytes or T cells are key components of the vertebrate response to pathogens and cancer. There are two T cell classes based on their TCRs, αß T cells and γδ T cells, and each plays a critical role in immune responses. The squamate reptiles may be unique among the vertebrate lineages by lacking an entire class of T cells, the γδ T cells. In this study, we investigated the basis of the loss of the γδ T cells in squamates. The genome and transcriptome of a sleepy lizard, the skink Tiliqua rugosa, were compared with those of tuatara, Sphenodon punctatus, the last living member of the Rhynchocephalian reptiles. We demonstrate that the lack of TCRγ and TCRδ transcripts in the skink are due to large deletions in the T. rugosa genome. We also show that tuataras are on a growing list of species, including sharks, frogs, birds, alligators, and platypus, that can use an atypical TCRδ that appears to be a chimera of a TCR chain with an Ab-like Ag-binding domain. Tuatara represents the nearest living relative to squamates that retain γδ T cells. The loss of γδTCR in the skink is due to genomic deletions that appear to be conserved in other squamates. The genes encoding the αßTCR chains in the skink do not appear to have increased in complexity to compensate for the loss of γδ T cells.

Endoscopic treatment of primary aorto-enteric fistulas: A case report and review of literature.

BACKGROUND: Primary aorto-enteric fistula (PAEF) is a rare condition, traditionally treated in the acute, bleeding phase with open surgery or endovascular repair. However, these approaches have high morbidity and mortality, indicating a need for new methods. With advances in endoscopic techniques and equipment, haemoclipping of fistulas has now become feasible. Therefore, we present a systematic review of the English literature and a rare case of a PAEF successfully treated by endoscopic haemoclipping. CASE SUMMARY: A 74-year-old man with an abdominal aortic aneurysm presented with symptoms of haemorrhagic shock and bloody stools. An oesophago-gastro-duodenoscopy was performed with haemoclipping of a suspected PAEF in the third part of the duodenum. Afterward, a computed tomography-angiography showed a contrast filled protrusion from the abdominal aortic aneurysm. Based on the clinical presentation and the combined endoscopic and radiographic findings, we argue that this is a case of a PAEF. CONCLUSION: Endoscopic therapy appears capable of achieving haemodynamic stabilisation in patients with bleeding PAEF, serving as a bridge to final therapy.

Developmental and comparative immunology single-cell transcriptome analysis of the B-cell repertoire reveals the usage of immunoglobulins in the gray short-tailed opossum (Monodelphis domestica).

B-cells are key to humoral immunity, are found in multiple lymphoid organs, and have the unique ability to mediate the production of antigen-specific antibodies in the presence of pathogens. The marsupial immunoglobulin (Ig) heavy (H) chain locus encodes four constant region isotypes, IgA, IgG, IgM and IgE, but no IgD, and there are two light (L) chain isotypes, lambda (Igλ) and kappa (Igκ). To gain an understanding of the marsupial humoral immune system, B-cell transcriptomes generated by single-cell RNA sequencing from gray short-tailed opossum (Monodelphis domestica) splenocytes, and peripheral blood mononuclear cells were analysed. The cells used were from a single unimmunized animal and the majority of B-cells were transcribing IgM heavy chains. The ratio of Ig light chain use was roughly 2:1, Igλ:Igκ in this individual. This was not predicted due to Igκ being the more complex of the two L chain loci. The variable (V) gene segment pairs used in individual B-cells confirm greater diversity provided by the L chain V. This study is the first to report on using single cell analysis to investigate Ig repertoires in a marsupial and confirms a number of prior hypothesis, as well as revealing some surprises.

Alemtuzumab treatment in Denmark: A national study based on the Danish Multiple Sclerosis Registry.

OBJECTIVE: To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark. METHODS: Data were retrieved from The Danish Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits. RESULTS: A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab (p < 0.001). The annual number of relapses was reduced by 69% in year 4 compared with the year prior alemtuzumab. More active disease before alemtuzumab increased the annual hazard rate for relapse (HR: 2.88, p < 0.001). The Expanded Disability Status Scale (EDSS) score remained stable or improved in 81% of patients after 2 years. The need for an additional treatment course was associated with higher number of relapses in the year before alemtuzumab (odds ratio (OR) = 1.95, p = 0.001). CONCLUSION: In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.

