KIF22 regulates mitosis and proliferation of chondrocyte cells.

Point mutations in KIF22 have been linked to spondyloepimetaphyseal dysplasia with joint laxity, type 2 (SEMDJL2). Skeletal features of SEMDJL2 include short stature and joint laxity. Mechanisms underlying these limb abnormalities are unknown. Here in this manuscript, we have investigated the function of KIF22 in chondrocytes. Quantitative PCR and immunostaining revealed that Kif22 was highly expressed in proliferating-zone growth-plate chondrocytes. Kif22 knockdown resulted in defective mitotic spindle formation and reduced cell proliferation. Forced expression of SEMDJL-associated mutant Kif22 constructs likewise induced abnormal mitotic spindle morphology and reduced proliferation. Mice expressing a KIF22 truncation mutant had shorter growth plates and shorter tibial bones compared to wild-type mice. These results suggest that KIF22 regulates mitotic spindle formation in proliferating chondrocytes thereby linking the stunted longitudinal bone growth observed in SEMDJL2 to failures of chondrocyte division.

Surfer's neurapraxia - an uncommon surfing injury of the saphenous nerve.

Surfer's neurapraxia is a rare surfing injury of the saphenous nerve secondary to persistent compression of the saphenous nerve along the medial thigh by the surfboard when paddling prone and while sitting upright on the board waiting for a wave. Symptoms may be nonspecific and consist of pain in the medial thigh with or without radiation along the saphenous nerve distribution (medial leg, medial ankle, medial arch of the foot). The saphenous nerve tension test can be utilized to reproduce the symptoms of surfer's neurapraxia. Treatment consists of conservative management while refractory cases may benefit from injection with local anesthetic. The authors propose the Obana Plan (WATER) for prevention of surfer's neurapraxia, consisting of Wetsuits, Abduction, Timing, Exercise, and Rest. Overall, surfer's neurapraxia is a benign condition that can be prevented and managed conservatively.

Artemisia fragrans Willd. Essential Oil: Chemical Profile and Insecticidal Potential against the Confused Flour Beetle, Tribolium confusum du Val.

The confused flour beetle, Tribolium confusum du Val, is one of the cosmopolitan and polyphagous storage insect pests. The frequent application of chemical insecticides has resulted in several side effects, including threats to human health and non-target organisms and the resistance of insect pests. In the current study, the fumigant toxicity and feeding deterrence potential of Artemisia fragrans Willd. essential oil on T. confusum adults were investigated. The essential oil was rich in terpenic compounds, in which α-thujone (27.8%) and 1,8-cineole (22.8%) were dominant. The essential oil displayed significant fumigant toxicity on T. confusum, where a concentration of 35.3 µL/L caused 100% mortality of the treated adults after 48 h. The LC30 and LC40 values (lethal concentrations to kill 30% and 40% of tested insects: 15.1 and 18.4 µL/L, respectively) significantly decreased the nutritional indices of the pest, including the consumption index, relative consumption rate, and relative growth rate. The feeding deterrence index of the essential oil were calculated as being 62.29 and 48.66% for the concentrations of 15.1 and 18.4 µL/L after 5 days, respectively. Accordingly, A. fragrans essential oil can be considered an efficient, available, and natural alternative to detrimental chemical pesticides in the management of T. confusum.

Forecasting the Burden of Cardiovascular Disease and Stroke in the United States Through 2050-Prevalence of Risk Factors and Disease: A Presidential Advisory From the American Heart Association.

