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Introduction: Initiated in June 2019, this collaborative effort involved 15 public and private sector hospitals in Pakistan. The primary objective was to enhance the capacity for pediatric neuro-oncology (PNO) care, supported by a My Child Matters/Foundation S grant. Methods: We aimed to establish and operate Multidisciplinary Tumor Boards (MTBs) on a national scale, covering 76% of the population (185.7 million people). In response to the COVID-19 pandemic, MTBs transitioned to videoconferencing. Fifteen hospitals with essential infrastructure participated, holding monthly sessions addressing diagnostic and treatment challenges. Patient cases were anonymized for confidentiality. Educational initiatives, originally planned as in-person events, shifted to a virtual format, enabling continued implementation and collaboration despite pandemic constraints. Results: A total of 124 meetings were conducted, addressing 545 cases. To augment knowledge, awareness, and expertise, over 40 longitudinal lectures were organized for healthcare professionals engaged in PNO care. Additionally, two symposia with international collaborators and keynote speakers were also held to raise national awareness. The project achieved significant milestones, including the development of standardized national treatment protocols for low-grade glioma, medulloblastoma, and high-grade glioma. Further protocols are currently under development. Notably, Pakistan's first pediatric neuro-oncology fellowship program was launched, producing two graduates and increasing the number of trained pediatric neuro-oncologists in the country to three. Discussion: The initiative exemplifies the potential for capacity building in PNO within low-middle income countries. Success is attributed to intra-national twinning programs, emphasizing collaborative efforts. Efforts are underway to establish a national case registry for PNO, ensuring a comprehensive and organized approach to monitoring and managing cases. This collaborative initiative, supported by the My Child Matters/Foundation S grant, showcases the success of capacity building in pediatric neuro-oncology in low-middle income countries. The establishment of treatment protocols, fellowship programs, and regional tumor boards highlights the potential for sustainable improvements in PNO care.
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The COVID-19 pandemic has been a major health concern in Bangladesh until very recently. Although the Bangladesh government has employed various infection control strategies, more targeted Non-Pharmaceutical interventions (NPIs), including school closure, mask-wearing, hand washing, and social distancing have gained special attention. Despite significant long-term adverse effects of school closures, authorities have opted to keep schools closed to curb the spread of COVID-19 infection. However, there is limited knowledge about the impact of reopening schools alongside other NPI measures on the course of the epidemic. In this study, we implemented a mathematical modeling framework developed by the CoMo Consortium to explore the impact of NPIs on the dynamics of the COVID-19 outbreak and deaths for Bangladesh. For robustness, the results of prediction models are then validated through model calibration with incidence and mortality data and using external sources. Hypothetical projections are made under alternative NPIs where we compare the impact of current NPIs with school closures versus enhanced NPIs with school openings. Results suggest that enhanced NPIs with schools opened may have lower COVID-19 related prevalence and deaths. This finding indicates that enhanced NPIs and school openings may mitigate the long-term negative impacts of COVID-19 in low- and middle-income countries. Potential shortcomings and ways to improve the research are also discussed.