The molecular assembly of the marsupial γµ T cell receptor defines a third T cell lineage.

αß and γδ T cell receptors (TCRs) are highly diverse antigen receptors that define two evolutionarily conserved T cell lineages. We describe a population of γµTCRs found exclusively in non-eutherian mammals that consist of a two-domain (Vγ-Cγ) γ-chain paired to a three-domain (Vµ-Vµj-Cµ) µ-chain. γµTCRs were characterized by restricted diversity in the Vγ and Vµj domains and a highly diverse unpaired Vµ domain. Crystal structures of two distinct γµTCRs revealed the structural basis of the association of the γµTCR heterodimer. The Vµ domain shared the characteristics of a single-domain antibody within which the hypervariable CDR3µ loop suggests a major antigen recognition determinant. We define here the molecular basis underpinning the assembly of a third TCR lineage, the γµTCR.

The effects of tributyrin supplementation on weight gain and intestinal gene expression in broiler chickens during Eimeria maxima-induced coccidiosis.

Butyrate is a feed additive that has been shown to have antibacterial properties and improve gut health in broilers. Here, we examined the performance and gene expression changes in the ileum of tributyrin-supplemented broilers infected with coccidia. Ninety-six, Ross 708 broilers were fed either a control corn-soybean-based diet (-BE) or a diet supplemented with 0.25% (w/w) tributyrin (+BE). Birds were further divided into groups that were inoculated with Eimeria maxima oocysts (EM) or sham-inoculated (C) on day 21 posthatch. At 7 d postinfection (7 d PI), the peak of pathology in E. maxima infection, tributyrin-supplemented birds had significantly improved feed conversion ratios (FCR, P < 0.05) and body weight gain (BWG, P < 0.05) compared with -BE-infected birds, despite both groups having similar feed intake (FI, P > 0.05). However, at 10 d post-infection (10 d PI) no significant effects of feed type or infection were observed. Gene expression in the ileum was examined for insights into possible effects of infection and tributyrin supplementation on genes encoding proteins related to immunity, digestion, and gut barrier integrity. Among immune-related genes examined, IL-1B and LEAP2 were only significantly affected at 7 d PI. Transcription of genes related to digestion (APN, MCT1, FABP2, and MUC2) were primarily influenced by infection at 7 d PI and tributyrin supplementation (FABP2 and MUC2) at 10 d PI. With exception of ZO1, tight junction genes were affected by either infection or feed type at 7 d PI. At 10 d PI, only CLDN1 was not affected by either infection or feed type. Overall tributyrin shows promise as a supplement to improve performance during coccidiosis in broiler chickens; however, its effect on gene expression and mode of action requires further research.

Initial high-efficacy disease-modifying therapy in multiple sclerosis: A nationwide cohort study.

OBJECTIVE: To determine the effectiveness of high-efficacy disease-modifying therapies (heDMTs) vs medium-efficacy disease-modifying therapies (meDMT) as the first treatment choice in treatment-naive patients with multiple sclerosis (MS) on disability worsening and relapses. We assessed this using a nationwide population-based MS registry. METHODS: We identified all patients starting a heDMT as first-time treatment from the Danish Multiple Sclerosis Registry and compared treatment outcomes with a propensity score matched sample of patients starting meDMT. RESULTS: We included 388 patients in the study: 194 starting initial therapy with heDMT matched to 194 patients starting meDMT. At 4 years of follow-up, the probabilities of a 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening were 16.7% (95% confidence interval [CI] 10.4%-23.0%) and 30.1% (95% CI 23.1%-37.1%) for heDMT and meDMT initiators, respectively (hazard ratio [HR] 0.53, 95% CI 0.33-0.83, p = 0.006). Patients initiating heDMT also had a lower probability of a first relapse (HR 0.50, 95% CI 0.37-0.67). Results were similar after pairwise censoring and in subgroups with high baseline activity, diagnosis after 2006, or information on baseline T2 lesion load. CONCLUSION: We found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.

Uterine epithelial remodelling during pregnancy in the marsupial Monodelphis domestica (Didelphidae): Implications for mammalian placental evolution.

