Distinct Phenotypic Consequences of Pathogenic Mutants Associated with Late-Onset Retinal Degeneration.

A pathologic feature of late-onset retinal degeneration caused by the S163R mutation in C1q-tumor necrosis factor-5 (C1QTNF5) is the presence of unusually thick deposits between the retinal pigmented epithelium (RPE) and the vascular choroid, considered a hallmark of this disease. Following its specific expression in mouse RPE, the S163R mutant exhibits a reversed polarized distribution relative to the apically secreted wild-type C1QTNF5, and forms widespread, prominent deposits that gradually increase in size with aging. The current study shows that S163R deposits expand to a considerable thickness through a progressive increase in the basolateral RPE membrane, substantially raising the total RPE height, and enabling their clear imaging as a distinct hyporeflective layer by noninvasive optical coherence tomography in advanced age animals. This phenotype bears a striking resemblance to ocular pathology previously documented in patients harboring the S163R mutation. Therefore, a similar viral vector-based gene delivery approach was used to also investigate the behavior of P188T and G216C, two novel pathogenic C1QTNF5 mutants recently reported in patients for which histopathologic data are lacking. Both mutants primarily impacted the RPE/photoreceptor interface and did not generate basal laminar deposits. Distinct distribution patterns and phenotypic consequences of C1QTNF5 mutants were observed in vivo, which suggested that multiple pathobiological mechanisms contribute to RPE dysfunction and vision loss in this disorder.

Sarafu Community Inclusion Currency 2020-2021.

We describe a dataset of account information and detailed transaction records for a digital complementary currency in Kenya. This "Sarafu system" initially encompassed several local, physical community currencies, which began transitioning to a feature-phone mobile interface in 2017. One unit of "Sarafu" is roughly equivalent in value to a Kenyan shilling. The published data includes anonymized account information for around 55,000 users and records of all Sarafu transactions conducted from January 25, 2020 to June 15, 2021. Transactions totaling around 300 million Sarafu capture various economic and financial activities such as purchases, transfers, and participation in savings and lending groups. So-called "chamas" are key to the operation of the Sarafu system and many such groups are labeled in the data. Describing this data contributes to research on the operation of community currencies, monetary systems, and economic networks in marginalized, food insecure areas. The observation period includes the first year of the COVID-19 pandemic and several documented pilot projects and interventions.

Palm readings: Manicaria saccifera palm fibers are biocompatible textiles with low immunogenicity.

Plant-based fibers are a potential alternative to synthetic polymer fibers that can yield enhanced biocompatibility and mechanical properties matching those properties of tissue. Given the unique morphology of the bract of the Manicaria saccifera palm, being an interwoven meshwork of fibers, we believe that these fibers with this built-in structure could prove useful as a tissue engineering scaffold material. Thus, we first investigated the fiber's in vitro biocompatibility and immunogenicity. We cultured NIH/3T3 mouse fibroblasts, human aortic smooth muscle cells, and human adipose-derived mesenchymal stem cells on the fiber mats, which all readily attached and over 21 days grew to engulf the fibers. Importantly, this was achieved without treating the plant tissue with extracellular matrix proteins or any adhesion ligands. In addition, we measured the gene expression and protein secretion of three target inflammatory cytokines (IL-1ß, IL-8, and TNFα) from THP-1 human leukemia monocytes cultured in the presence of the biotextile as an in vitro immunological model. After 24 h of culture, gene expression and protein secretion were largely the same as the control, demonstrating the low immunogenicity of Manicaria saccifera fibers. We also measured the tensile mechanical properties of the fibers. Individual fibers after processing had a Young's modulus of 9.51 ± 4.38 GPa and a tensile strength of 68.62 ± 27.93 MPa. We investigated the tensile mechanical properties of the fiber mats perpendicular to the fiber axis (transverse loading), which displayed upwards of 100% strain, but with a concession in strength compared to longitudinal loading. Collectively, our in vitro assessments point toward Manicaria saccifera as a highly biocompatible biotextile, with a range of potential clinical and engineering applications.

A Novel Immunocompetent Mouse Model for Testing Antifungal Drugs Against Invasive Candida albicans Infection.

Disseminated infection by Candida species represents a common, often life-threatening condition. Increased resistance to current antifungal drugs has led to an urgent need to develop new antifungal drugs to treat this pathogen. However, in vivo screening of candidate antifungal compounds requires large numbers of animals and using immunosuppressive agents to allow for fungal dissemination. To increase the efficiency of screening, to use fewer mice, and to remove the need for immunosuppressive agents, which may interfere with the drug candidates, we tested the potential for a novel approach using in vivo imaging of a fluorescent strain of Candida albicans, in a mouse strain deficient in the host defense peptide, murine ß-defensin 1 (mBD-1). We developed a strain of C. albicans that expresses red fluorescent protein (RFP), which exhibits similar infectivity to the non-fluorescent parent strain. When this strain was injected into immunocompetent mBD-1-deficient mice, we observed a non-lethal disseminated infection. Further, we could quantify its dissemination in real time, and observe the activity of an antifungal peptide mimetic drug by in vivo imaging. This novel method will allow for the rapid in vivo screening of antifungal drugs, using fewer mice, and increase the efficiency of testing new antifungal agents.

Today´s medical self and the other: Challenges and evolving solutions for enhanced humanization and quality of care.

