Prognostic role of SOX2 and STAT3 expression on circulating T lymphocytes and CD44+/CD24neg cells in the locally advanced and metastatic breast cancer.

BACKGROUND: Breast cancer (BC) is associated with a continuous increase in incidence, with high mortality rates in several countries. CD44, STAT3, and SOX2 are related to regulating of somatic cell division, tumorigenesis, and metastasis in BC. METHODS: A cross-sectional study was carried out at the Hospital de Cancer de Pernambuco (HCP) between 2017 and 2018. Fifty-one women with locally advanced (LA) and 14 with metastatic BC were included in the study. RESULTS: High CD44+/CD24neg and CD44+/CD24neg/SOX2+ levels in Luminal B (LB), HER2+, and triple-negative breast cancer (TNBC) compared with controls (p < 0.05). Low CD44+/CD24negSTAT3+ levels in LB, HER2+, and TNBC compared with controls (p < 0.05). High T lymphocytes, and low STAT3 + T, and SOX2 + T levels in BC patients (p < 0.05). High SOX2 + T levels in patients with axillary lymph node-negative (N0) compared with the axillary lymph node-positives (N1 and N2 groups; p < 0.05). High SOX2 + T levels in N1 compared to N2 (p < 0.05). High T lymphocytes and low SOX2 + T levels in the LA tumor compared to metastatic disease (p = 0.0007 and p = 0.02, respectively). High CD44 + /CD24negSTAT3+, and T lymphocyte levels in TNBC patients with LA tumor compared to metastatic (p < 0.05). Low STAT3 + T levels in TBNC patients with LA tumor compared to metastatic (p = 0.0266). CONCLUSION: SOX2 and STAT3 expression on circulating T lymphocytes and CD44 + /CD24neg cells in peripheral blood have prognostic roles in breast cancer. SOX2 and STAT3 expression are potential predictive biomarkers of disease progression in breast cancer regardless of tumor subtype.

Service delivery approaches related to hearing aids in low- and middle-income countries or resource-limited settings: A systematic scoping review.

Hearing loss is an important global public health issue which can be alleviated through treatment with hearing aids. However, most people who would benefit from hearing aids do not receive them, in part due to challenges in accessing hearing aids and related services, which are most salient in low- and middle-income countries (LMIC) and other resource-limited settings. Innovative approaches for hearing aid service delivery can overcome many of the challenges related to access, including that of limited human resources trained to provide ear and hearing care. The purpose of this systematic scoping review is to synthesize evidence on service delivery approaches for hearing aid provision in LMIC and resource-limited settings. We searched 3 databases (PubMed, Scopus, Ovid MEDLINE) for peer-reviewed articles from 2000 to 2022 that focused on service delivery approaches related to hearing aids in LMIC or resource-limited settings. Fifteen peer-reviewed articles were included, which described hospital-based (3 studies), large-scale donation program (1 studies), community-based (7 studies), and remote (telehealth; 4 studies) service delivery approaches. Key findings are that hearing aid services can be successfully delivered in hospital- and community-based settings, and remotely, and that both qualified hearing care providers and trained non-specialists can provide quality hearing aid services. Service delivery approaches focused on community-based and remote care, and task sharing among qualified hearing care providers and trained non-specialists can likely improve access to hearing aids worldwide, thereby reducing the burden of untreated hearing loss.

Neuroprotective Profile of Triazole Grandisin Analogue against Amyloid-Beta Oligomer-Induced Cognitive Impairment.

Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-ß oligomers (AßO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AßO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AßO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AßO (90 µM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AßO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AßO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AßO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AßO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AßO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.

QSAR Studies, Synthesis, and Biological Evaluation of New Pyrimido-Isoquinolin-Quinone Derivatives against Methicillin-Resistant Staphylococcus aureus.

According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds.

Scaling the Andean Shilajit: A Novel Neuroprotective Agent for Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder without a cure, despite the enormous number of investigations and therapeutic approaches. AD is a consequence of microglial responses to "damage signals", such as aggregated tau oligomers, which trigger a neuro-inflammatory reaction, promoting the misfolding of cytoskeleton structure. Since AD is the most prevalent cause of dementia in the elderly (>60 years old), new treatments are essential to improve the well-being of affected subjects. The pharmaceutical industry has not developed new drugs with efficacy for controlling AD. In this context, major attention has been given to nutraceuticals and novel bioactive compounds, such as molecules from the Andean Shilajit (AnSh), obtained from the Andes of Chile. Primary cultures of rat hippocampal neurons and mouse neuroblastoma cells were evaluated to examine the functional and neuroprotective role of different AnSh fractions. Our findings show that AnSh fractions increase the number and length of neuronal processes at a differential dose. All fractions were viable in neurons. The AnSh fractions inhibit tau self-aggregation after 10 days of treatment. Finally, we identified two candidate molecules in M3 fractions assayed by UPLC/MS. Our research points to a novel AnSh-derived fraction that is helpful in AD. Intensive work toward elucidation of the molecular mechanisms is being carried out. AnSh is an alternative for AD treatment or as a coadjuvant for an effective treatment.