BACKGROUND: Cardiovascular disease and stroke are common and costly, and their prevalence is rising. Forecasts on the prevalence of risk factors and clinical events are crucial. METHODS: Using the 2015 to March 2020 National Health and Nutrition Examination Survey and 2015 to 2019 Medical Expenditure Panel Survey, we estimated trends in prevalence for cardiovascular risk factors based on adverse levels of Life's Essential 8 and clinical cardiovascular disease and stroke. We projected through 2050, overall and by age and race and ethnicity, accounting for changes in disease prevalence and demographics. RESULTS: We estimate that among adults, prevalence of hypertension will increase from 51.2% in 2020 to 61.0% in 2050. Diabetes (16.3% to 26.8%) and obesity (43.1% to 60.6%) will increase, whereas hypercholesterolemia will decline (45.8% to 24.0%). The prevalences of poor diet, inadequate physical activity, and smoking are estimated to improve over time, whereas inadequate sleep will worsen. Prevalences of coronary disease (7.8% to 9.2%), heart failure (2.7% to 3.8%), stroke (3.9% to 6.4%), atrial fibrillation (1.7% to 2.4%), and total cardiovascular disease (11.3% to 15.0%) will rise. Clinical CVD will affect 45 million adults, and CVD including hypertension will affect more than 184 million adults by 2050 (>61%). Similar trends are projected in children. Most adverse trends are projected to be worse among people identifying as American Indian/Alaska Native or multiracial, Black, or Hispanic. CONCLUSIONS: The prevalence of many cardiovascular risk factors and most established diseases will increase over the next 30 years. Clinical and public health interventions are needed to effectively manage, stem, and even reverse these adverse trends.

Forecasting the Economic Burden of Cardiovascular Disease and Stroke in the United States Through 2050: A Presidential Advisory From the American Heart Association.

BACKGROUND: Quantifying the economic burden of cardiovascular disease and stroke over the coming decades may inform policy, health system, and community-level interventions for prevention and treatment. METHODS: We used nationally representative health, economic, and demographic data to project health care costs attributable to key cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia) and conditions (coronary heart disease, stroke, heart failure, atrial fibrillation) through 2050. The human capital approach was used to estimate productivity losses from morbidity and premature mortality due to cardiovascular conditions. RESULTS: One in 3 US adults received care for a cardiovascular risk factor or condition in 2020. Annual inflation-adjusted (2022 US dollars) health care costs of cardiovascular risk factors are projected to triple between 2020 and 2050, from $400 billion to $1344 billion. For cardiovascular conditions, annual health care costs are projected to almost quadruple, from $393 billion to $1490 billion, and productivity losses are projected to increase by 54%, from $234 billion to $361 billion. Stroke is projected to account for the largest absolute increase in costs. Large relative increases among the Asian American population (497%) and Hispanic American population (489%) reflect the projected increases in the size of these populations. CONCLUSIONS: The economic burden of cardiovascular risk factors and overt cardiovascular disease in the United States is projected to increase substantially in the coming decades. Development and deployment of cost-effective programs and policies to promote cardiovascular health are urgently needed to rein in costs and to equitably enhance population health.

Corrigendum: Trickle infection with Heligmosomoides polygyrus results in decreased worm burdens but increased intestinal inflammation and scarring.

[This corrects the article DOI: 10.3389/fimmu.2022.1020056.].

Seasonal influence on the essential oil chemical composition of Hyptis crenata Pohl ex Benth.: a valuable plant from Marajó, Brazil.

Introduction: Essential oils (EOs) from the Hyptis genus have been reported as bactericides and fungicides. However, the properties of these oils can be affected by climatic factors, as well as the collection period, which promotes changes in the chemical composition of the oil. In this context, this study aimed to evaluate the climatological influences on the chemical composition of the essential oil from the leaves of Hyptis crenata. Methods: The leaves were collected in Marajó island (Brazil) monthly for a year. The EOs were obtained by hydrodistillation and analyzed by Gas Chromatography coupled to Mass Spectrometry (GC-MS). Pearson's correlation was used to evaluate the relationship between climatic parameters, content, and chemical composition of essential oil; multivariate analysis was used to evaluate the interrelationship between samples and their chemical constituents. Results and Discussion: The constituents with the highest contents (>2.0%) in essential oils during the studied period were 1,8-cineole (28.48% ± 4.32%), α-pinene (19.58% ± 2.29%), camphor (11.98% ± 2.54%), ß-pinene (9.19% ± 1.47%), limonene (6.12% ± 3.15%), α-terpineol (2.42% ± 0.25%) and borneol (2.34% ± 0.48%). ß-Pinene significantly correlated (p < 0.05) with precipitation and humidity. According to the chemometric tools, two groups were formed: chemical profile I, marked by 1,8 cineole, α-pinene, ß-pinene, borneol, α-terpineol, and limonene, while group II (July) presented a chemical type characterized by camphor. It is understood that the species in question can be a reliable source of biologically active components during different climatic periods in the Amazon. The chemical variability could have significant implications for the pharmaceutical industry and traditional medicine.

