Abstract Purpose This review summarizes the current state of the science related to fear of hypoglycemia (FOH) in adults with type 1 diabetes. Fear of hypoglycemia is a critical deterrent to diabetes ...self-management, psychological well-being, and quality of life. We examine the influence of contemporary treatment regimens, technology, and interventions to identify gaps in knowledge and opportunities for research and practice. Basic Procedures A literature search was conducted of MEDLINE, PsycINFO, and EMBASE. Fifty-three studies that examined fear of hypoglycemia were included. Main Findings Fear of hypoglycemia influences diabetes management and quality of life. Gender and age differences exist in experiences and responses. Responses vary from increased vigilance to potentially immobilizing distress. Fear of hypoglycemia is greater at night and may contribute to poor sleep quality. Strategies to reduce fear of hypoglycemia have had varying success. Newer technologies hold promise but require further examination. Conclusions Fear of hypoglycemia remains a problem, despite advances in technology, insulin analogs, and evidence-based diabetes management. Clinical care should consistently include assessment for its influence on diabetes self-management and psychological health. Further research is needed regarding the influence of newer technologies and individualized strategies to reduce fear of hypoglycemia while maintaining optimal glucose control.
The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its ...therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.
Inhalation errors frequently occur in patients receiving inhalation treatment, which can significantly impair treatment success. While this underscores the importance of inhalation training, the role ...of modern web-based instructional videos has not yet been investigated.
A randomized controlled trial using standardized checklists (10 items: preparation, N = 3, inhalation routine, N = 6, and closure of inhalation, N = 1) was carried out to determine the relative effects of web-based, device-specific videos versus standard personal instruction on reducing multiple (≥2) inhalation errors in severe COPD patients requiring hospitalisation. Investigators assessing inhalation errors were blinded to the intervention.
Multiple handling errors were recorded at baseline in 152 out of 159 patients (95.6%). Each teaching method led to a similar reduction in errors (videos: from 4.2±1.6 to 1.5±1.5 errors; personal instruction: from 3.8±1.5 to 1.3±1.6; p<0.0001), although non-inferiority of web-based video teaching could not be confirmed statistically due to an unpredictably high number of patients in both groups still making multiple handling errors (44.0% versus 40.3%, mean difference 3.7%; 95%CI -12.0-19.4%).
Multiple inhalation errors regularly occur in severe COPD patients requiring hospitalisation. Web-based video teaching is capable of reducing inhalation errors. However, compared to personal instruction non-inferiority could not be established. This was due to an unexpectedly high number of patients with persisting inhalation errors despite training.
Clinical trial Registration: German Clinical Trial Register, DRKS 00004320.
One of three short companion essays to Terry Shoemaker's “World Religion and Fake News: A Pedagogical Response in an Age of Post‐Truth,” published in this issue of the journal.
Type I interferons (IFNs), including IFN-α, upregulate an array of IFN-stimulated genes (ISGs) and potently suppress Human immunodeficiency virus type 1 (HIV-1) infectivity in CD4(+) T cells, ...monocyte-derived macrophages, and dendritic cells. Recently, we and others identified ISG myxovirus resistance 2 (MX2) as an inhibitor of HIV-1 nuclear entry. However, additional antiviral blocks exist upstream of nuclear import, but the ISGs that suppress infection, e.g., prior to (or during) reverse transcription, remain to be defined. We show here that the HIV-1 CA mutations N74D and A105T, both of which allow escape from inhibition by MX2 and the truncated version of cleavage and polyadenylation specific factor 6 (CPSF6), as well as the cyclophilin A (CypA)-binding loop mutation P90A, all increase sensitivity to IFN-α-mediated inhibition. Using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology, we demonstrate that the IFN-α hypersensitivity of these mutants in THP-1 cells is independent of MX2 or CPSF6. As expected, CypA depletion had no additional effect on the behavior of the P90A mutant but modestly increased the IFN-α sensitivity of wild-type virus. Interestingly, the infectivity of wild-type or P90A virus could be rescued from the MX2-independent IFN-α-induced blocks in THP-1 cells by treatment with cyclosporine (Cs) or its nonimmunosuppressive analogue SDZ-NIM811, indicating that Cs-sensitive host cell cyclophilins other than CypA contribute to the activity of IFN-α-induced blocks. We propose that cellular interactions with incoming HIV-1 capsids help shield the virus from recognition by antiviral effector mechanisms. Thus, the CA protein is a fulcrum for the dynamic interplay between cell-encoded functions that inhibit or promote HIV-1 infection.