Mammalian pregnancy involves remodelling of the uterine epithelium to enable placentation. In marsupials, such remodelling has probably played a key role in the transition from ancestral invasive placentation to non-invasive placentation. Identifying uterine alterations that are unique to marsupials with non-invasive placentation can thus elucidate mechanisms of marsupial placental evolution. We identified apical alterations to uterine epithelial cells prior to implantation in Monodelphis domestica, a member of the least derived living marsupial clade (Didelphidae) with invasive (endotheliochorial) placentation. We then compared these traits with those of Macropus eugenii (Macropodidae) and Trichosurus vulpecula (Phalangeridae), both with non-invasive placentation, to identify which alterations to the uterine epithelium are ancestral and which facilitate secondarily evolved non-invasive placentation. In M. domestica, remodelling of the uterine epithelium involves reduced cellular heterogeneity and development of uterodome-like cells, suggesting that similar alterations may also have occurred in the marsupial common ancestor. These alterations also overlap with those of both T. vulpecula and Ma. eugenii, suggesting that the placental shift from invasive to non-invasive placentation in marsupials involves essential, conserved characteristics, irrespective of placental mode. However, unique apical alterations of both T. vulpecula and Ma. eugenii, relative to M. domestica, imply that lineage-specific alterations underpin the evolutionary shift to non-invasive placentation in marsupials.

Evidence for regulation of the complement system during pregnancy being ancient and conserved in mammals.

Here we demonstrate that regulation of the Complement (C') components of the immune system is an ancient and conserved feature of mammalian pregnancy. Transcript levels were reduced for complement components C3 and C4 throughout pregnancy in a marsupial, Monodelphis domestica. Downstream C' component transcripts were significantly less abundant relative to non-pregnant controls at the start of pregnancy but increased during late pregnancy, in some cases peaking close to parturition. These results are consistent with observations in human pregnancy that deposition of C5 through C9 on fetal membranes is associated with labor and parturition. Complement regulators CD46 and CD59 are present at the fetomaternal interface during M. domestica pregnancy as well, implying regulation of C' effector mechanisms is necessary for maintenance of normal marsupial pregnancy. Collectively these results support regulating the complement system may have contributed to the transition from oviparity to viviparity in mammals over 165 million years ago.

Clinically stable disease is associated with a lower risk of both income loss and disability pension for patients with multiple sclerosis.

OBJECTIVE: To assess the risk of losing income from salaries and risk disability pension for multiple sclerosis patients with a clinically stable disease course 3 years after the start of disease-modifying therapy (DMT). METHODS: Data from the Danish Multiple Sclerosis Registry were linked to other Danish nationwide population-based databases. We included patients who started treatment with a DMT between 2001 and 2014. Patients were categorised into a clinically stable group (No Evidence of Disease Activity (NEDA-2)) and a clinically active group (relapse activity or 6-month confirmed Expanded Disability Status Scale worsening). Outcomes were: (1) loss of regular income from salaries and (2) a transfer payment labelled as disability pension. We used a Cox proportional hazards model to estimate confounder-adjusted HRs, and absolute risks were plotted using cumulative incidence curves accounting for competing risks. RESULTS: We included 2406 patients for the income analyses and 3123 patients for the disability pension analysis. Median follow-up from index date was ~5 years in both analyses. The NEDA-2 group had a 26% reduced rate of losing income (HR 0.74; 95% CI 0.60 to 0.92). HRs were calculated for 5-year intervals in the disability pension analysis: year 0-5: a 57% reduced rate of disability pension for the NEDA-2 group (HR 0.43; 95% CI 0.33 to 0.55) and year 5-10: a 36% reduced rate (HR 0.64; 95% CI 0.40 to 1.01). CONCLUSION: Clinically stable disease course (NEDA-2) is associated with a reduced risk of losing income from salaries and a reduced risk of disability pension.

A 'devil' of a problem.

The discovery of a second facial tumor disease in the Tasmanian devil has provided insights into the emergence of contagious cancers.

A pronounced uterine pro-inflammatory response at parturition is an ancient feature in mammals.

