summary:The emergence of global history has been one of the more notable features of academic history over the past three decades. Although historians of disease were among the pioneers of one of its earlier incarnations—world history—the recent “global turn” has made relatively little impact on histories of health, disease, and medicine. Most continue to be framed by familiar entities such as the colony or nation-state or are confined to particular medical “traditions.” This article aims to show what can be gained from taking a broader perspective. Its purpose is not to replace other ways of seeing or to write a new “grand narrative” but to show how transnational and transimperial approaches are vital to understanding some of the key issues with which historians of health, disease, and medicine are concerned. Moving on from an analysis of earlier periods of integration, the article offers some reflections on our own era of globalization and on the emerging field of global health.
BACKGROUND Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).
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Williams Monier Texidor, Matthew A. Miller, Kyle C. Molina
et al.
Abstract Background Oritavancin, a long-acting lipoglycopeptide approved for use in acute bacterial skin and skin structure infections, has limited data evaluating use in serious infections due to Gram-positive organisms. We aimed to assess the effectiveness and safety of oritavancin for consolidative treatment of Gram-positive bloodstream infections (BSI), including infective endocarditis (IE). Methods We conducted a retrospective cohort study evaluating adult patients admitted to University of Colorado Hospital from March 2016 to January 2022 who received ≥ 1 oritavancin dose for treatment of Gram-positive BSI. Patients were excluded if the index culture was drawn at an outside facility or were > 89 years of age. The primary outcome was a 90-day composite failure (clinical or microbiological failure) in those with 90-day follow-up. Secondary outcomes included individual components of the primary outcome, acute kidney injury (AKI), infusion-related reactions (IRR), and institutional cost avoidance. Results Overall, 72 patients were included. Mean ± SD age was 54 ± 16 years, 61% were male, and 10% had IE. Organisms most commonly causing BSI were Staphylococcus aureus (68%, 17% methicillin-resistant), followed by Streptococcus spp. (26%), and Enterococcus spp. (10%). Patients received standard-of-care antibiotics before oritavancin for a median (IQR) of 11 (5–17) days. Composite failure in the clinically evaluable population (n = 64) at 90-days occurred in 14% and was composed of clinical and microbiological failure, which occurred in 14% and 5% of patients, respectively. Three patients (4%) experienced AKI after oritavancin, and two (3%) experienced an IRR. Oritavancin utilization resulted in earlier discharge for 94% of patients corresponding to an institutional cost-avoidance of $3,055,804 (mean $44,938/patient) from 1,102 hospital days saved (mean 16 days/patient). Conclusions The use of oritavancin may be an effective sequential therapy for Gram-positive BSI to facilitate early discharge resulting in institutional cost avoidance.
Jiawen Fong, Dawn Sinn Yii Chia, Darryl Ee Ming Chew
et al.
The Bacillus Calmette–Guerin (BCG) vaccine, derived from wild-type Mycobacterium bovis, is administered in an attenuated form to prevent Mycobacterium tuberculous (MTB) infections in children residing in endemic regions. Since the introduction of the Singapore Tuberculosis Elimination Programme in 1997—specifying mandatory BCG-immunisation at birth—the incidence fell drastically to 32.6 per 100,000 population in 2021,1 with the paediatric population contributing 2.1% of infections.2
Veronica Obregon-Perko, Amanda Mannino, Jason T. Ladner
et al.