Python tooth-inspired fixation device for enhanced rotator cuff repair.

Rotator cuff repair surgeries fail frequently, with 20 to 94% of the 600,000 repairs performed annually in the United States resulting in retearing of the rotator cuff. The most common cause of failure is sutures tearing through tendons at grasping points. To address this issue, we drew inspiration from the specialized teeth of snakes of the Pythonoidea superfamily, which grasp soft tissues without tearing. To apply this nondamaging gripping approach to the surgical repair of tendon, we developed and optimized a python tooth-inspired device as an adjunct to current rotator cuff suture repair and found that it nearly doubled repair strength. Integrated simulations, 3D printing, and ex vivo experiments revealed a relationship between tooth shape and grasping mechanics, enabling optimization of the clinically relevant device that substantially enhances rotator cuff repair by distributing stresses over the attachment footprint. This approach suggests an alternative to traditional suturing paradigms and may reduce the risk of tendon retearing after rotator cuff repair.

Lippia alba essential oil: A powerful and valuable antinociceptive and anti-inflammatory medicinal plant from Brazil.

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazilian popular medicine, Lippia alba leaves are used in teas to treat pain and inflammatory diseases. AIM OF THE STUDY: to evaluate the chemical composition, antinociceptive, and anti-inflammatory activities of Lippia alba essential oil and its major compound geraniol. MATERIAL AND METHODS: Lippia alba leaves were collected in Pará state, Brazil. The leaf essential oil was obtained using a modified Clevenger-type extractor. Then, the oil was analyzed by GC and GC-MS analyses. To evaluate the toxicity of LaEO and geraniol, the doses of 50, 300, and 2000 mg/kg were used in a mouse model. For antinociception tests, abdominal contortion, hot plate, and formalin tests were used; all groups were treated with LaEO and geraniol at doses of 25, 50, and 100 mg/kg; and to evaluate inflammation using the ear edema model. RESULTS: The constituents identified in the highest content were oxygenated monoterpenes: geraniol (37.5%), geranial (6.7%) and neral (3.8%). The animals treated with LaEO and geraniol demonstrated atypical behaviors with aspects of lethargy and drowsiness, characteristics of animals in a state of sedation; the relative weights showed no significant difference compared to the controls. In the abdominal contortion test, LaEO at 25 mg/kg, 50 mg/kg doses, and 100 mg/kg reduced the number of contortions, representing a percentage reduction of 84.64%, 81.23%, and 66.21% respectively. In the hot plate test, LaEO and geraniol increased the latency time at doses of 25, 50, and 100 mg/kg in all test periods; there was no statistical difference between LaEO and geraniol. In the first phase of the formalin test, only doses of 25 mg/kg and 100 mg/kg of LaEO showed significant activity, reducing the latency time by 53.40% and 58.90%. LaEO at doses of 25 mg/kg and 100 mg/kg reduced the size of the edema, demonstrating an anti-inflammatory activity of 59.38% (25 mg/kg) and 50% (100 mg/kg). CONCLUSION: Lippia alba essential oil and geraniol showed central/peripheral analgesic and anti-inflammatory potential and can be used as an alternative or complementary treatment to conventional drugs. More studies are needed to evaluate its action mechanisms and its analgesic effects.

The retina's neurovascular unit: Müller glial sheaths and neuronal contacts.