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COVID-19 , Humanos , Bangladesh/epidemiología , COVID-19/epidemiología , COVID-19/prevención & control , Pandemias/prevención & control , Brotes de Enfermedades/prevención & control , CalibraciónRESUMEN
PURPOSE: To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia. DESIGN: Multinational, prospective study including treatment-naïve patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter. PARTICIPANTS: A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries. INTERVENTIONS: Chemotherapy, radiotherapy, enucleation, and orbital exenteration. MAIN OUTCOME MEASURES: Enucleation and death. RESULTS: Within the cohort, 1021 patients (48%) were from South Asia (SA), 503 patients (24%) were from East Asia (EA), 310 patients (15%) were from Southeast Asia (SEA), 218 patients (10%) were from West Asia (WA), and 60 patients (3%) were from Central Asia (CA). Mean age at presentation was 27 months (median, 23 months; range, < 1-261 months). The cohort included 1195 male patients (57%) and 917 female patients (43%). The most common presenting symptoms were leukocoria (72%) and strabismus (13%). Using the American Joint Committee on Cancer Staging Manual, Eighth Edition, classification, tumors were staged as cT1 (n = 441 [16%]), cT2 (n = 951 [34%]), cT3 (n = 1136 [41%]), cT4 (n = 267 [10%]), N1 (n = 48 [2%]), and M1 (n = 129 [6%]) at presentation. Retinoblastoma was treated with intravenous chemotherapy in 1450 eyes (52%) and 857 eyes (31%) underwent primary enucleation. Three-year Kaplan-Meier estimates for enucleation and death were 33% and 13% for CA, 18% and 4% for EA, 27% and 15% for SA, 32% and 22% for SEA, and 20% and 11% for WA (P < 0.0001 and P < 0.0001), respectively. CONCLUSIONS: At the conclusion of this study, significant heterogeneity was found in treatment outcomes of retinoblastoma among the regions of Asia. East Asia displayed better outcomes with higher rates of globe and life salvage, whereas Southeast Asia showed poorer outcomes compared with the rest of Asia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Neoplasias de la Retina , Retinoblastoma , Niño , Humanos , Masculino , Femenino , Lactante , Preescolar , Retinoblastoma/diagnóstico , Retinoblastoma/epidemiología , Retinoblastoma/terapia , Neoplasias de la Retina/diagnóstico , Neoplasias de la Retina/epidemiología , Neoplasias de la Retina/terapia , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Asia/epidemiología , Estudios Retrospectivos , Enucleación del OjoRESUMEN
PURPOSE: Communication is a fundamental aspect of patient- and family-centered care. Unfortunately, there is a dearth of evidence regarding pediatric cancer communication in low- and middle-income countries, where over 90% of all children with childhood cancer live. The purpose of this study was to explore barriers and facilitators of quality communication within two pediatric cancer centers in Pakistan. METHODS: Semistructured interviews were conducted with 20 multidisciplinary pediatric cancer clinicians and 18 caregivers of children with cancer at Children's Hospital of Lahore and Indus Hospital in Karachi, Pakistan. Interviews were conducted in English or Urdu, audio-recorded, transcribed, and translated to English. Two researchers coded each transcript using an inductively derived codebook. Thematic content analysis focused on barriers and facilitators of high-quality communication. RESULTS: Pakistani clinicians and caregivers identified factors that affected the quality of patient-centered cancer communication. These included structural factors including setting, available interpreters, documentation, patient volume, teamwork, and financial support. Clinician-level communication barriers and facilitators included communication training, clinician distress/boundaries, and the ability to have recurrent conversations. Patient or family characteristics affecting communication included education, income status, primary language, and geography; the child's specific disease type; and relational elements such as social support, empowerment, and split decision makers. Participants identified existing or potential interventions related to each factor. CONCLUSION: Multilevel factors serve as either barriers or facilitators for pediatric cancer communication in Pakistan. Identification of these elements of communication is an essential step toward interventions aimed at improving patient- and family-centered care in resource limited settings.
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Comunicación , Neoplasias , Humanos , Niño , Pakistán , Investigación Cualitativa , Cuidadores , Neoplasias/terapiaRESUMEN
The management of medulloblastoma in children has dramatically changed over the past four decades, with the development of chemotherapy protocols aiming at improving survival and reducing long-term toxicities of high-dose craniospinal radiotherapy. While the staging and treatment of medulloblastoma were until recently based on the modified Chang's system, recent advances in the molecular biology of medulloblastoma have revolutionized approaches in the management of this increasingly complex disease. The evolution of systemic therapies is described in this review.
