Surgical Treatment for Women with Breast Cancer in Relation to Socioeconomic and Insurance Status

Based on the National Breast Cancer Audit of the Royal Australasian College of Surgeons an association between patient age and type of breast cancer surgery received has already been demonstrated. The aim of this study is to assess the patterns of surgical treatment for women with early breast cancer in relation to socioeconomic and insurance status. Data on patient demographics, diagnostic, and surgical procedures and cancer characteristics in 115,872 episodes of early breast cancer reported to the National Breast Cancer Audit between 1998 and 2012 is used for this study. Tumor size, histologic grade, number of tumors, lymph node positivity, and lymphovascular invasion are the major prognostic factors adjusted for. Reconstruction following mastectomy is the most likely surgical procedure for the higher socioeconomic and privately insured patients. Mastectomy alone is the most likely surgical procedure for the lower socioeconomic and for public patients. No surgery is the most likely surgical outcome for the lower socioeconomic and the least likely for the higher socioeconomic population. Open biopsy is the most likely diagnostic procedure for the lower socioeconomic and fine needle aspiration for the higher socioeconomic population. Socioeconomic and insurance status, are both independently associated with the types of treatment and diagnostic procedure for women with breast cancer. Opportunities present to investigate an association of these factors with morbidity and survival outcomes.     

What matters to users of services? An explorative study to promote shared decision making in health care

Background Involving service users and carers in decisions about their health care is a key feature of health‐care practice. Professional health and social care students need to develop skills and attributes to best enable this to happen. Aims The aims were to explore service user and carer perceptions of behaviours, attributes and context required to enable shared decision making; to compare these perceptions to those of students and academic staff with a view to utilizing the findings to inform the development of student assessment tools. Methods A mixed methods approach was used including action learning groups (ALG) and an iterative process alongside a modified Delphi survey. Participants The ALGs were from an existing service user and carer network. The survey was sent to sixty students, sixty academics and 30 service users from 16 different professional disciplines, spanning four Universities in England. Results The collaborative enquiry process and survey identified general agreement that being open and honest, listening, showing respect, giving time and being up to date were important. The qualitative findings identified that individual interpretation was a key factor. An unexpected result was an insight into possible insecurities of students. Conclusions The findings indicate that distilling rich qualitative information into a format for student assessment tools could be problematic as the individual context could be lost, it is therefore proposed that the information could be better used as a learning rather than assessment tool. Several of those involved identified how they valued the process and found it beneficial.     

Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5–10% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWtSOD1 propagation has been established, misfolding of HuWtSOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates. Conditioned media transmission of HuWtSOD1 misfolding in HEK293 cells is blocked by HuWtSOD1 siRNA knockdown, consistent with human SOD1 being a substrate for conversion, and attenuated by ultracentrifugation or incubation with SOD1 misfolding-specific antibodies, indicating a relatively massive transmission particle which possesses antibody-accessible SOD1. Finally, misfolded and protease-sensitive HuWtSOD1 comprises up to 4% of total SOD1 in spinal cords of patients with sporadic ALS (SALS). Propagation of HuWtSOD1 misfolding, and its subsequent cell-to-cell transmission, is thus a candidate process for the molecular pathogenesis of SALS, which may provide novel treatment and biomarker targets for this devastating disease.Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular condition that afflicts as many as 1 of 350 males and 420 females over the age of 18 (1). In ALS, degeneration of upper and lower motor neurons causes progressive muscle paralysis and spasticity, affecting mobility, speech, swallowing, and respiration (2). Half of affected individuals die within 3 y, and less than 20% survive for more than 5 y (3); 90–95% of ALS cases are sporadic (SALS) in which some apparently facilitating gene mutations, such as repeat expansions in the gene that encodes ataxin-2 (4), have been identified. The remaining 5–10% of ALS cases are familial (FALS) and predominantly associated with Mendelian-inherited mutations in the genes encoding Cu/Zn superoxide dismutase (SOD1), TAR-DNA–binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), C9ORF72, and other genes (reviewed in ref. 3).Despite the profusion of functionally diverse genes implicated in FALS and SALS, clinical and pathological similarities between all forms of ALS suggest the existence of a common pathogenic pathway that could be united by a single gene/protein (5). One of the mechanisms by which a mutant or wild-type (WT) protein can dominate pathogenesis of phenotypically diverse diseases is by propagated protein misfolding, such as that underpinning the prion diseases, which has been increasingly implicated in other neurodegenerative and systemic disorders (6, 7). A role for propagated protein misfolding in ALS is supported by the prion-like spatiotemporal progression of disease through the neuroaxis (8, 9). However, given the disparity in protein inclusion pathology between subtypes of ALS, a single unifying prion-like protein that could explain such a progression remains obscure.Whereas it is generally accepted SOD1 is not found in large perikaryal cytoplasmic inclusions outside of SOD1 FALS cases, misfolded SOD1 has been increasingly identified in SALS and non-SOD1 FALS (5, 10, 11). Indeed, we have reported that misfolded human wild-type SOD1 (HuWtSOD1) can be detected by spinal cord immunohistochemistry (IHC) in FALS secondary to FUS mutation, and in SALS patients with cytosolic WT TDP-43 accumulation (11). Moreover, in cell models, overexpression of WTTDP-43, or expression of mutant FUS or TDP-43, is associated with HuWtSOD1 misfolding (11). Collectively, these data are consistent with SOD1 being a molecular common denominator for all types of ALS. Furthermore, prion-like activity has been described for the cell-to-cell transmission of misfolding of mutant SOD1 (12), and we have reported that mutant SOD1 can confer its misfold on HuWtSOD1 (13). However, mutant SOD1 cannot explain propagation in SALS.To test if HuWtSOD1 participates in cell-to-cell transmission of protein misfolding, we make use of previously developed mouse mAb probes for misfolded/oxidized SOD1, recognizing either full-length human mutant or WT SOD1, generated against regions that are antibody-inaccessible in natively folded SOD1 (13–15). Misfolded SOD1 mAbs used in this work are 10E11C11 and 3H1, directed against an unstructured electrostatic loop [disease-specific epitope-2 (DSE2)], and 10C12, directed against a C-terminal dimer interface peptide in which the cysteine at position 146 is substituted by a cysteic acid residue to mimic oxidation of this residue (DSE1a) (13). The use of such antibody probes have enabled us to unambiguously determine the role of misfolded mutant G127X in the induced misfolding of HuWtSOD1, which upon misfolding acquires a marked increase in sensitivity to protease digestion, consistent with global loosening of structure (13). The finding that misfolded endogenous HuWtSOD1 was observed long after transfected G127X-SOD1 was degraded suggested that HuWtSOD1, once misfolded, is capable of triggering an intracellular propagated misfolding reaction (13). We now report for the first time that misfolded HuWtSOD1 can transit cell to cell both via exosomes, and release of protein aggregates and subsequent uptake in neuronal cells. In addition, misfolded HuWtSOD1 can sustain intercellular propagated misfolding in vitro and is detectable in the spinal cord of all ALS patients tested, regardless of the genetic etiology of the disease. Collectively, these data indicate that HuWtSOD1 is competent to participate in propagated misfolding, suggesting a common pathogenic mechanism linking FALS and SALS.     

The contribution of primary care practitioners to interventions reducing loneliness and social isolation in older people—An integrative review

Background

Social connection is a fundamental human need. Its absence can lead to loneliness and social isolation, adversely impacting health and well-being. Given their regular contact and trusted relationships with older people, practitioners delivering community-based primary care are well-positioned to address this issue. However, their contribution to addressing loneliness and social isolation is unclear.

Aim

This integrative review explores the contribution of the primary care workforce to interventions aimed at reducing loneliness and social isolation in community-dwelling older people.