Regulating maternal immunity is necessary for successful human pregnancy. Whether this is needed in mammals with less invasive placentation is subject to debate. Indeed, the short gestation times in marsupials have been hypothesized to be due to a lack of immune regulation during pregnancy. Alternatively, the maternal marsupial immune system may be unstimulated in the absence of a highly invasive placenta. Transcripts encoding pro-inflammatory cytokines were found to be overrepresented in the whole uterine transcriptome at terminal pregnancy in the opossum, Monodelphis domestica To investigate this further, immune gene transcripts were quantified throughout opossum gestation. Transcripts encoding pro-inflammatory cytokines remained relatively low during pre- and peri-attachment pregnancy stages. Levels dramatically increased late in gestation, peaking within 12 h prior to parturition. These results mirror the spike of inflammation seen at eutherian parturition but not at attachment or implantation. Our results are consistent with the role of pro-inflammatory cytokines at parturition being an ancient and conserved birth mechanism in therian mammals.

On the prenatal initiation of T cell development in the opossum Monodelphis domestica.

Thymus-dependent lymphocytes (T cells) are a critical cell lineage in the adaptive immune system of all jawed vertebrates. In eutherian mammals the initiation of T cell development takes place prenatally and the offspring of many species are born relatively immuno-competent. Marsupials, in contrast, are born in a comparatively altricial state and with a less well developed immune system. As such, marsupials are valuable models for studying the peri- and postnatal initiation of immune system development in mammals. Previous results supported a lack of prenatal T cell development in a variety of marsupial species. In the gray short-tailed opossum, Monodelphis domestica, however, there was evidence that αßT cells were present on postnatal day 1 and likely initiated development prenatally. Demonstrated here is the presence of CD3ε+ lymphocytes in late-stage embryos at a site in the upper thoracic cavity, the site of an early developing thymus. CD3ε+ cells were evident as early as 48 h prior to parturition. In day 14 embryos, where there is clear organogenesis, CD3ε+ cells were only found at the site of the early thymus, consistent with no extra-thymic sites of T cell development in the opossum. These observations are the first evidence of prenatal T cell lineage commitment in any marsupial.

Transcriptomic Changes Associated with Pregnancy in a Marsupial, the Gray Short-Tailed Opossum Monodelphis domestica.

Live birth has emerged as a reproductive strategy many times across vertebrate evolution; however, mammals account for the majority of viviparous vertebrates. Marsupials are a mammalian lineage that last shared a common ancestor with eutherians (placental mammals) over 148 million years ago. Marsupials are noted for giving birth to highly altricial young after a short gestation, and represent humans' most distant viviparous mammalian relatives. Here we ask what insight can be gained into the evolution of viviparity in mammals specifically and vertebrates in general by analyzing the global uterine transcriptome in a marsupial. Transcriptome analyses were performed using NextGen sequencing of uterine RNA samples from the gray short-tailed opossum, Monodelphis domestica. Samples were collected from late stage pregnant, virgin, and non-pregnant experienced breeders. Three different algorithms were used to determine differential expression, and results were confirmed by quantitative PCR. Over 900 opossum gene transcripts were found to be significantly more abundant in the pregnant uterus than non-pregnant, and over 1400 less so. Most with increased abundance were genes related to metabolism, immune systems processes, and transport. This is the first study to characterize the transcriptomic differences between pregnant, non-pregnant breeders, and virgin marsupial uteruses and helps to establish a set of pregnancy-associated genes in the opossum. These observations allowed for comparative analyses of the differentially transcribed genes with other mammalian and non-mammalian viviparous species, revealing similarities in pregnancy related gene expression over 300 million years of amniote evolution.

The Evolution and Structure of Atypical T Cell Receptors.

The T cell receptor structure and genetic organization have been thought to have been stable in vertebrate evolution relative to the immunoglobulins. For the most part, this has been true and the content and organization of T cell receptor genes has been fairly conserved over the past 400 million years of gnathostome evolution. Analyses of TCRδ chains in a broad range of vertebrate lineages over the past decade have revealed a remarkable and previously unrealized degree of plasticity. This plasticity can generally be described in two forms. The first is broad use of antibody heavy chain variable genes in place of the conventional Vδ. The second form containing an unusual three extracellular domain structures has evolved independently in both cartilaginous fishes and mammals. Two well-studied vertebrate lineages, the eutherian mammals such as mice and humans and teleost fishes, lack any of these alternative TCR forms, contributing to why they went undiscovered for so long after the initial description of the conventional TCR chains three decades ago. This chapter describes the state of knowledge of these unusual TCR forms, both their structure and genetics, and current ideas on their function.