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BACKGROUND: The COVID-19 pandemic has highlighted the importance of a well-equipped and supported healthcare workforce, and Bangladesh still faces challenges in providing adequate and well-equipped healthcare services. Therefore, the study aims to assess the level of working conditions of the clinical health workers in Bangladesh and their relative importance in delivering quality healthcare services. METHODS: The study followed a cross-sectional study design and collected primary data adopting a quantitative method. A total of 319 clinical workforces from four districts and eight sub-districts were randomly selected using a multi-stage sampling technique. A 26-component questionnaire used to assess various components of working conditions. Descriptive statistics, and bivariate analysis were used to analyze the data. RESULTS: The study found that the working conditions of clinical health workers in primary and secondary healthcare facilities in Bangladesh were quite poor (3.40), with almost two-thirds of respondents showing negative views in 23 out of 26 indicators. The results also showed that working conditions were significantly (p ≤ 0.05) higher in primary compared to secondary level facilities. Moreover, men, younger workforce, and workforce with shorter length of service were more likely to report poor working conditions than their counterparts. Lastly, receiving monthly salary in due time was top-ranked (99.15) in terms of importance for delivering quality healthcare, followed by availability of medicines (98.04), and medical and surgical requisites (97.57), and adequate mentoring and support to perform duties (97.50). CONCLUSION: The study highlights the poor working conditions of clinical health workers in public health facilities in Bangladesh. It recommends that policymakers should prioritize improving working conditions by addressing the factors that are crucial for delivering quality healthcare. Improving working conditions will have a positive impact on the retention and motivation of workers, which will ultimately lead to better health outcomes for the population.
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Fuerza Laboral en Salud , Condiciones de Trabajo , Masculino , Humanos , Bangladesh , Estudios Transversales , Pandemias , Instituciones de SaludRESUMEN
OBJECTIVES: Alpha-mannosidosis is a rare genetic lysosomal storage condition leading to the systemic buildup of oligomannoside. Clinical presentation and associated conditions, as well as the full extent of histopathologic changes associated with this disease process, are not fully understood. CASE PRESENTATION: We present the case of an 8-year-1-month old patient with persistent anemia and who was initially diagnosed with Celiac disease before ultimately being diagnosed with alpha-mannosidosis. As part of his diagnostic work-up, duodenal and bone marrow biopsies were examined by pathology. Duodenal biopsies showed foamy plasma cells expanding the lamina propria which triggered a workup for a genetic storage disease; features suggestive of Celiac disease which resolved on gluten-free diet were also noted by pathology. Bone marrow analysis via electron microscopy showed cytoplasmic granules and inclusions in multiple immune cell lines. CONCLUSIONS: Alpha-mannosidosis can occur with Celiac disease and milder forms may only be suspected from incidental pathology findings. The ultrastructural bone marrow findings from this case, the first to be reported from human, show numerous disease-associated changes in multiple immune cell lines whose contribution to disease-associated immunodeficiency is unclear.
