It is thought that monocytes rapidly differentiate to macrophages or dendritic cells (DCs) upon leaving blood. Here we have shown that Ly-6C+ monocytes constitutively trafficked into skin, lung, and ...lymph nodes (LNs). Entry was unaffected in gnotobiotic mice. Monocytes in resting lung and LN had similar gene expression profiles to blood monocytes but elevated transcripts of a limited number of genes including cyclo-oxygenase-2 (COX-2) and major histocompatibility complex class II (MHCII), induced by monocyte interaction with endothelium. Parabiosis, bromodoxyuridine (BrdU) pulse-chase analysis, and intranasal instillation of tracers indicated that instead of contributing to resident macrophages in the lung, recruited endogenous monocytes acquired antigen for carriage to draining LNs, a function redundant with DCs though differentiation to DCs did not occur. Thus, monocytes can enter steady-state nonlymphoid organs and recirculate to LNs without differentiation to macrophages or DCs, revising a long-held view that monocytes become tissue-resident macrophages by default.
•Ly-6C+ not Ly-6C− monocytes enter tissues in the steady state•Tissue monocytes can retain monocyte profile without becoming macrophages or DCs•Tissue monocytes may mediate antigen surveillance: they are MHCII+ and migrate to LNs•MHCII induction on tissue monocytes can be driven by interactions with endothelium
Kinases are principal components of signal transduction pathways and the focus of intense basic and drug discovery research. Irreversible inhibitors that covalently modify non-catalytic cysteines in ...kinase active sites have emerged as valuable probes and approved drugs. Many protein classes, however, have functional cysteines, and therefore understanding the proteome-wide selectivity of covalent kinase inhibitors is imperative. Here, we accomplish this objective using activity-based protein profiling coupled with quantitative MS to globally map the targets, both specific and nonspecific, of covalent kinase inhibitors in human cells. Many of the specific off-targets represent nonkinase proteins that, notably, have conserved active site cysteines. We define windows of selectivity for covalent kinase inhibitors and show that, when these windows are exceeded, rampant proteome-wide reactivity and kinase target-independent cell death conjointly occur. Our findings, taken together, provide an experimental road map to illuminate opportunities and surmount challenges for the development of covalent kinase inhibitors.
Background/Objectives
To address the underrepresentation of older adults in clinical research, the National Institutes of Health will require investigators to include individuals across the lifespan. ...As investigators from other fields endeavor to recruit participants who are more representative of the patient population, geriatricians may have the opportunity to influence a broad range of research studies in older adults. Our aims were to elicit challenges to inclusion of older adults in clinical research and to develop a preliminary framework for communicating these challenges to non–geriatrics‐trained researchers.
Design
Communication framework development.
Setting
Academic hospital and Veterans Affairs Medical Center.
Participants
Nongeriatrician researchers and staff, aging research experts.
Measurements
Interviews were used to elicit challenges nongeriatrician investigators and research staff experience when conducting research that includes older adults and then solicit experienced aging researchers' responses to these challenges.
Results
Challenges described by nongeriatrician investigators included lack of knowledge, rigid study structures, and a disease‐focused approach. Responses from our geriatrics experts included communicating practical advice for avoiding common pitfalls. Our resulting framework is the 5Ts: Target Population, Team, Tools, Time, and Tips to Accommodate. This tool complements the 5Ms (Mind, Mobility, Medications, Multicomplexity, and Matters Most to Me) model for geriatric care and emphasizes representation of the Target Population, building research Teams that include aging expertise, incorporating appropriate Tools for function and patient‐reported outcomes, anticipating Time for longer study visits, and accommodating common needs with practical Tips. Limitations include convenience sampling and lack of formal qualitative thematic analysis.
Conclusion
Communicating with nongeriatrician researchers using the 5Ts may offer a practical approach to avoiding barriers to inclusion of older adults in research and complements an existing framework for communicating the value of geriatric medicine. Next steps in developing the 5Ts will be to include additional stakeholders (eg, national samples of nongeriatrician investigators, older adults and their families) and evaluating the impact of its implementation. J Am Geriatr Soc 67:342–346, 2019.
See related Editorial by George Kuchel in this issue.
Abstract Background Nocturia (ie, waking at night to void) is common and disrupts sleep. Traditionally, one nightly episode has been regarded as clinically meaningless, yet the justification for this ...belief remains weak. Objective To evaluate the association among frequency of nocturia and bother and health-related quality of life (HRQoL). Design, setting, and participants In 2003–2004, a survey was mailed to a random sample of 6000 subjects aged 18–79 yr who were identified from the Finnish Population Register Centre (response proportion was 62.4%; 53.7% were females). Measurements HRQoL and bother from nocturia were examined in relation to self-reported nocturia frequency (using the American Urological Association Symptom Index and the Danish Prostatic Symptom Score). Bother from nocturia was assessed on a four-point scale (none, small, moderate, major). HRQoL was measured with the generic 15D instrument on a 0–1 scale with a minimum clinically important difference of 0.03. Results and limitations Degree of bother increased with nocturia frequency ( p < 0.01). The most commonly cited degree of bother for those with one, two, and three nightly voids was no bother, small bother, and moderate bother, respectively. The mean age-adjusted 15D score for men (and women) without nocturia was 0.953 (0.950) and 0.925 (0.927) with one void per night, 0.898 (0.890) with two voids per night, and 0.833 (0.840) with three or more voids per night. Statistically significant decreases were found in 15D score and in all 15D dimensions except eating. Although the response rate was high, approximately one third of those contacted did not participate in the study. Conclusions At least two voids per night is associated with impaired HRQoL. The majority of people report having bother when the number of nocturia episodes is two and moderate or major bother when the number is three or more. One void per night does not identify subjects with interference from nocturia and, thus, is not a suitable criterion for clinically relevant nocturia.
Although nocturia is associated with various comorbidities, its impact on falls and fractures remains unclear. We performed a systematic review and meta-analysis to evaluate the association between ...nocturia and falls and fractures as a prognostic and as a causal risk factor.
We searched PubMed®, Scopus®, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and abstracts of major urological meetings up to December 31, 2018. We conducted random effects meta-analyses of adjusted relative risks of falls and fractures. We applied the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for nocturia as a prognostic and causal factor of falls and fractures.
Among 5,230 potential reports 9 observational longitudinal studies provided data on the association between nocturia and falls or fractures (1 for both, 4 for falls, 4 for fractures). Pooled estimates demonstrated a risk ratio of 1.20 (95% CI 1.05-1.37, I
=51.7%, annual risk difference 7.5% among the elderly) for association between nocturia and falls and 1.32 (95% CI 0.99-1.76, I
=57.5%, annual risk difference 1.2%) for association between nocturia and fractures. Subgroup analyses showed no significant effect modification by age, gender, followup time, nocturia case definition or risk of bias. We rated the quality of evidence for nocturia as a prognostic factor as moderate for falls and low for fractures, and as very low as a cause of falls/fractures.
Nocturia is probably associated with an approximately 1.2-fold increased risk of falls and possibly an approximately 1.3-fold increased risk of fractures.
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