The dizzying cycle: a qualitative study showing the effects of vestibular disorders and stress on work experience.

OBJECTIVE: Quantitative studies have explored the work abilities of persons with specific vestibular-related symptoms, but there seems to be a dearth of research that has explored the work experience of persons-with- vestibular- disorders, so this qualitative study explored this phenomenon. DESIGN: Audio-recorded semi-structured interviews were conducted online. Thematic analysis was used to analyse the transcripts. Together, two researchers coded the transcripts and deductively identified the main themes on the main components of the expanded International Classification of Functioning, Disability, and Health scheme, and thereafter generated the sub-themes inductively. STUDY SAMPLE: Fourteen people with various vestibular disorders and occupations in South Africa participated in the study. RESULTS: Participants reported having difficulty performing work-related tasks requiring attention to detail and ambulation, and work environmental conditions triggered their vestibular-related symptoms. Some participants received time off from work and support from their supervisors and colleagues, while others did not. Seeking mental services allowed them to overcome their negative feelings, medication suppressed their vestibular-related symptoms, and vestibular rehabilitation allowed them to focus on their work. CONCLUSION: Vestibular-related symptoms may hinder persons- with- vestibular- disorders from completing and participating in work-related activities, which may result in them experiencing negative feelings. The nature of some of the work-related tasks that they need to complete and experiencing negative feelings may trigger their vestibular-related symptoms. Together, the work-related activity limitations, participation restrictions, and environmental and personal factors may cause persons- with- vestibular- disorders to experience disability in their workplaces. To prevent this potential disability, persons with vestibular disorders should be supported by and receive workplace accommodations. Furthermore, they should be enrolled into work rehabilitation programmes that include, vestibular rehabilitation, medication regimens, and mental health services.

Yerba mate consumption by ovariectomized rats alters white adipose tissue.

INTRODUCTION: Menopause and post-menopause are characterized by low levels of estrogen that can be associated with the emergence of metabolic diseases. While hormone replacement therapy can alleviate many symptoms, it can also exacerbate other diseases such as breast cancer. In the search for natural alternatives, Ilex paraguariensis (Yerba Mate) has been identified as a potential therapy for the onset of obesity. Here, the effect of MATE consumption on white adipose tissue (WAT) was studied in ovariectomized rats, an animal model for post-menopause hormone loss. METHODS: Four groups of animals were used: ovariectomy with MATE (OVX MATE) and without MATE (OVX), as well as sham surgery with MATE (Sham MATE) and without MATE (Sham). MATE was provided by gavage at 1 g/kg of body weight for eight weeks before measuring biochemical parameters in plasma and characterizing WAT morphology. RESULTS: The consumption of Yerba MATE significantly decreased weight gain in ovariectomized rats and presented near control levels of triglycerides, total cholesterol, and LDL. A morphometric analysis of WAT showed a significant decrease in the area occupied by adipocytes in the group that consumed MATE. Finally, MATE consumption increased the UCP1 content in the WAT of the ovariectomized group. Yerba MATE treatment was also associated with higher levels of SIRT1 protein. CONCLUSION: MATE consumption has a preventive effect on the weight gain observed in ovariectomized rats and potential benefits in naturally avoiding the onset of obesity post menopause.

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer's Disease Aetiopathogenesis in Men.

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10-20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

'I don't really know where I stand because I don't know if I took something away from her': Moral injury in South African speech-language therapists and audiologists due to patient death and dying.