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Enfermedad Celíaca , Enfermedades por Almacenamiento Lisosomal , alfa-Manosidosis , Humanos , Lactante , alfa-Manosidosis/diagnóstico , alfa-Manosidosis/complicaciones , alfa-Manosidosis/genética , Microscopía , Enfermedad Celíaca/complicaciones , Enfermedades por Almacenamiento Lisosomal/diagnósticoRESUMEN
This study examined the disparity in antenatal care (ANC) visits and institutional delivery between high-disaster-prone (HDP) and low-disaster-prone (LDP) areas, defined based on multi-hazards, in Bangladesh and assessed the influencing factors using Andersen's behavioral model. In this study, cross-sectional data of 345 mothers, who had live birth the year preceding the survey, were used from the second-round multipurpose survey of a longitudinal research project conducted in May-June 2011. Hierarchical multinomial logistic and binary logistic models were respectively used to assess the determinants of ANC contacts and choice of childbirth place. We found very low utilization of 4+ ANC visits in both HDP (20%) and LDP (15%) areas. The difference is also not significant. The strong influencing factors of receiving 4+ ANC were mother's education, household size, income, and proximity to health facility. The level of institutional delivery was also low (21%), and no significant difference between HDP (15.2%) and LDP (25.7%) was found. However, in the case of institutional delivery, significant (p-value ≤ .01) difference was found in C-section between HDP (42%) and LDP (79%). A significant (p-value ≤ .05) difference was also found in the attendance of graduate doctors/gynecologists between HDP (58%) and LDP (88%). Mothers of HDP areas were 52 percent less likely to choose institutional delivery compared to those of LDP areas. Moreover, there was 30 percent less likelihood of choosing institutional delivery with an increase in distance to the nearest health facility. Specific demand-side (e.g., awareness raising, expanding maternal voucher scheme, covering more mothers under maternal allowance, and facilitating more income-generating activities especially off-farm ones) and supply-side interventions (e.g., providing training to local traditional birth attendants, and deployment of boat-based medical teams in coastal and char areas) need to be undertaken to increase institutional delivery, especially in HDP areas. However, the ultimate solution depends on adopting long-term measures to prepare facilities ready by filling the vacant posts and reducing absenteeism. Public-private partnerships modality can also be introduced especially in the HDP areas. Policy attention is needed to introduce such interventions.
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BACKGROUND: Healthcare professionals' involvement and reporting of adverse drug reactions are essential for the success of a pharmacovigilance program. The aim of this study was to assess healthcare professionals (medical doctors, pharmacists, nurses, dentists, midwives, and paramedics) current knowledge, attitude, practices, and barriers regarding pharmacovigilance and adverse drug reactions reporting in multicentral healthcare settings. METHODS: A cross-sectional face-to-face survey was conducted among currently working healthcare professionals in various hospitals in ten districts of Adana province, Türkiye from March to October 2022. A self-administered, pretested questionnaire (Cronbach's alpha = 0.894 for knowledge, attitudes and practices variables) was used for data collection. The questionnaire's final draft included five sections (sociodemographic/general information, knowledge, attitude, practices, and barriers) with 58 questions. The collected data was analyzed in SPSS (version 25) using descriptive statistics, the chi-square test, and logistic regression. RESULTS: Of the total 435 distributed questionnaires, 412 completed the entire questionnaire, yielding a 94% response rate. The majority of healthcare professionals (60.4%; n = 249) had never received pharmacovigilance training. Among healthcare professionals 51.9% (n = 214), 71.1% (n = 293) and 92.5% (n = 381) had poor knowledge, positive attitudes and poor practices, respectively. Only 32.5% of healthcare professionals kept the record of an adverse drug reaction and only 13.1% reported adverse drug reactions. The profession (medical doctors, pharmacists, nurses, dentists, midwives, and paramedics) of healthcare professionals and a lack of training were predictors of poor adverse drug reaction reporting (p < 0.05). A statistically significant difference in healthcare professionals and knowledge, attitude and practices scores was also observed (p < 0.05). The main barriers which were supposed to discourage adverse drug reactions reporting by the healthcare professionals were higher workload (63.8%) followed by thinking that a single adverse drug reaction report makes no impact (63.6%) and lack of a professional atmosphere (51.9%). CONCLUSION: In the current study, most healthcare professionals had poor knowledge and practice, but they had a positive attitude toward pharmacovigilance and adverse drug reactions reporting. Barriers to under-reporting of adverse drug reactions were also highlighted. Periodic training programs, educational interventions, systematic follow-up of healthcare professionals by local healthcare authorities, interprofessional links between all healthcare professionals, and the implementation of mandatory reporting policies are critical for improving healthcare professionals knowledge, practices, patient safety and pharmacovigilance activities.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Conocimientos, Actitudes y Práctica en Salud , Humanos , Estudios Transversales , Farmacovigilancia , Personal de Salud , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiologíaRESUMEN
With the increasing growth of online shopping, businesses are intertwining to establish new shopping antecedents. Customer experience has steadily become the most important source of retailers' long-term competitive advantage via difference. To preserve long-term and sustained consumer loyalty, retailers must continually improve the customer experiences. This study presents a framework for online retailing in a digital environment called the Online Customer Experience-Engagement Context model in the presence of value co-creation (VCC). Data was gathered from 189 people who purchased products online. For additional analysis, testing the hypothesis, and model construction, SPSS 26 and Smart-PLS were used. The data was then evaluated further using descriptive statistics, path analysis, measurement, and structural model. The findings show that the online customer experience (measured as shopping environment, shopping procedure, staff service experience, and product experience) substantially influenced customer engagement, which improved customer loyalty. The VCC strengthened the link between online customer experience and customer engagement. It suggests that including consumers in co-creating a delightful online customer experience from time to time may be a valuable strategy for online retailers to increase customer engagement and loyalty. To create an overarching outcome, information integration theory (IIT), multi-attribute utility theory (MAUT), and the attitude-behavior-context theory (ABC) theories are converged to explain the proposed model in the study.
