Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Pulmonary vein dose and risk of atrial fibrillation in patients with non-small cell lung cancer following definitive radiotherapy: An NI-HEART analysis.

BACKGROUND AND PURPOSE: Symptomatic arrhythmia is common following radiotherapy for non-small cell lung cancer (NSCLC), frequently resulting in morbidity and hospitalization. Modern treatment planning technology theoretically allows sparing of cardiac substructures. Atrial fibrillation (AF) comprises the majority of post-radiotherapy arrhythmias, but efforts to prevent this cardiotoxicity have been limited as the causative cardiac substructure is not known. In this study we investigated if incidental radiation dose to the pulmonary veins (PVs) is associated with AF. MATERIAL AND METHODS: A single-centre study of patients completing contemporary (chemo)radiation for NSCLC, with modern planning techniques. Oncology, cardiology and death records were examined, and AF events were verified by a cardiologist. Cardiac substructures were contoured on planning scans for retrospective dose analysis. RESULTS: In 420 eligible patients with NSCLC treated with intensity-modulated (70%) or 3D-conformal (30%) radiotherapy with a median OS of 21.8 months (IQR 10.8-35.1), there were 26 cases of new AF (6%). All cases were grade 3 except two cases of grade 4. Dose metrics for both the left (V55) and right (V10) PVs were associated with the incidence of new AF. Metrics remained statistically significant after accounting for the competing risk of death and cardiovascular covariables for both the left (HR 1.02, 95%CI 1.00-1.03, p = 0.005) and right (HR 1.01 (95%CI 1.00-1.02, p = 0.033) PVs. CONCLUSION: Radiation dose to the PVs during treatment of NSCLC was associated with the onset of AF. Actively sparing the PVs during treatment planning could reduce the incidence of AF during follow-up, and screening for AF may be warranted for select cases.

Undocumented migrants' access to healthcare in Sweden, and the impact of Act 2013:407.

BACKGROUND: Research shows that undocumented migrants have difficulties in accessing healthcare. Act 2013:407 came into force in 2013 and entitled undocumented migrants to healthcare that cannot be deferred. To date, studies about undocumented migrants' access to care in Sweden and the impact of Act 2013:407 are sparse. Hence, the aim of this study was to describe professionals' experiences of access to healthcare for undocumented migrants in Sweden and the impact of Act 2013:407. METHODS: A qualitative design with semi-structured interviews was employed. Nine interviews were carried out in 2015 with nurses at two NGO healthcare centres for undocumented migrants - and an additional seven interviews in 2022 with staff at an NGO healthcare centre for undocumented migrants and personnel at a regional health and medical care administration. Interpretive description was used for the analyses. ETHICAL CONSIDERATIONS: Permission to carry out the study was obtained from managers at the participating NGOs and the regional health and medical care administration. Participants received verbal and written information about the study, and informed consent was obtained from all participants. FINDINGS: Six categories emerged from the analysis: Changes since the Act was introduced, General problems with healthcare access, Care for undocumented migrants - politics and social economy, Lack of knowledge, 'Healthcare that cannot be deferred' and Being an undocumented migrant. CONCLUSION: Undocumented migrants' social needs are as great as their needs for healthcare. Healthcare staff are burdened with healthcare cost considerations which affect their judgement of care provision and prioritization. Healthcare staff attitudes towards undocumented migrants affect their access to healthcare. Undocumented migrants in need of healthcare are especially vulnerable due to their legal status, being ill and the fear of being reported and deported. To assure undocumented migrants' access to healthcare and maintain healthcare ethics, the only possible solution is to provide healthcare based on needs.

Loss of Fgfr1 and Fgfr2 in Scleraxis-lineage cells leads to enlarged bone eminences and attachment cell death.