BACKGROUND: Speech-language therapists and audiologists (SLT&As) may encounter difficulties when confronted with patient death and dying, which may conflict with their moral beliefs and result in moral injury. Furthermore, South African SLT&As practice in a country with a high mortality rate, which may add to the complexity of their experience. Moreover, they may be influenced by African philosophies promoting care, which might conflict with their experiences of patient death and dying. AIMS: To explore the moral injury experienced by South African SLT&As in patient death and dying, and how they overcame the injury. METHODS & PROCEDURES: This article forms part of a larger qualitative study that explored SLT&As' experiences of patient death and dying in South Africa. Thematic analysis was conducted on the transcripts of 25 episodic narrative interviews conducted with South African SLT&As on their experiences of patient death and dying. OUTCOMES & RESULTS: Findings suggest that South African SLT&As experienced helplessness, guilt and anger in patient death and dying. However, with support from the allied team, engaging in self-reflection and religious practices, they reported alleviation of moral injury. CONCLUSIONS & IMPLICATIONS: In order to mitigate moral injury in South African SLT&As, they require professional education, self-care strategies, guidelines and support from the teams in which they work and their supervisors. Research is needed that explores how SLT&As' biographical characteristics and interactions with significant others of dying and deceased patients, may result in moral injury. WHAT THIS PAPER ADDS?: What is already known on this subject? Moral injury and measures used to overcome the injury have been explored in military personnel, doctors and nurses, but not in SLT&As. However, studies that explored the perceptions of SLTs and/or audiologists regarding providing palliative care and of death and dying, particularly that by Rivers et al. in 2009, suggested that these professionals may be at risk of experiencing emotional trauma due to patient death, particularly when not receiving undergraduate education on this subject. However, the extent of this trauma and the support needed to overcome it is unknown because the participants in these studies may have not experienced patient death, and were only students or just SLTs. What this article adds? This article highlights the complexity of speech-language therapy and audiology practice when confronted with patient death and dying. South African SLT&As may have to make decisions that conflict with their morals and professional practice standards, especially as the helping nature of their profession is characterized by African philosophies that promote care, which may result in moral injury. Clinical implications of this article This article indicates that in addition to undergraduate education on patient death and dying, SLTs and audiologists require continuous professional education on this topic, self-care strategies, support from the teams in which they work, and their supervisors and guidelines for when they encounter patient death and dying.

In the Wake of COVID-19: The Developmental and Mental Health Fallout Amongst South African University Students.

Multiple studies have noted the impacts on student mental health of the COVID-19 pandemic, associated national lockdowns and emergency remote teaching. In light of COVID-19 shifting from pandemic to endemic status, this study investigates the developmental and mental health consequences of the pandemic for a group of South African undergraduate students. A qualitative design allowed for the thematic analysis of the narratives of 140 humanities students, gathered through an online survey. This paper presents the 'voices' of this group to convey the intensity of their COVID-19 experience. The results suggest a loss of a sense of freedom and opportunities to explore and experiment, high levels of depression with a notable sense of hopelessness regarding the future and decreased motivation, and significant reports of social anxiety related to delays in the development of social skills due to social isolation, particular to the first-year cohort.

'All of a sudden, you know, you can't go to these services, because of the risk of infection': Audiological service considerations at residential care homes for older persons during COVID-19.

BACKGROUND:  Residential care homes for older persons were especially affected during the coronavirus disease 2019 (COVID-19) pandemic lockdowns which resulted in limited social interactions and service provision. Communication became challenging due to the prophylactic use of masks and social distancing. OBJECTIVES:  This qualitative research study set out to explore audiological service considerations in residential care homes for older persons during the COVID-19 restrictions. METHOD:  Through purposive sampling, nine managers from residential care homes for older persons in Johannesburg participated in semi-structured, online interviews. The transcriptions of these recorded interviews underwent thematic analysis. RESULTS:  Managers employed various strategies to attend to residents' audiological needs, audiological health, hearing aid use, and hearing aid provision. Furthermore, it transpired that other health related services were prioritised over audiological services in general, but especially during the pandemic lockdowns. Managers reported that staff had to use various communication strategies due to COVID-19 precautions and that masks and social distancing made communication more challenging for residents with hearing loss. Moreover, isolation and modified service provision were extremely taxing on residents. CONCLUSION:  This study highlights the need for continued audiological services at residential care homes, but also the need to balance audiological needs with other health needs because these seem to be prioritised over hearing loss, especially in this population who may have limited agency and choice in the health care options available to them. Furthermore, adapted strategies need to be considered to support communication considering COVID-19 precautions so that communicative difficulties do not exacerbate lockdown isolation.

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.

Amyloid-beta 42 (Aß42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aß42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aß42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

The Use of Information Communication Technologies in a South African Deaf Older Adult Population Living in a Residential Care Home to Communicate with Emigrant Family Members.

South Africa has experienced considerable international outward migration in the last half century, which has had a severe psychological impact on members of families affected by this phenomenon. Older parents who remain behind may experience feelings of loss and isolation. Information Communication Technologies (ICTs) are useful in maintaining relationships between family members separated by migration and increasingly allow migrant families to experience a virtual co-presence despite geographical separation. However, the process may be challenging, especially for older people with hearing difficulties. This article reports on a qualitative study exploring the perceptions of a group of older adults who have difficulty hearing and who live in a residential care home about using ICTs to communicate with family abroad. Interview data were analysed using thematic analysis. Most of the participants used either a fixed line telephone or a mobile phone. They reported challenges in communicating with family members abroad arising from their deafness, as well as difficulties using technological devices together with their hearing aids. These challenges resulted in feelings of helplessness and frustration. Although the data collection took place prior to the COVID-19 pandemic, these findings may be of particular relevance to situations such as those during the pandemic when many older adults became more reliant on technology to communicate with family members because of restrictions on direct contact. Accordingly, suggestions are made to address challenges in communication between older adults and loved ones who are geographically separated.