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INTRODUCTION: Brain tumors are the most common solid neoplasms and the second most common malignancy in the pediatric age group. Due to the complexity of their management, pediatric central nervous system (CNS) tumors are not a priority in low- and middle-income countries (LMICs). METHODS: In an attempt to improve the survival rate and overall care, we introduced a dedicated pediatric neuro-oncology service in our institute and evaluated its impact by dividing the pre- and post-era into two cohorts and comparing them: 1998-2013 (16 years: cohort A) and 2014-2019 (6 years: cohort B, after the start of dedicated neuro-oncology services). RESULTS: We observed that after the implementation of a proper neuro-oncology service, the proportion of patients treated with curative intent increased, and survival improved in cohort B. The patient volume also increased from 15.5 per year in cohort A to 44.8 per year in cohort B. The percentage of children given radiation therapy also increased significantly, while the proportion of children treated with chemotherapy remained stable. CONCLUSION: A dedicated multidisciplinary team trained and knowledgeable in the specialty of pediatric neuro-oncology can enhance and improve outcomes, and supportive care and help can provide good quality of life to children and their families with brain neoplasms.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Neoplasias Encefálicas/terapia , Neoplasias del Sistema Nervioso Central/terapia , Niño , Países en Desarrollo , Humanos , Pakistán , Calidad de VidaRESUMEN
This article investigates the nexus between bank-specific risks and the financial stability of the banks for a panel data set of 15 scheduled banks in Pakistan over a 12-year period from 2009 to 2020. Using the fixed-effect model, the study result shows that bank-specific risks, i.e., credit risk and liquidity risk are detrimental to bank stability, whereas funding risk has no significant impact on bank stability. Besides these, bank size has also a negative impact on bank stability, whereas the return on assets (ROA) revealed a positive influence. To ensure stability, bank management should establish policies that confirm secure loan granting and timely reimbursement from customers to minimize the credit risk. Besides this, management should keenly observe the liquidity position and should also effectively mobilize the customer deposits to attain financial stability.
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Happiness, well-being, human freedom, and life events are interconnected. Nevertheless, the debate about human well-being struggles to find an exact definition. Literature debates on the importance of positive psychology or adverse effects of negative psychology in the well-being context discuss separately. However, both counter each other but have their significance and indisputable fact. Human psychology evolves around determinism and Free Will. One type of determinism is hard, while the other is soft. Individuals who are adamant about and embrace acceptance of chances are driven by their nature and psychology to choose negative behaviors under hard determinism. They give up their free will, whereas soft determinists use it to make choices and behave positively. However, the researchers looked at negative psychology as a useful aspect and positive psychology's dark side. We argued that there are reasons to suppose that chances can develop into options and vice versa. From a well-being perspective, negative and positive psychological strengths and weaknesses can be investigated. From the literature review, useful hypotheses for future research have been derived from our synthesis.