BACKGROUND: Tendons and ligaments attach to bone are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (ie, entheses) are found at bony protrusions (ie, eminences), and the shape and size of these protrusions depend on both mechanical forces and cellular cues during growth. Tendon eminences also contribute to mechanical leverage for skeletal muscle. Fibroblast growth factor receptor (FGFR) signaling plays a critical role in bone development, and Fgfr1 and Fgfr2 are highly expressed in the perichondrium and periosteum of bone where entheses can be found. RESULTS AND CONCLUSIONS: We used transgenic mice for combinatorial knockout of Fgfr1 and/or Fgfr2 in tendon/attachment progenitors (ScxCre) and measured eminence size and shape. Conditional deletion of both, but not individual, Fgfr1 and Fgfr2 in Scx progenitors led to enlarged eminences in the postnatal skeleton and shortening of long bones. In addition, Fgfr1/Fgfr2 double conditional knockout mice had more variation collagen fibril size in tendon, decreased tibial slope, and increased cell death at ligament attachments. These findings identify a role for FGFR signaling in regulating growth and maintenance of tendon/ligament attachments and the size and shape of bony eminences.

Evaluation and pilot testing of a multidisciplinary model of care to mainstream genomic testing for paediatric inborn errors of immunity.

Molecular diagnosis of paediatric inborn errors of immunity (IEI) influences management decisions and alters clinical outcomes, through early use of targeted and curative therapies. The increasing demand for genetic services has resulted in growing waitlists and delayed access to vital genomic testing. To address this issue, the Queensland Paediatric Immunology and Allergy Service, Australia, developed and evaluated a mainstreaming model of care to support point-of-care genomic testing for paediatric IEI. Key features of the model of care included a genetic counsellor embedded in the department, state-wide multidisciplinary team meetings, and variant prioritisation meetings to review whole exome sequencing (WES) data. Of the 62 children presented at the MDT, 43 proceeded to WES, of which nine (21%) received a confirmed molecular diagnosis. Changes to treatment and management were reported for all children with a positive result, including curative hematopoietic stem cell transplantation (n = 4). Four children were also referred for further investigations of variants of uncertain significance or additional testing due to ongoing suspicion of genetic cause after negative result. Demonstrating engagement with the model of care, 45% of the patients were from regional areas and on average, 14 healthcare providers attended the state-wide multidisciplinary team meetings. Parents demonstrated understanding of the implications of testing, reported minimal decisional regret post-test, and identified benefits to genomic testing. Overall, our program demonstrated the feasibility of a mainstreaming model of care for paediatric IEI, improved access to genomic testing, facilitated treatment decision-making, and was acceptable to parents and clinicians alike.

Mechanics and differential healing outcomes of small and large defect injuries of the tendon-bone attachment in the rat rotator cuff.

INTRODUCTION: Rotator cuff tear size affects clinical outcomes following rotator cuff repair and is correlated with the risk of recurrent tendon defects. This study aimed to understand if and how the initial defect size influences the structural and mechanical outcomes of the injured rotator cuff attachment in vivo. METHODS: Full-thickness punch injuries of the infraspinatus tendon-bone attachment in Long Evans rats were created to compare differences in healing outcomes between small and large defects. Biomechanical properties, gross morphology, bone remodeling, and cell and tissue morphology were assessed at both 3- and 8-weeks of healing. RESULTS: At the time of injury (no healing), large defects had decreased mechanical properties compared to small defects, and both defect sizes had decreased mechanical properties compared to intact attachments. However, the mechanical properties of the two defect groups were not significantly different from each other after 8-weeks of healing and significantly improved compared to no healing but failed to return to intact levels. Local bone volume at the defect site was higher in large compared to small defects on average and increased from 3- to 8-weeks. In contrast, bone quality decreased from 3- to 8-weeks of healing and these changes were not dependent on defect size. Qualitatively, large defects had increased collagen disorganization and neovascularization compared to small defects. DISCUSSION: In this study, we showed that both large and small defects did not regenerate the mechanical and structural integrity of the intact rat rotator cuff attachment following healing in vivo after 8 weeks of healing.

Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination.

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines.

Team characteristics associated with weight loss in a First Nations community intervention: An observational study.