Interleukin-6 Signaling in Triple Negative Breast Cancer Cells Elicits the Annexin A1/Formyl Peptide Receptor 1 Axis and Affects the Tumor Microenvironment.

Annexin A1 (AnxA1) is a pleiotropic protein that exerts essential roles in breast cancer (BC) growth and aggressiveness. In our previous work, we described the autocrine signaling of AnxA1 through formyl peptide receptor 1 (FPR1) in the triple-negative (TN) BC cell line, MDA-MB-231. Here, we aimed to describe the interaction between the AnxA1/FPR1 and the Interleukin-6 (IL-6) signaling pathways and their role in the tumor microenvironment (TME). First, we demonstrated that AnxA1 and IL-6 expression levels are correlated in BC tissue samples. In three TNBC cell lines, overexpression of both AnxA1 and IL-6 was also identified. Next, we inhibited FPR1, the IL-6 receptor and STAT3 in both MDA-MB-231 and MDA-MB-157 cells. The FPR1 inhibition led to increased levels of IL-6 and secreted AnxA1 in both cell lines. On the other side, inhibition of the IL-6 receptor or STAT3 led to the impairment of AnxA1 secretion, suggesting the essential role of the IL-6 signaling cascade in the activation of the AnxA1/FPR1 autocrine axis. Finally, we described the interaction between IL-6 and the AnxA1/FPR1 pathways and their role on the TME by analyzing the effect of supernatants derived from MDA-MB-231 and MDA-MB-157 cells under the inhibition of FPR1 or IL-6 signaling on fibroblast cell motility.

Clinical outcomes of patients with pancreatic tumors discussed in Tumor Board.

OBJECTIVE: the recommendations of the decisions made by the Tumor Board (TB) should be followed to identify barriers that may interfere with the execution of the previously decided, best care for the patient. The aim of this study is to assess whether the TB conduct decision was performed in patients with pancreatic tumors, their life status 90 days after the TB decision, and to analyze the reasons why the conduct was not performed. METHODS: we conducted a retrospective study with patients with pancreas tumors, evaluated between 2017 and 2019. We collected data on epidemiological status, whether the TB procedure was performed, the reason for not performing it, life status 90 days after the TB decision, and how many times each patient was discussed at a meeting. We compared categorical variables using the chi square test, numerical variables were presented as means and standard deviation. RESULTS: we studied 111 session cases, in 95 patients, 86 (90.5%) diagnosed with cancer. After 90 days of TB, 83 patients (87.37%) remained alive, 9 had (9.47%) died, and 3 (3.16%) were lost to follow-up. The TB decision was not observed in 12 (10.8%) cases and the reasons were: 25% (3) for loss of follow-up, 8.33% (1) for patient refusal, and 66.67% (8) due to clinical worsening. The cases of patients with metastases had a lower rate of TB conduct compliance (p=0.006). CONCLUSIONS: the TB conduct was performed in most cases and the most evident reason for non-compliance with the conducts is the patient's clinical worsening.

Priorities for cancer research in low- and middle-income countries: a global perspective.

Cancer research currently is heavily skewed toward high-income countries (HICs), with little research conducted in, and relevant to, the problems of low- and middle-income countries (LMICs). This regional discordance in cancer knowledge generation and application needs to be rebalanced. Several gaps in the research enterprise of LMICs need to be addressed to promote regionally relevant research, and radical rethinking is needed to address the burning issues in cancer care in these regions. We identified five top priorities in cancer research in LMICs based on current and projected needs: reducing the burden of patients with advanced disease; improving access and affordability, and outcomes of cancer treatment; value-based care and health economics; quality improvement and implementation research; and leveraging technology to improve cancer control. LMICs have an excellent opportunity to address important questions in cancer research that could impact cancer control globally. Success will require collaboration and commitment from governments, policy makers, funding agencies, health care organizations and leaders, researchers and the public.

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Cultural Competency and Surgical Decision Making in Otolaryngology.

Given the high prevalence of otolaryngology infections such as tonsillitis, otitis, and pharyngitis in low and middle income countries, the field of global otolaryngology continues to grow to accommodate patients around the world. This commentary focuses on best practices in transcultural communications between US doctors and foreign patients with an emphasis on cultural competency. We use alternative medicine as an exemplar for how to collaborate with patients to develop treatment plans that respect their cultural beliefs and lifestyles. Rather than assigning value to the patient's alternative medicine practices, we believe that instructing and counseling a patient on how to incorporate follow-up visits and rehabilitation after allopathic medical procedures such as surgical tonsillectomy should be done in a way that respects the patient's preexisting health regimen. By doing so, these new aspects of their health care will take a discrete place in their wellness practices and engender more trust and better health outcomes.