LATE-NC staging in routine neuropathologic diagnosis : an update

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.Peer reviewe

Exploring the Perspectives and Experiences of Older Adults With Asthma and Chronic Obstructive Pulmonary Disease Toward Mobile Health: Qualitative Study

BackgroundThe use of mobile health (mHealth) in asthma and chronic obstructive pulmonary disease (COPD) is growing, and as the population ages, a greater number of older adults stand to benefit from mHealth-enhanced airway disease care. Though older adults are a heterogeneous population of health technology users, older age represents a potential barrier to health technology adoption, and there is currently a lack of knowledge on how older age influences mHealth use in asthma and COPD. ObjectiveIn this qualitative study, we sought to explore the experiences and perspectives of adults who were aged 65 years and older with asthma and COPD toward mHealth use. MethodsSemistructured individual interviews were conducted with adults who were aged 65 years and older with asthma or COPD and owned a smartphone. Applying phenomenological methodology, we analyzed interview transcripts in order to develop themes and propose an essential experience of mHealth use among older adults with airway disease. We then summarized our qualitative findings and proposed strategies to leverage our results in order to guide future research and implementation efforts targeting older adults’ use of airway mHealth. ResultsTwenty participants (mean age 79.8, SD 4.4 years) were interviewed. Participants described a central tension between (1) the perception that mHealth could help maintain independence throughout aging and (2) an apprehension toward the ways in which mHealth could negatively affect established health care experiences. Several elements of these 2 themes are absent from previous research focusing on younger adults with asthma and COPD. The individual elements of these 2 themes informed potential strategies to optimize future older adults’ use of asthma and COPD mHealth tools. ConclusionsFocusing on the perspectives and experiences of older adults with asthma and COPD in their use of mHealth identified novel understandings of health technology use in this important demographic in need of greater care. These lessons were translated into potential strategies that will need to be objectively evaluated in future airway mHealth research, development, and implementation efforts

Tumors That Acquire Resistance to Low-Dose Metronomic Cyclophosphamide Retain Sensitivity to Maximum Tolerated Dose Cyclophosphamide1

Low-dose metronomic (LDM) chemotherapy is emerging as an alternative or supplemental dosing strategy to conventional maximum tolerated dose (MTD) chemotherapy. It is characterized primarily, but not exclusively, by antiangiogenic mechanisms of action and the absence of high-grade adverse effects commonly seen with MTD chemotherapy. However, similar to other anticancer therapies, inherent resistance to LDM chemotherapy is common. Moreover, even tumors that initially respond to metronomic regimens eventually develop resistance through mechanisms that are as yet unknown. Thus, we have developed in vivo models of PC-3 human prostate cancer cells resistant to extended LDM cyclophosphamide therapy. Such PC-3 variants show stable resistance to LDM cyclophosphamide in vivo yet retain in vitro sensitivity to 4-hydroperoxy-cyclophosphamide (precursor of the active cyclophosphamide metabolite 4-hydroxy-cyclophosphamide) and other chemotherapeutic agents, namely, docetaxel and doxorubicin. Moreover, LDM cyclophosphamide-resistant PC-3 variants remain sensitive to MTD cyclophosphamide therapy in vivo. Conversely, PC-3 variants made resistant in vivo to MTD cyclophosphamide show varying levels of resistance to metronomic cyclophosphamide when grown in mice. These results and additional studies of variants of the breast cancer cell line MDA-MB-231 suggest that resistance to LDM cyclophosphamide is a distinct phenomenon from resistance to MTD cyclophosphamide and that LDM cyclophosphamide administration does not select for MTD chemotherapy resistance. As such, our findings have various implications for the clinical use of metronomic chemotherapy

Do providers use computerized clinical decision support systems? A systematic review and meta-regression of clinical decision support uptake

BACKGROUND: Computerized clinical decision support systems (CDSSs) are a promising knowledge translation tool, but often fail to meaningfully influence the outcomes they target. Low CDSS provider uptake is a potential contributor to this problem but has not been systematically studied. The objective of this systematic review and meta-regression was to determine reported CDSS uptake and identify which CDSS features may influence uptake. METHODS: Medline, Embase, CINAHL, and the Cochrane Database of Controlled Trials were searched from January 2000 to August 2020. Randomized, non-randomized, and quasi-experimental trials reporting CDSS uptake in any patient population or setting were included. The main outcome extracted was CDSS uptake, reported as a raw proportion, and representing the number of times the CDSS was used or accessed over the total number of times it could have been interacted with. We also extracted context, content, system, and implementation features that might influence uptake, for each CDSS. Overall weighted uptake was calculated using random-effects meta-analysis and determinants of uptake were investigated using multivariable meta-regression. RESULTS: Among 7995 citations screened, 55 studies involving 373,608 patients and 3607 providers met full inclusion criteria. Meta-analysis revealed that overall CDSS uptake was 34.2% (95% CI 23.2 to 47.1%). Uptake was only reported in 12.4% of studies that otherwise met inclusion criteria. Multivariable meta-regression revealed the following factors significantly associated with uptake: (1) formally evaluating the availability and quality of the patient data needed to inform CDSS advice; and (2) identifying and addressing other barriers to the behaviour change targeted by the CDSS. CONCLUSIONS AND RELEVANCE: System uptake was seldom reported in CDSS trials. When reported, uptake was low. This represents a major and potentially modifiable barrier to overall CDSS effectiveness. We found that features relating to CDSS context and implementation strategy best predicted uptake. Future studies should measure the impact of addressing these features as part of the CDSS implementation strategy. Uptake reporting must also become standard in future studies reporting CDSS intervention effects. REGISTRATION: Pre-registered on PROSPERO, CRD42018092337 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13012-022-01199-3

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Prolonged, frequently administered low-dose metronomic chemotherapy (LDM) is being explored (pre)clinically as a promising antiangiogenic antitumor strategy. Although appealing because of a favorable side effect profile and mostly oral dosing, LDM involves new challenges different from conventional maximum tolerated dose chemotherapy. These include possible altered pharmacokinetic characteristics due to long-term drug exposure potentially resulting in acquired resistance and increased risk of unfavorable drug interactions. We therefore compared the antitumor and antivascular effects of LDM cyclophosphamide (CPA) given to mice that had been pretreated with either LDM CPA or normal saline, obtained blood 4-hydroxy-CPA (activated CPA) concentrations using either gas chromatography/mass spectrometry or liquid chromatography/tandem mass spectrometry in mice treated with LDM CPA, and measured hepatic and intratumoral activity of enzymes involved in the biotransformation of CPA and many other drugs [i.e., cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase]. Exposure of mice to LDM CPA for ≥ 8 weeks did not compromise subsequent activity of LDM CPA therapy, and biologically active 4-hydroxy-CPA levels were maintained during long-term LDM CPA administration. Whereas the effects on CYP3A4 were complex, aldehyde dehydrogenase activity was not affected. In summary, our findings suggest that acquired resistance to LDM CPA is unlikely accounted for by altered CPA biotransformation. In the absence of reliable pharmacodynamic surrogate markers, pharmacokinetic parameters might become helpful to individualize/optimize LDM CPA therapy. LDM CPA-associated changes of CYP3A4 activity point to a potential risk of unfavorable drug interactions when compounds that are metabolized by CYP3A4 are coadministered with LDM CPA