ISSUE ADDRESSED: Group-based weight-loss programs can be effective in addressing high rates of overweight and obesity among Aboriginal and Torres Strait Islander Peoples. The purpose was to determine associations between demographic and baseline weight-related variables and team weight loss in a community-based intervention as no previous studies have analysed this at a team level. METHODS: Binomial models tested associations between team-level age, proportion female and baseline weight and classification as higher weight-loss team (HWT) (>50% persons losing 2.5% of initial weight) vs lower weight-loss team (LWT). Linear regressions compared HWT and LWT on diet and physical activity (PA) outcomes adjusted for age and gender. RESULTS: For each 1 kg increment in mean baseline weight, a team's likelihood of higher weight loss was increased by 4% (APR: 1.04, 95%CI: 1.00, 1.08). HWTs increased vigorous PA by 0.32 sessions more than LWTs (P = .02). Fruit and vegetable intakes were not associated with team weight loss classification. CONCLUSIONS: Only baseline weight and vigorous PA distinguished HWT and LWT. Promoting PA components in team-based weight-loss approaches may be beneficial as these lend themselves to group participation. SO WHAT?: Demographic and baseline weight-related variables are largely not predictive of weight loss success in group programs. Identifying other characteristics shared by HWT may help teams achieve weight loss.

Mitochondrial Disease and Hearing Loss in Children: A Systematic Review.

OBJECTIVES: Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care. METHODS: Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria. RESULTS: A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations. CONCLUSION: Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up. LEVEL OF EVIDENCE: NA Laryngoscope, 132:2459-2472, 2022.

Team members influence retention in a First Peoples' community-based weight-loss program.

The aim of this study was to evaluate program retention factors in a repeated team-based weight-loss and healthy lifestyle program for Aboriginal and Torres Strait Islander Peoples. Data comprised 3107 participants in 10 Aboriginal Knockout Health Challenge contests. Multiple variable and bivariate analyses compared age, gender, self-reported behaviors (physical activity and fruit and vegetable consumption) and objectively measured weight between completers and non-completers. First-time participants (n = 3107) who completed were more likely to be female, be older, weigh less and have more completing members in their team; only the number of team members completing was significant among participants (n = 1245) who took part in a second contest participation. Multivariate results were similar, with a participant's odds of completing on their first and second participation occasion increasing by 1.16 and 1.18, respectively, with every teammate completed. Given that the strongest effect centered on a social factor, this highlights the importance of having community-driven design and the benefits of a group-based approach to engage and maintain First Peoples' engagement in preventive health programs. Further, by identifying a change in factors associated with retention in successive weight-loss attempts, this study improves understanding of retention in weight-loss programs more generally.

Hyper-IgE Syndrome due to an Elusive Novel Intronic Homozygous Variant in DOCK8.

Rare, biallelic loss-of-function mutations in DOCK8 result in a combined immune deficiency characterized by severe and recurrent cutaneous infections, eczema, allergies, and susceptibility to malignancy, as well as impaired humoral and cellular immunity and hyper-IgE. The advent of next-generation sequencing technologies has enabled the rapid molecular diagnosis of rare monogenic diseases, including inborn errors of immunity. These advances have resulted in the implementation of gene-guided treatments, such as hematopoietic stem cell transplant for DOCK8 deficiency. However, putative disease-causing variants revealed by next-generation sequencing need rigorous validation to demonstrate pathogenicity. Here, we report the eventual diagnosis of DOCK8 deficiency in a consanguineous family due to a novel homozygous intronic deletion variant that caused aberrant exon splicing and subsequent loss of expression of DOCK8 protein. Remarkably, the causative variant was not initially detected by clinical whole-genome sequencing but was subsequently identified and validated by combining advanced genomic analysis, RNA-seq, and flow cytometry. This case highlights the need to adopt multipronged confirmatory approaches to definitively solve complex genetic cases that result from variants outside protein-coding exons and conventional splice sites.

The Additional Value of Endolymphatic Hydrops Imaging With Intratympanic Contrast for Diagnostic Work-Up-Experience From a Neurotology Center in Austria.