BACKGROUND: Recent scientific developments, along with growing awareness of cultural and social diversity, have led to a continuously growing range of available treatment options; however, such developments occasionally lead to an undesirable imbalance between science, technology and humanism in clinical practice. This study explores the understanding and practice of values and value clusters in real-life clinical settings, as well as their role in the humanization of medicine and its institutions. The research focuses on the values of clinical practice as a means of finding ways to enhance the pairing of Evidence-Based Medicine (EBM) with Values-based Medicine (VBM) in daily practice. METHODS AND FINDINGS: The views and representations of clinical practice in 15 pre-CME and 15 post-CME interviews were obtained from a random sampling of active healthcare professionals. These views were then identified and qualitatively analyzed using a three-step hermeneutical approach. A clinical values space was identified in which ethical and epistemic values emerge, grow and develop within the biomedical, ethical, and socio-economic dimensions of everyday health care. Three main values-as well as the dynamic clusters and networks that they tend to form-were recognized: healthcare personnel-patient relationships, empathy, and respect. An examination of the interviews suggested that an adequate conceptualization of values leads to the formation of a wider axiological system. The role of clinician-as-consociate emerged as an ideal for achieving medical excellence. CONCLUSIONS: By showing the intricate clusters and networks into which values are interwoven, our analysis suggests methods for fine-tuning educational interventions so they can lead to demonstrable changes in attitudes and practices.

Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism.

Lethal systemic fungal infections of Candida species are increasingly common, especially in immune compromised patients. By in vitro screening of small molecule mimics of naturally occurring host defense peptides (HDP), we have identified several active antifungal molecules, which also exhibited potent activity in two mouse models of oral candidiasis. Here we show that one such compound, C4, exhibits a mechanism of action that is similar to the parent HDP upon which it was designed. Specifically, its initial interaction with the anionic microbial membrane is electrostatic, as its fungicidal activity is inhibited by cations. We observed rapid membrane permeabilization to propidium iodide and ATP efflux in response to C4. Unlike the antifungal peptide histatin 5, it did not require energy-dependent transport across the membrane. Rapid membrane disruption was observed by both fluorescence and electron microscopy. The compound was highly active in vitro against numerous fluconazole-resistant clinical isolates of C. albicans and non-albicans species, and it exhibited potent, dose-dependent activity in a mouse model of invasive candidiasis, reducing kidney burden by three logs after 24 hours, and preventing mortality for up to 17 days. Together the results support the development of this class of antifungal drug to treat invasive candidiasis.

Do doctors undertreat pain?

Routinely, physicians discount patients' pain reports and provide too little analgesia too late. Critics call them callous, sadistic, and Puritanical, but the causes of these clinical pratices are different -- namely, a psychological need to distance themselves from the pain they encounter and inflict, and more subtly, a peculiar concept of pain acquired in medical training. Physicians learn to think of pain as a symptom to observe and explore in diagnosing and monitoring disease -- not as a complaint to relieve quickly or fully. Moreover, pain-relief is regarded as subordinate to, and competing with, efforts to cure or maintain the life of a patient. This training, I suggest, gives physicians a new, clinical concept of pain at odds with their prior, lay concept of pain whose manifestations standardly call for sympathetic efforts at relief. The conceptual nature of this difference is obscured by thinking of pain as a solely private sensation, rather than as a sensation with public and social aspects (à la Wittgenstein). Although suppressed in certain clinical circumstances, these standard public and social aspects are shown in the very tests used in clinical pain research. This clinical pain concept is rooted in Medicine conceived as preeminently curative and life-prolonging. Physicians are, however, themselves undermining this professional self-definition (by treating AIDS and Alzheimer's patients; by no longer pressing their patients to 'fight to the end'; by collaborating with non-medical healers). Accordingly, pain-relief may gain greater therapeutic status, and, so too, the ordinary concept of pain that medical training has suppressed.

Hope and deception.

Convinced of hope's therapeutic benefits, physicians routinely support patients' false hopes, often with family collusion and vague, euphemistic diagnoses and prognoses, if not overt lies. Bioethicists charge them with paternalistic violations of Patient Autonomy. There are, I think, too many morally significant exceptions to accept the physician's rationales, or the bioethicist's criticisms, stated sweepingly. Physicians need to take account of the harms caused by loss of hopes, especially false hopes due to deception, as well as of the harms of successfully maintained deceptive hopes. As for autonomy, hopes -- even if based on deception -- can protect and enhance autonomy, understood broadly as the capacity to lead a chosen or embraced life. Deception aside, patients' hopes often rest on beliefs about possible rather than probable outcomes -- beliefs themselves supported by optimism, 'denial', or self-deception. Such 'possibility-hopes' may conflict with physicians' often more fact-sensitive 'probability hopes.' To resolve such conflicts physicians may try to 'down-shift' patients' or parents' hopes to lesser, more realistic hopes. Alternatively, physicians may alter or enlarge their own professional hopes to include the 'vital hopes' that define the lives of patients or parents, as well as 'survival hopes' needed to face and bear the loss of loved ones, especially children. A principle of Hope-giving might help guide such sympathetic hope-accommodations. More generally, it would give Hope a distinct place among Beneficence, Autonomy, and the other moral factors already highlighted by canonical principles of Medical Ethics. To formulate such a principle, however, we will need a collective Project Hope to pursue deeper philosophical and psychological studies.