While simian immunodeficiency virus (SIV) infection is non-pathogenic in naturally infected African nonhuman primate hosts, experimental or accidental infection in rhesus macaques often leads to AIDS. Baboons, widely distributed throughout Africa, do not naturally harbor SIV, and experimental infection of baboons with SIVmac results in transient low-level viral replication. Elucidation of mechanisms of natural immunity in baboons could uncover new targets of antiviral intervention. We tested the hypothesis that an SIVmac adapted to replicate in baboon primary cells will gain the capacity to establish chronic infections in vivo. Here, we generated SIVmac variants in baboon cells through serial passage in PBMC from different donors (SIVbn-PBMC s1), in PBMC from the same donors (SIVbn-PBMC s2), or in isolated CD4 cells from the same donors used for series 2 (SIVbn-CD4). While SIVbn-PBMC s1 and SIVbn-CD4 demonstrated increased replication capacity, SIVbn-PBMC s2 did not. Pharmacological blockade of CCR5 revealed SIVbn-PBMC s1 could more efficiently use available CCR5 than SIVmac, a trait we hypothesize arose to circumvent receptor occupation by chemokines. Sequencing analysis showed that all three viruses accumulated different types of mutations, and that more non-synonymous mutations became fixed in SIVbn-PBMC s1 than SIVbn-PBMC s2 and SIVbn-CD4, supporting the notion of stronger fitness pressure in PBMC from different genetic backgrounds. Testing the individual contribution of several newly fixed SIV mutations suggested that is the additive effect of these mutations in SIVbn-PBMC s1 that contributed to its enhanced fitness, as recombinant single mutant viruses showed no difference in replication capacity over the parental SIVmac239 strain. The replicative capacity of SIVbn-PBMC passage 4 (P4) s1 was tested in vivo by infecting baboons intravenously with SIVbn-PBMC P4 s1 or SIVmac251. While animals infected with SIVmac251 showed the known pattern of transient low-level viremia, animals infected with SIVbn-PBMC P4 s1 had undetectable viremia or viral DNA in lymphoid tissue. These studies suggest that adaptation of SIV to grow in baboon primary cells results in mutations that confer increased replicative capacity in the artificial environment of cell culture but make the virus unable to avoid the restrictive factors generated by a complex multicellular organism.
The multi-disciplinary nature of palliative care is emphasized throughout the book. As palliative care has become an established specialty, there is the need for the evidence-base to match other areas of clinical medicine. Ethical and communication issues are explored and the treatment of symptoms is comprehensively covered, with particular focus on the management of pain. The book also includes specific chapters devoted to the role of palliative care in non-malignant diseases and conditions, whilst education and training are highlighted as critical to future best practice.
Sehar-un-Nisa Hassan,1,2 Aqeela Zahra,3 Nuzhat Parveen,4 Naveed Iqbal,4 Sarwat Mumtaz,5 Asma Batool6 1Department of Public Health, College of Public Health and Health Informatics, University of Ha’il, Ha’il, 81451, Kingdom of Saudi Arabia; 2Department of Behavioral Sciences, School of Social Sciences and Humanities, National University of Sciences and Technology (NUST), Islamabad, Pakistan; 3Department of Family and Community Medicine, College of Medicine, University of Ha’il, Ha’il, 81451, Kingdom of Saudi Arabia; 4Department of Obstetrics and Gynecology, College of Medicine, University of Ha’il, Ha’il, 81451, Kingdom of Saudi Arabia; 5Department of Health Management, College of Public Health and Health Informatics, University of Ha’il, Ha’il, 81451, Kingdom of Saudi Arabia; 6Obstetrics and Gynecology, Maternity and Children Hospital Ha’il, Ha’il, Kingdom of Saudi ArabiaCorrespondence: Sehar-un-Nisa Hassan, Department of Public Health, College of Public Health and Health Informatics, University of Ha’il, Ha’il, 81451, Kingdom of Saudi Arabia, Tel +966 5576 629 275, Email s.nisa@uoh.edu.sa; sehar_nisa@hotmail.com Nuzhat Parveen, Department of Obstetrics and Gynecology, College of Medicine, University of Ha’il, Ha’il, 81451, Kingdom of Saudi Arabia, Email n.parveen@uoh.edu.saAbstract: Background: Treatment tolerability and treatment environment are two major spheres of infertility care that