Objective: To illustrate the merit of hydrops imaging during clinical workup of dizziness and balance disorders. Background: Ever since the first description of in-vivo endolymphatic hydrops imaging in 2007, this diagnostic tool has been implemented in an increasing number of centers. The more experience in its clinical application is gathered, the more it is possible to critically assess its potential value for the diagnostic workup. This article intends to provide information about the experience of handling and utilization of endolymphatic hydrops imaging in one of the first centers in Austria. Methods: Retrospective analysis and review of clinical cases. Results: Based on our experience of endolymphatic hydrops imaging (EHI), which was established in cooperation between our departments of radiology and otorhinolaryngology in 2017, we have exclusively used intratympanic application of a contrast agent prior to magnetic resonance imaging, as this approach provides high quality imaging results. In 42.6% of cases, EHI could lead to the diagnosis of MD or HED. Since precise vestibular examination is still necessary, EHI is not a tool to replace the clinical examination but rather to add significantly to the interpretation of the results. Conclusion: Endolymphatic hydrops imaging represents a valuable, safe and well-applicable tool for evaluating cases with inconclusive clinical results. However, its potential additional diagnostic benefits rely on a correct indication based on prior thorough vestibular investigations.

Support received by family members before, at and after an ill person's death.

BACKGROUND: It is widely recognised, that family members are central to care of people with advanced illness, and that support should be provided to all family members in need thereof. The aim of this study was to investigate family members' experiences of support received during the last three months of life, at the time of death and after the death of a person with advanced illness. METHODS: A retrospective cross-sectional survey design was employed, using the VOICES(SF) questionnaire and multiple methods for data analyses. The sample consisted of 485 bereaved family members (aged: 20-90 years old, 70% women) of people who died in hospital between August 2016-April 2017. RESULTS: Of the family members, 58,8% reported they had received enough help and support during the illness, whereas 30,2% had not. Family members' comments about support during the illness were mainly related to care the ill person had or had not received, rather than about support they themselves received. Of all family members, 52,8% reported having had enough support at the time of the ill person's death. Related to support at death, 14,6% reported that the imminence of death was not clear, which was described as having affected their opportunity to be with the dying person at the time of death. Of all, 25,2% had a follow-up conversation after the death, 48% did not and did not want to, and 21% had no follow-up conversation, but would have liked one. A follow-up conversation was described as helpful for the bereavement process, and disappointment was expressed when not receiving support after the death. CONCLUSIONS: Family members' experiences of support were partly related to whether the ill person's care needs were fulfilled. Healthcare staff expressing empathy and respect in the care of dying people and their family members were important for family members' experiences of support. Family members' difficulty recognising that death was imminent and the importance of healthcare staff providing them with clear information were expressed in connection with support at death. Follow-up conversations were valued by family members, especially if with a healthcare professional who was present at the time of death.

The influence of care place and diagnosis on care communication at the end of life: bereaved family members' perspective.

OBJECTIVE: To investigate the influence of care place and diagnosis on care communication during the last 3 months of life for people with advanced illness, from the bereaved family members' perspective. METHOD: A retrospective survey design using the VOICES(SF) questionnaire with a sample of 485 bereaved family members (aged: 20-90 years old, 70% women) of people who died in hospital was employed to meet the study aim. RESULTS: Of the deceased people, 79.2% had at some point received care at home, provided by general practitioners (GPs) (52%), district nurses (36.7%), or specialized palliative home care (17.9%), 27.4% were cared for in a nursing home and 15.7% in a specialized palliative care unit. The likelihood of bereaved family members reporting that the deceased person was treated with dignity and respect by the staff was lowest in nursing homes (OR: 0.21) and for GPs (OR: 0.37). A cancer diagnosis (OR: 2.36) or if cared for at home (OR: 2.17) increased the likelihood of bereaved family members reporting that the deceased person had been involved in decision making regarding care and less likely if cared for in a specialized palliative care unit (OR: 0.41). The likelihood of reports of unwanted decisions about the care was higher if cared for in a nursing home (OR: 1.85) or if the deceased person had a higher education (OR: 2.40). SIGNIFICANCE OF RESULTS: This study confirms previous research about potential inequalities in care at the end of life. The place of care and diagnosis influenced the bereaved family members' reports on whether the deceased person was treated with respect and dignity and how involved the deceased person was in decision making regarding care.