The neurovascular unit (NVU), comprising vascular, glial and neural elements, supports the energetic demands of neural computation, but this aspect of the retina's trilaminar vessel network is poorly understood. Only the innermost vessel layer - the superficial vascular plexus (SVP) - is ensheathed by astrocytes, like brain capillaries, whereas glial ensheathment in other layers derives from radial Müller glia. Using serial electron microscopy reconstructions from mouse and primate retina, we find that Müller processes cover capillaries in a tessellating pattern, mirroring the tiled astrocytic endfeet wrapping brain capillaries. However, gaps in the Müller sheath, found mainly in the intermediate vascular plexus (IVP), permit different neuron types to contact pericytes and the endothelial cells directly. Pericyte somata are a favored target, often at spine-like structures with a reduced or absent vascular basement lamina. Focal application of adenosine triphosphate (ATP) to the vitreal surface evoked Ca2+ signals in Müller sheaths in all three vascular layers. Pharmacological experiments confirmed that Müller sheaths express purinergic receptors that, when activated, trigger intracellular Ca2+ signals that are amplified by IP3-controlled intracellular Ca2+ stores. When rod photoreceptors die in a mouse model of retinitis pigmentosa (rd10), Müller sheaths dissociate from the deep vascular plexus (DVP) but are largely unchanged within the IVP or SVP. Thus, Müller glia interact with retinal vessels in a laminar, compartmentalized manner: glial sheathes are virtually complete in the SVP but fenestrated in the IVP, permitting direct neural-to-vascular contacts. In the DVP, the glial sheath is only modestly fenestrated and is vulnerable to photoreceptor degeneration.

Sex-dependent phosphorylation of Argonaute 2 reduces the mitochondrial translocation of miR-181c and induces cardioprotection in females.

Obesity-induced cardiac dysfunction is growing at an alarming rate, showing a dramatic increase in global prevalence. Mitochondrial translocation of miR-181c in cardiomyocytes results in excessive reactive oxygen species (ROS) production during obesity. ROS causes Sp1, a transcription factor for MICU1, to be degraded via post-translational modification. The subsequent decrease in MICU1 expression causes mitochondrial Ca2+ accumulation, ultimately leading to a propensity for heart failure. Herein, we hypothesized that phosphorylation of Argonaute 2 (AGO2) at Ser 387 (in human) or Ser 388 (in mouse) inhibits the translocation of miR-181c into the mitochondria by increasing the cytoplasmic stability of the RNA-induced silencing complex (RISC). Initially, estrogen offers cardioprotection in pre-menopausal females against the consequences of mitochondrial miR-181c upregulation by driving the phosphorylation of AGO2. Neonatal mouse ventricular myocytes (NMVM) treated with insulin showed an increase in pAGO2 levels and a decrease in mitochondrial miR-181c expression by increasing the binding affinity of AGO2-GW182 in the RISC. Thus, insulin treatment prevented excessive ROS production and mitochondrial Ca2+ accumulation. In human cardiomyocytes, we overexpressed miR-181c to mimic pathological conditions, such as obesity/diabetes. Treatment with estradiol (E2) for 48 h significantly lowered miR-181c entry into the mitochondria through increased pAGO2 levels. E2 treatment also normalized Sp1 degradation and MICU1 transcription that normally occurs in response to miR-181c overexpression. We then investigated these findings using an in vivo model, with age-matched male, female and ovariectomized (OVX) female mice. Consistent with the E2 treatment, we show that female hearts express higher levels of pAGO2 and thus, exhibit higher association of AGO2-GW182 in cytoplasmic RISC. This results in lower expression of mitochondrial miR-181c in female hearts compared to male or OVX groups. Further, female hearts had fewer consequences of mitochondrial miR-181c expression, such as lower Sp1 degradation and significantly decreased MICU1 transcriptional regulation. Taken together, this study highlights a potential therapeutic target for conditions such as obesity and diabetes, where miR-181c is upregulated. NEW AND NOTEWORTHY: In this study, we show that the phosphorylation of Argonaute 2 (AGO2) stabilizes the RNA-induced silencing complex in the cytoplasm, preventing miR-181c entry into the mitochondria. Furthermore, we demonstrate that treatment with estradiol can inhibit the translocation of miR-181c into the mitochondria by phosphorylating AGO2. This ultimately eliminates the downstream consequences of miR-181c overexpression by mitigating excessive reactive oxygen species production and calcium entry into the mitochondria.