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The double-stranded RNA-dependent protein kinase activating protein (PACT), an RNA-binding protein that is part of the RNA-induced silencing complex, plays a key role in miR-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RNA-induced silencing complex, and determines proper miR length. Apart from PACT's role in mediating the antiviral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a posttranscriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial complex IV subunit I (Mtco1) and sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT.
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Tejido Adiposo Pardo , MicroARNs , Mitocondrias , Biogénesis de Organelos , Proteínas de Unión al ARN , Tejido Adiposo Pardo/metabolismo , Animales , Complejo I de Transporte de Electrón/metabolismo , Ratones , MicroARNs/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Complejo Silenciador Inducido por ARN/metabolismoRESUMEN
BACKGROUND: Low- and middle-income countries sustain the majority of pediatric cancer burden, with significantly poorer survival rates compared to high-income countries. Collaboration between institutions in low- and middle-income countries and high-income countries is one of the ways to improve cancer outcomes. METHODS: Patient characteristics and effects of a pediatric neuro-oncology twinning program between the Hospital for Sick Children in Toronto, Canada and several hospitals in Karachi, Pakistan over 7 years are described in this article. RESULTS: A total of 460 patients were included in the study. The most common primary central nervous system tumors were low-grade gliomas (26.7%), followed by medulloblastomas (18%), high-grade gliomas (15%), ependymomas (11%), and craniopharyngiomas (11.7%). Changes to the proposed management plans were made in consultation with expert physicians from the Hospital for Sick Children in Toronto, Canada. On average, 24% of the discussed cases required a change in the original management plan over the course of the twinning program. However, a decreasing trend in change in management plans was observed, from 36% during the first 3.5 years to 16% in the last 3 years. This program also led to the launch of a national pediatric neuro-oncology telemedicine program in Pakistan. CONCLUSIONS: Multidisciplinary and collaborative efforts by experts from across the world have aided in the correct diagnosis and treatment of children with brain tumors and helped establish local treatment protocols. This experience may be a model for other low- and middle-income countries that are planning on creating similar programs.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Encefálicas/terapia , Canadá , Niño , Países en Desarrollo , Ecosistema , Humanos , PakistánRESUMEN
Historically, qualitative research has complemented quantitative biologic and epidemiologic studies to provide a more complete understanding of pandemics. The COVID-19 pandemic has generated unique and novel challenges for qualitative researchers, who have embraced creative solutions including virtual focus groups and rapid analyses to continue their work. We present our experience conducting a multilingual global qualitative study of healthcare resilience among teams of pediatric oncology professionals during the COVID-19 pandemic. We provide an in-depth description of our methodology and an analysis of factors we believe contributed to our study's success including our use of technology, engagement of a large multilingual team, global partnerships, and framework-based rapid analysis. We hope these techniques may be useful to qualitative researchers conducting studies during the current pandemic, as well as for all pediatric oncology studies including multiple languages or geographically disparate subjects.
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Kawasaki disease (KD) is the leading cause of noncongenital heart disease in children. Studies in mice and humans propound the NLRP3/IL-1ß pathway as the principal driver of KD pathophysiology. Endoplasmic reticulum (ER) stress can activate the NLRP3 inflammasome, but the potential implication of ER stress in KD pathophysiology has not been investigated to our knowledge. We used human patient data and the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to characterize the impact of ER stress on the development of cardiovascular lesions. KD patient transcriptomics and single-cell RNA sequencing of the abdominal aorta from LCWE-injected mice revealed changes in the expression of ER stress genes. Alleviating ER stress genetically, by conditional deletion of inositol-requiring enzyme 1 (IRE1) in myeloid cells, or pharmacologically, by inhibition of IRE1 endoribonuclease (RNase) activity, led to significant reduction of LCWE-induced cardiovascular lesion formation as well as reduced caspase-1 activity and IL-1ß secretion. These results demonstrate the causal relationship of ER stress to KD pathogenesis and highlight IRE1 RNase activity as a potential new therapeutic target.