Using tools in mechanobiology to repair tendons.

PURPOSE OF REVIEW: The purpose of this review is to describe the mechanobiological mechanisms of tendon repair as well as outline current and emerging tools in mechanobiology that might be useful for improving tendon healing and regeneration. Over 30 million musculoskeletal injuries are reported in the US per year and nearly 50% involve soft tissue injuries to tendons and ligaments. Yet current therapeutic strategies for treating tendon injuries are not always successful in regenerating and returning function of the healing tendon. RECENT FINDINGS: The use of rehabilitative strategies to control the motion and transmission of mechanical loads to repairing tendons following surgical reattachment is beneficial for some, but not all, tendon repairs. Scaffolds that are designed to recapitulate properties of developing tissues show potential to guide the mechanical and biological healing of tendon following rupture. The incorporation of biomaterials to control alignment and reintegration, as well as promote scar-less healing, are also promising. Improving our understanding of damage thresholds for resident cells and how these cells respond to bioelectrical cues may offer promising steps forward in the field of tendon regeneration. SUMMARY: The field of orthopaedics continues to advance and improve with the development of regenerative approaches for musculoskeletal injuries, especially for tendon, and deeper exploration in this area will lead to improved clinical outcomes.

Dimethylsulfoxide Inhibits Oligodendrocyte Fate Choice of Adult Neural Stem and Progenitor Cells.

Several clinical trials address demyelinating diseases via transplantation of mesenchymal stromal cells (MSCs). Published reports detail that administration of MSCs in patients may provide a beneficial immunomodulation, and that factors secreted by MSCs are potent inducers of oligodendrogenesis. Dimethylsulfoxide (DMSO) is widely used in life science and medicine as solvent, vehicle or cryoprotectant for cells used in transplantation. Importantly, most transplantation protocols do not include the removal of DMSO before injecting the cell suspension into patients. This indifferent application of DMSO is coming under increasing scrutiny following reports investigating its potential toxic side-effects. While the impact of DMSO on the central nervous system (CNS) has been partially studied, its effect on oligodendrocytes and oligodendrogenesis has not been addressed yet. Consequently, we evaluated the influence of DMSO on oligodendrogenesis, and on the pro-oligodendrogenic effect of MSCs' secreted factors, using adult rat neural stem and progenitor cells (NSPCs). Here, we demonstrate that a concentration of 1% DMSO robustly suppressed oligodendrogenesis and drove the fate of differentiating NSPCs toward astrogenesis. Furthermore, the pro-oligodendrogenic effect of MSC-conditioned medium (MSCCM) was also nearly completely abolished by the presence of 1% DMSO. In this condition, inhibition of the Erk1/2 signal transduction pathway and high levels of Id2 expression, a specific inhibitor of oligodendrogenic differentiation, were detected. Furthermore, inflammatory demyelinating diseases may even potentiate the impact of DMSO on oligodendrogenesis. Our results demonstrate the imperative of considering the strong anti-oligodendrogenic activity of DMSO when designing future clinical trial protocols.

Vortioxetine reverses medial prefrontal cortex-mediated cognitive deficits in male rats induced by castration as a model of androgen deprivation therapy for prostate cancer.