may associate with women’s emotional health and coping mechanisms.Aim: The present study aimed at assessing the relationship between infertility treatment quality and various aspects of emotion-focus coping, problem-focus coping, and avoidance coping mechanisms.Method: The study was completed by using standardized tools and data from this descriptive, cross-sectional, correlational study were collected from 350 women undergoing infertility treatments in private reproductive healthcare centers in Quetta, Pakistan.Findings: Treatment tolerability was found to be positively associated with positive reframing (p < 0.02) and negatively associated with the use of emotional support (p < 0.03); acceptance (p < 0.01); humor (p < 0.03); behavioral disengagement (p < 0.01) and venting (p < 0.01). The quality of the treatment environment demonstrated a negative correlation between religious coping (p < 0.02) and behavioral disengagement (p < 0.01), whereas it showed a positive correlation with active coping (p < 0.03) and planning (p < 0.02). The linear regression analysis demonstrated that treatment tolerability significantly increased with positive reframing (R2 = 0.118, F(304) = 2.22, p < 0.03). Behavioral disengagement significantly decreased with better treatment environment (R2 = 0.111, F(304) = 2.09, p < 0.02).Discussion: We discussed the findings keeping in view the role of social, cultural, and economic factors related to infertility care in the context South-Asian culture, and recommendations are made to promote women’s mental health and coping by improving some specific aspects of infertility treatment quality.Conclusions: High treatment tolerability may associate with some useful aspects of emotion-focus coping, such as positive reframing, whereas low treatment tolerability may associate with avoidance coping, such as behavioral disengagement and venting. Besides, the quality of the infertility treatment environment enables women to use problem-focus coping mechanisms, such as planning and active coping.Keywords: infertility, treatment quality, FertiQol, coping mechanisms, mental health, reproductive healthcare, treatment tolerability, treatment environment, psychological well-being
Aymen M. Madkhali, Ahmad Hassn Ghzwani, Hesham M. Al-Mekhlafi
This cross-sectional study aimed to assess the performances of a rapid diagnostic test (RDT)—the AllTest Malaria p.f./p.v., microscopy, and nested polymerase chain reaction (PCR) for diagnosing <i>Plasmodium falciparum</i> malaria in 400 febrile patients from a low-transmission region (Jazan) in southwestern Saudi Arabia. Diagnostic performance of all three methods was compared using microscopy and nested PCR as reference methods. Overall, 42 (10.5%), 48 (12.0%), and 57 (14.3%) samples were found positive by microscopy, RDT, and PCR, respectively. With PCR as reference method, the RDT showed higher sensitivity (79% vs. 71.9%), similar specificity (99.1% vs. 99.7%), and better NLR (0.20 vs. 0.27) and area under the curve (89.0% vs. 85.8%) than microscopy. The sensitivity of RDT and microscopy decreased as age increased, and false negatives were associated with low parasite density. In addition, the sensitivity of RDT and microscopy was higher in non-Saudi than in Saudi participants. Against microscopy, both RDT and PCR showed high sensitivity (83.3% vs. 97.6%), specificity (96.4% vs. 95.5%), and NPVs (98.0% vs. 99.7%), but reduced PPVs (72.9% vs. 71.9%), respectively. The results showed that the performance of the AllTest Malaria p.f./p.v RDT was better than that of microscopy in diagnosing <i>P. falciparum</i> malaria among febrile patients in the Jazan region when nested PCR was used as the reference. However, further studies are required to assess malaria diagnostic methods among asymptomatic individuals in the region.
Sanna Laurila, Sanna Laurila, Sanna Laurila
et al.
Secretin is the first hormone that has been discovered, inaugurating the era and the field of endocrinology. Despite the initial focus, the interest in its actions faded away over the decades. However, there is mounting evidence regarding the pleiotropic beneficial effects of secretin on whole-body homeostasis. In this review, we discuss the evidence from preclinical and clinical studies based on which secretin may have a role in the treatment of obesity.
Diseases of the endocrine glands. Clinical endocrinology