Context: Few population-based studies have examined the incidence of meniscal injuries, and limited information is available on the influence of patient's demographic and occupational factors.Objective: To examine the incidence of meniscal injuries and the influence of demographic and occupational factors among active-duty US service members between 1998 and 2006.Design: Cohort study. Setting: Using the International Classification of Diseases (9th revision) codes 836.0 (medial meniscus), 836.1 (lateral meniscus), and 836.2 (meniscus unspecified), we extracted injury data from the Defense Medical Surveillance System to identify all acute meniscal injuries among active-duty military personnel.Patients or Other Participants: Active-duty military personnel serving in all branches of military service during the study period.Main Outcome Measure(s): Incidence rate (IR) per 1000 person-years at risk and crude and adjusted rates by strata for age, sex, race, rank, and service.Results: During the study period, 100201 acute meniscal injuries and 12115606 person-years at risk for injury were documented. The overall IR was 8.27 (95% confidence interval [CI] = 8.22, 8.32) per 1000 person-years. Main effects were noted for all demographic and occupational variables (P< .001), indicating that age, sex, race, rank, and service were associated with the incidence of meniscal injuries. Men were almost 20% more likely to experience an acute meniscal injury than were women (incidence rate ratio = 1.18, 95% CI = 1.15, 1.20). The rate of meniscal injury increased with age; those older than 40 years of age experienced injuries more than 4 times as often as those under 20 years of age (incidence rate ratio = 4.25, 95% CI=4.08,4.42).Conclusions: The incidence of meniscal injury was substantially higher in this study than in previously reported studies. Male sex, increasing age, and service in the Army or Marine Corps were factors associated with meniscal injuries.Key Words: knee injuries, lower extremity injuries, military athletes, injury epidemiology Key Points• To our knowledge, this is the largest population-based study to examine the incidence of meniscal tears within a physically active population that is at elevated risk of sport-and training-related knee injuries. • The overall incidence rate for meniscal injury was more than 10 times that previously documented in civilian populations.• Factors associated with a greater incidence of meniscal injury were male sex, increasing age, and Army or Marine Corps service.

Background & Aims Loss of leucine-rich repeat-containing G-protein–coupled receptor 5–positive crypt base columnar cells provides permissive conditions for different facultative stem cell populations to dedifferentiate and repopulate the stem cell compartment. In this study, we used a defensin α4-Cre recombinase (Defa4Cre) line to define the potential of Paneth cells to dedifferentiate and contribute to intestinal stem cell (ISC) maintenance during normal homeostasis and after intestinal injury. Methods Small intestine and enteroids from Defa4 Cre ; Rosa26 tandem dimer Tomato (tdTomato), a red fluoresent protein, (or Rosa26 Enhanced Yellow Fluorescent Protein (EYFP)) reporter, Notch gain-of-function ( Defa4 Cre ;Rosa26 Notch Intracellular Domain (NICD)-ires-nuclear Green Fluorescent Protein (nGFP) and Defa4 Cre ;Rosa26 reverse tetracycline transactivator–ires Enhanced Green Fluorescent Protein (EGFP) ;TetO NICD ), A Disintegrin and Metalloproteinase domain-containing protein 10 (ADAM10) loss-of-function ( Defa4 Cre ;ADAM10 flox/flox ), and Adenomatous polyposis coli (APC) inactivation ( Defa4 Cre ;APC flox/flox ) mice were analyzed. Doxorubicin treatment was used as an acute intestinal injury model. Lineage tracing, proliferation, and differentiation were assessed in vitro and in vivo. Results Defa4 Cre -expressing cells are fated to become mature Paneth cells and do not contribute to ISC maintenance during normal homeostasis in vivo. However, spontaneous lineage tracing was observed in enteroids, and fluorescent-activated cell sorter–sorted Defa4 Cre -marked cells showed clonogenic enteroid growth. Notch activation in Defa4 Cre -expressing cells caused dedifferentiation to multipotent ISCs in vivo and was required for adenoma formation. ADAM10 deletion had no significant effect on crypt homeostasis. However, after acute doxorubicin-induced injury, Defa4 Cre -expressing cells contributed to regeneration in an ADAM10–Notch–dependent manner. Conclusions Our studies have shown that Defa4 Cre -expressing Paneth cells possess cellular plasticity, can dedifferentiate into multipotent stem cells upon Notch activation, and can contribute to intestinal regeneration in an acute injury model.