RATIONALE: Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer, but induces profound cognitive impairment. Little research has addressed mechanisms underlying these deficits or potential treatments. This is an unmet need to improve quality of life for prostate cancer survivors. OBJECTIVES: We investigated mechanisms of cognitive impairment after ADT in rats and potential utility of the multimodal serotonin-targeting drug, vortioxetine, to improve the impairment, as vortioxetine has specific efficacy against cognitive impairment in depression. METHODS: Male Sprague-Dawley rats were surgically castrated. Vortioxetine (28 mg/kg/day) was administered in the diet. The attentional set-shifting test was used to assess medial prefrontal cortex (mPFC) executive function. Afferent-evoked field potentials were recorded in the mPFC of anesthetized rats after stimulating the ventral hippocampus (vHipp) or medial dorsal thalamus (MDT). Gene expression changes were assessed by microarray. Effects of vortioxetine on growth of prostate cancer cells were assessed in vitro. RESULTS: ADT impaired cognitive set shifting and attenuated responses evoked in the mPFC by the vHipp afferent, but not the MDT. Both the cognitive impairment and attenuated vHipp-evoked responses were reversed by chronic vortioxetine treatment. Preliminary investigation of gene expression in the mPFC indicates that factors involved in neuronal plasticity and synaptic transmission were down-regulated by castration and up-regulated by vortioxetine in castrated animals. Vortioxetine neither altered the growth of prostate cancer cells in vitro nor interfered with the antiproliferative effects of the androgen antagonist, enzalutamide. CONCLUSIONS: These results suggest that vortioxetine may be useful in mitigating cognitive impairment associated with ADT for prostate cancer.

Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

Bereaved Family Members' Satisfaction with Care during the Last Three Months of Life for People with Advanced Illness.

BACKGROUND: Studies evaluating the end-of-life care for longer periods of illness trajectories and in several care places are currently lacking. This study explored bereaved family members' satisfaction with care during the last three months of life for people with advanced illness, and associations between satisfaction with care and characteristics of the deceased individuals and their family members. METHODS: A cross-sectional survey design was used. The sample was 485 family members of individuals who died at four different hospitals in Sweden. RESULTS: Of the participants, 78.7% rated the overall care as high. For hospice care, 87.1% reported being satisfied, 87% with the hospital care, 72.3% with district/county nurses, 65.4% with nursing homes, 62.1% with specialized home care, and 59.6% with general practitioners (GPs). Family members of deceased persons with cancer were more likely to have a higher satisfaction with the care. A lower satisfaction was more likely if the deceased person had a higher educational attainment and a length of illness before death of one year or longer. CONCLUSION: The type of care, diagnoses, length of illness, educational attainment, and the relationship between the deceased person and the family member influences the satisfaction with care.

Adaptation and validation of the VOICES (SF) questionnaire - for evaluation of end-of-life care in Sweden.

OBJECTIVES: Instruments for evaluating end-of-life care by voicing experiences of family members have previously been lacking in Sweden. The objective of this study was therefore to adapt and validate the VOICES (SF) questionnaire to evaluate quality of end-of-life care in Sweden. The VOICES (SF) [Views of Informal Carers - Evaluation of Services (Short form)] is a questionnaire about bereaved relatives' experiences of care in the last three months of life of a deceased family member. METHODS: This study was performed based on translation and back translation, cross-cultural adaptation and content validation through cognitive interviewing and feedback from professional experts. For the cognitive interviews, a purposeful sample of 35 bereaved family members was recruited from home care, hospital wards and nursing homes. The participants were 13 men and 22 women (age ranged between 20 and 90+, mean age 66), who were relatives of persons who died from life-limiting conditions. The bereaved family members' and the professional experts' concerns were summarised and analysed based on clarity, understanding, relevance, sensitivity and alternative response/wording. RESULTS: The main concerns emerging from the content validation related to the understanding and clarity of some of the questionnaire items', and a few concerns regarding the relevance of different response alternatives or items. Only two of the family members found it emotional to complete the questionnaire, and they still deemed completing it to be important and manageable. SIGNIFICANCE OF RESULTS: The VOICES (SF) can be considered as feasible in the Swedish context, provided that cultural adaptation has been achieved, that is translation alone is not enough. The Swedish version will be available for healthcare professionals to use for quality monitoring of the care provided over the last three months in life, and for research, it enables national and cross-national comparisons between different healthcare places and organisations.