Method

Using an integrative review method, Scopus, Web of Science, CINAHL and PubMed were searched for original research published between 2000 and 2022. Fourteen papers reporting 13 primary studies were appraised for methodological quality and included in the review. Data were extracted into a summary table and analysed using thematic analysis.

Results

Included studies came from over six countries. Internationally, primary care services have diverse structures, funding and workforces influencing their response to loneliness and social isolation. All but one intervention was multi-component, with ten studies including a group-based activity and three providing primarily individual-level activities. Only six studies reported reductions in loneliness following the intervention. Three themes were identified: characteristics of interventions; implementation context, barriers and facilitators; and differing contributions of primary care practitioners in addressing loneliness and social isolation of older people.

Conclusion

There is increasing demand and scope for primary care practitioners to assist lonely and socially isolated older people. It is important to understand how to equip and incentivise these practitioners to routinely identify, assess and respond to lonely and socially isolated older people despite varying implementation contexts. There is a need for further research that explores how the primary care team can be better utilised to deliver effective interventions that reduce the health impacts of loneliness and social isolation.     

骨髓增生异常综合征患者的asxli基因变异分析

目的探讨骨髓增生异常综合征(myelodysplastic syndromes,MDS)患者ASXL1基因变异的发生情况及其与其他基因变异和部分临床参数之间的相关性。方法采用PCR扩增产物直接测序法检测149例MDS患者ASXU、U2AF1、SF3B1、DNMT3A、TET2、IDH1/2、NPM1、FLT3-ITD.C-KIT等基因的变异情况。结果在149例患者中,ASXU基因变异的检出率为24.8%(37/149),变异率>5%的基因分别是U2AF1(22.8%)、TET2(11.4%)、DNMT3A(9.4%)、NPM1(8.1%).SF3B1(6.0%)。ASXL1变异最常见的共存变异基因为U2AF1(27.0%,10/37)及TET2(18.9%,7/37)。ASXL1变异组与野生组患者在中位年龄、MDS亚型、染色体核型、外周白细胞、血红蛋白、血小板水平及骨髓原始细胞计数等方面的差异均无统计学意义(P>0.05)o对29例ASXL1变异患者进行了有效的随访,其中11例进展为急性髓系白血病(acute myeloid leukemia,AML),白血病转化率为37.9%。在92例野生型患者中,13例进展为AML,白血病转化率为14.1%。ASXL1变异组白血病转化率明显高于野生组,差异有统计学意义(PV 0.01)。结论ASXL1变异在MDS中有较高的发生率,并常与U2AF1及TET2基因变异共存,伴有该变异的患者具有更高的白血病转化率。     

Nutrition in Spondyloarthritis and Related Immune-Mediated Disorders

Recent research on the pathogenesis of spondyloarthritis and related immune-mediated diseases associated with human leukocyte antigen class I molecule B27 (HLA-B27) has led to significant progress in terms of management and prognosis, with multiple treatments being constantly evaluated and implemented. Correlations between the genetic background of spondyloarthritis and inflammatory bowel diseases and the inflammatory processes involving gut microbiota have been established. This knowledge has allowed progress in pharmacological therapy. The role of diet in the pathogenesis and treatment of diseases pertaining to the HLA-B27 spectrum is of great significance, considering possible future applications in individualized medicine. Diet impacts the composition of gut microbiota, representing a substrate for the synthesis of metabolites affecting the mucosal immune system. Certain pro-inflammatory mediators, such as emulsifiers and microparticles, induce a more profound cytokine response, promoting inflammation. Numerous diets, including the low-starch diet, the Mediterranean diet, diets with low contents of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (low-FODMAP diets), gluten-free diets and fasting, have been analysed and correlated with patients’ symptomatology and dietary adherence. The aim of this review is to provide an extensive perspective on the diets available to patients with spondyloarthritis and related immune-mediated disorders.