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Lacticaseibacillus casei , Síndrome Mucocutáneo Linfonodular , Vasculitis , Animales , Modelos Animales de Enfermedad , Endorribonucleasas/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/patología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas Serina-Treonina Quinasas/genética , RibonucleasasRESUMEN
Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.
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Aterosclerosis , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Proteínas de la Membrana , Proteínas Serina-Treonina Quinasas , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/prevención & control , Estrés del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Hepatitis C virus (HCV) infection is a debilitating chronic health problem and can be fatal if left untreated. Illness perceptions are self-manifested beliefs that influence the ability of individuals to cope with their disease and perceive it as manageable or threatening condition. Limited evidence is available from low resource settings regarding patient perception about HCV. In this study, we aimed to assess the perception of individuals with HCV, the impact of their sociodemographic and clinical characteristics on their HCV perception, and its link to patient-oriented treatment outcomes. METHODS: A cross-sectional survey was undertaken enrolling individuals with HCV who attended Hepatitis C clinics at two hospitals of Khyber Pakhtunkhwa, Pakistan. Illness perception was measured using Brief Illness Perception Questionnaire (BIPQ). Descriptive statistics, Kruskal Wallis tests and Mann Whitney U tests were performed to study patient sociodemographic and clinical characteristics and to analyze the questionnaire results. Multivariable linear regression was used to assess determinants associated with perception scores. RESULTS: Participants represented poor HCV perception and their overall mean BIPQ score was 43.35, SD = 13.15. Participants had a low degree of understanding about their illness (mean coherence score = 2.92, SD = 1.85). Individuals with more than four years, compared to less than one year, of estimated HCV infection were more likely to view that their illness would continue (mean timeline score = 6.27, SD = 2.50 versus 5.36, SD = 2.53; respectively, p < 0.01). Similarly, individuals with hepatic cirrhosis, compared to without, were more likely to attribute symptoms to their disease (mean identity score = 5.48, SD = 2.14 versus 4.89, SD = 2.38; respectively, p = 0.04). Female participants reported higher degrees at which the illness affected them emotionally (i.e., emotional representation) and lower coherence about HCV than males (p = 0.04 and 0.006, respectively). Individuals who did not achieve sustained virological response 24 weeks after treatment with interferon-based therapy, compared to treatment naïve individuals, reported lower trust in being successfully treated with newer anti-HCV agents (i.e., direct acting antivirals) (p = 0.029). However, multivariable linear regression revealed that no sociodemographic or clinical determinants were associated with a higher BIPQ score (i.e., more threatening, or negative perceptions). CONCLUSION: Individuals with HCV in Pakistan generally report threatening or negative views about HCV infection. Lack of trust in treatment efficacy was also apparent, especially in those who experienced failed anti-HCV treatments in the past. Healthcare professionals should consider these perceptions when treating individuals with HCV to optimize their compliance by aligning their perception with the high effectiveness of current anti-HCV therapies.
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Hepatitis C Crónica , Hepatitis C , Antivirales/uso terapéutico , Estudios Transversales , Femenino , Hepacivirus , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Masculino , Pakistán , PercepciónRESUMEN
Customer experience is a source of retailers' long-term competitive advantage. This study has examined the relationship between online customer experience and brand love through the mechanism of relationship quality in the context of online shopping in Pakistan. The moderating effect of value co-creation on the relationship of online customer experience with relationship quality and brand love has also been examined. Data were collected from a purposive sampling of 189 online customers in an online survey. Results showed that online customer experience significantly impacts customer relationship quality, which leads to brand love. The relationship between online customer experience and relationship quality is found more robust at high levels of value co-creation. However, we observed a significant negative moderating effect of value co-creation on the direct relationship between online customer experience and brand love. It suggests that including customers in the value co-creation process and affording them a pleasurable online shopping experience may be an excellent way to enhance customer relationship quality and brand love. Theoretical and practical implications of these findings are discussed.