In air-breathing vertebrates, the physiologically optimal blood-O2 affinity is jointly determined by the prevailing partial pressure of atmospheric O2, the efficacy of pulmonary O2 transfer, and internal metabolic demands. Consequently, genetic variation in the oxygenation properties of hemoglobin (Hb) may be subject to spatially varying selection in species with broad elevational distributions. Here we report the results of a combined functional and evolutionary analysis of Hb polymorphism in the rufous-collared sparrow (Zonotrichia capensis), a species that is continuously distributed across a steep elevational gradient on the Pacific slope of the Peruvian Andes. We integrated a population genomic analysis that included all postnatally expressed Hb genes with functional studies of naturally occurring Hb variants, as well as recombinant Hb (rHb) mutants that were engineered through site-directed mutagenesis. We identified three clinally varying amino acid polymorphisms: Two in the α(A)-globin gene, which encodes the α-chain subunits of the major HbA isoform, and one in the α(D)-globin gene, which encodes the α-chain subunits of the minor HbD isoform. We then constructed and experimentally tested single- and double-mutant rHbs representing each of the alternative α(A)-globin genotypes that predominate at different elevations. Although the locus-specific patterns of altitudinal differentiation suggested a history of spatially varying selection acting on Hb polymorphism, the experimental tests demonstrated that the observed amino acid mutations have no discernible effect on respiratory properties of the HbA or HbD isoforms. These results highlight the importance of experimentally validating the hypothesized effects of genetic changes in protein function to avoid the pitfalls of adaptive storytelling.

A disintegrin and metalloproteinases (ADAMs) are a family of cell surface proteases that regulate diverse cellular functions, including cell adhesion, migration, cellular signaling, and proteolysis. Proteolytically active ADAMs are responsible for ectodomain shedding of membrane-associated proteins. ADAMs rapidly modulate key cell signaling pathways in response to changes in the extracellular environment (e.g., inflammation) and play a central role in coordinating intercellular communication within the local microenvironment. ADAM10 and ADAM17 are the most studied members of the ADAM family in the gastrointestinal tract. ADAMs regulate many cellular processes associated with intestinal development, cell fate specification, and the maintenance of intestinal stem cell/progenitor populations. Several signaling pathway molecules that undergo ectodomain shedding by ADAMs [e.g., ligands and receptors from epidermal growth factor receptor (EGFR)/ErbB and tumor necrosis factor α (TNFα) receptor (TNFR) families] help drive and control intestinal inflammation and injury/repair responses. Dysregulation of these processes through aberrant ADAM expression or sustained ADAM activity is linked to chronic inflammation, inflammation-associated cancer, and tumorigenesis.

Flow cytometry (FCM) offers a multiparametric technology capable of characterizing single extracellular vesicles (EVs). However, most flow cytometers are designed to detect cells, which are larger than EVs. Whereas cells exceed the background noise, signals originating from EVs partly overlap with the background noise, thereby making EVs more difficult to detect than cells. This technical mismatch together with complexity of EV‐containing fluids causes limitations and challenges with conducting, interpreting and reproducing EV FCM experiments. To address and overcome these challenges, researchers from the International Society for Extracellular Vesicles (ISEV), International Society for Advancement of Cytometry (ISAC), and the International Society on Thrombosis and Haemostasis (ISTH) joined forces and initiated the EV FCM working group. To improve the interpretation, reporting, and reproducibility of future EV FCM data, the EV FCM working group published an ISEV position manuscript outlining a framework of minimum information that should be reported about an FCM experiment on single EVs (MIFlowCyt‐EV). However, the framework contains limited background information. Therefore, the goal of this compendium is to provide the background information necessary to design and conduct reproducible EV FCM experiments. This compendium contains background information on EVs, the interaction between light and EVs, FCM hardware, experimental design and preanalytical procedures, sample preparation, assay controls, instrument data acquisition and calibration, EV characterization, and data reporting. Although this compendium focuses on EVs, many concepts and explanations could also be applied to FCM detection of other particles within the EV size range, such as bacteria, lipoprotein particles, milk fat globules, and viruses.