HIV-1 is the causative agent of AIDS. During acute HIV-1 infection, numerous proinflammatory cytokines are produced, including type I interferons (IFNs). IFNs can limit HIV-1 replication by inducing the expression of a set of antiviral genes that inhibit HIV-1 at multiple steps in its life cycle, including the postentry steps of reverse transcription and nuclear import. This is observed in cultured cell systems, as well as in clinical trials in HIV-1-infected patients. The identities of the cellular antiviral factors, their viral targets, and the underpinning mechanisms are largely unknown. We show here that the HIV-1 Capsid protein plays a central role in protecting the virus from IFN-induced inhibitors that block early postentry steps of infection. We further show that host cell cyclophilins play an important role in regulating these processes, thus highlighting the complex interplay between antiviral effector mechanisms and viral survival.
Background Veno-venous extracorporeal CO.sub.2 removal (vv-ECCO.sub.2R) and non-invasive neurally adjusted ventilator assist (NIV-NAVA) are two promising techniques which may prevent complications ...related to prolonged invasive mechanical ventilation in patients with acute exacerbation of COPD. Methods A physiological study of the electrical activity of the diaphragm (Edi) response was conducted with varying degrees of extracorporeal CO.sub.2 removal to control the respiratory drive in patients with severe acute exacerbation of COPD breathing on NIV-NAVA. Results Twenty COPD patients (SAPS II 37 + or - 5.6, age 57 + or - 9 years) treated with vv-ECCO.sub.2R and supported by NIV-NAVA were studied during stepwise weaning of vv-ECCO.sub.2R. Based on dyspnea, tolerance, and blood gases, weaning from vv-ECCO.sub.2R was successful in 12 and failed in eight patients. Respiratory drive (measured via the Edi) increased to 19 + or - 10 muV vs. 56 + or - 20 muV in the successful and unsuccessful weaning groups, respectively, resulting in all patients keeping their CO.sub.2 and pH values stable. Edi was the best predictor for vv-ECCO.sub.2R weaning failure (ROC analysis AUC 0.95), whereas respiratory rate, rapid shallow breathing index, and tidal volume had lower predictive values. Eventually, 19 patients were discharged home, while one patient died. Mortality at 90 days and 180 days was 15 and 25%, respectively. Conclusions This study demonstrates for the first time the usefulness of the Edi signal to monitor and guide patients with severe acute exacerbation of COPD on vv-ECCO.sub.2R and NIV-NAVA. The Edi during vv-ECCO.sub.2R weaning was found to be the best predictor of tolerance to removing vv-ECCO.sub.2R. Keywords: Non-invasive ventilation, Extracorporeal carbon dioxide removal, COPD, Exacerbation, Neurally adjusted ventilatory assist
Rather than placing the onus on stigmatized and disenfranchised communities as hard-to-reach in sexual health research, we challenge researchers to recognize and provide outreach to populations who ...are hardly reached, such as cisgender Black women. We posit that the disparate human immunodeficiency virus (HIV) and sexually transmitted infection (STI) rates experienced by Black women in the USA are due in part to social and structural inequities and lack of researcher outreach within these communities. Social inequities give rise to racial and gender discrimination, which often results in structural barriers that researchers may not acknowledge. Structural barriers include medical mistrust and lack of access to preventative sexual health services, health care, education, and other resources. To achieve health equity, researchers must engage with Black women to understand the unique struggles they face and intervene with non-stigmatizing, culturally appropriate interventions. Interventions must utilize gatekeepers, influencers, community organizations, community advisory boards, and peer support. It is critical that sexual health researchers reach out to those who do not fall under the traditional hard-to-reach category but are hardly reached to counteract the current projection that 1 in 32 Black women will be diagnosed with HIV in their lifetime.
Canine dorsal root ganglion (DRG) neurons, isolated post mortem from adult dogs, could provide a promising tool to study neuropathogenesis of neurotropic virus infections with a non-rodent host ...spectrum. However, access to canine DRG is limited due to lack of donor tissue and the cryopreservation of DRG neurons would greatly facilitate experiments. The present study aimed (i) to establish canine DRG neurons as an in vitro model for canine distemper virus (CDV) infection; and (ii) to determine whether DRG neurons are cryopreservable and remain infectable with CDV. Neurons were characterized morphologically and phenotypically by light microscopy, immunofluorescence, and functionally, by studying their neurite outgrowth and infectability with CDV. Cryopreserved canine DRG neurons remained in culture for at least 12 days. Furthermore, both non-cryopreserved and cryopreserved DRG neurons were susceptible to infection with two different strains of CDV, albeit only one of the two strains (CDV R252) provided sufficient absolute numbers of infected neurons. However, cryopreserved DRG neurons showed reduced cell yield, neurite outgrowth, neurite branching, and soma size and reduced susceptibility to CDV infection. In conclusion, canine primary DRG neurons represent a suitable tool for investigations upon the pathogenesis of neuronal CDV infection. Moreover, despite certain limitations, cryopreserved canine DRG neurons generally provide a useful and practicable alternative to address questions regarding virus tropism and neuropathogenesis.
Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, ...dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2–like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi-Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.
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