Unravelling Guest Dynamics in Crystalline Molecular Organics Using 2H Solid-State NMR and Molecular Dynamics Simulation.

2H solid-state NMR and atomistic molecular dynamics (MD) simulations are used to understand the disorder of guest solvent molecules in two cocrystal solvates of the pharmaceutical furosemide. Traditional approaches to interpreting the NMR data fail to provide a coherent model of molecular behavior and indeed give misleading kinetic data. In contrast, the direct prediction of the NMR properties from MD simulation trajectories allows the NMR data to be correctly interpreted in terms of combined jump-type and libration-type motions. Time-independent component analysis of the MD trajectories provides additional insights, particularly for motions that are invisible to NMR. This allows a coherent picture of the dynamics of molecules restricted in molecular-sized cavities to be determined.

2-Octyl-Cyanoacrylate Mesh Dressings for Total Joint Arthroplasty: Dressing Design Influences Risks of Wound Complications.

INTRODUCTION: Recent liquid adhesive skin closure systems with a mesh patch and a 2-octyl cyanoacrylate liquid formula have shown promising results in total joint arthroplasty (TJA). Chemical accelerators are typically included to promote the rapid polymerization of 2-octyl cyanoacrylate. The goal of the study is to distinguish designs and wound complication differences between two similar systems. METHODOLOGY: An eighteen-week retrospective study was conducted from July to December 2023, including 207 total hip arthroplasty (THA) and 212 total knee arthroplasty (TKA) cases from four attending surgeons at one institution that used one of two dressing designs. Both dressings had a 2-octyl cyanoacrylate liquid adhesive formula that applied topically to a polyester-based mesh overlaying the wound. Mesh A (used in 274 cases) included an accelerator, a quaternary ammonium salt, on the mesh patch, whereas Mesh B (used in 145 cases) included a similar accelerator within the adhesive applicator. RESULTS: Wound complications (3.2 versus 7.6%; X2 = 3.86; df = 1; P = 0.049), early periprosthetic joint infections (PJI) (0 versus 2.8%; X2 = 7.63; df = 1; P = 0.006), and 90-day reoperations for wound complications (0.4 versus 3.4%; X2 = 6.39; df = 1; P = 0.011) were significantly lower in patients who received Mesh A versus B, respectively. There was no difference in superficial surgical site infections (SSI) (0.7 versus 0%; X2 = 1.06; df = 1; P = 0.302) or allergy rates (3.3 versus 4.1%; X2 = 0.12; df = 1; P = 0.655) between Mesh A and B. CONCLUSION: We observed significantly different performance in wound complications, early postoperative PJI, and 90-day reoperation between the two designs. Having the accelerator in the applicator rather than on the mesh patch, may lead to premature polymerization before bonding appropriately with the mesh to create the desired wound closure and seal.

Six-Month Real-World Study to Assess the Effectiveness of Ixekizumab After Switching from IL-23 Inhibitors and Other Biologic Therapies: The CorEvitas Psoriasis Registry.

BACKGROUND: Prior work showed that patients from the CorEvitas Psoriasis Registry who had previously failed a prior biologic and then initiated ixekizumab demonstrated improvements in disease severity and patient-reported outcomes after 6 months. However, newer therapies such as interleukin-23 inhibitors (IL-23i) were not considered. Here, with more recent data including IL-23i, 6-month effectiveness of ixekizumab following a switch from any biologic was assessed as well as whether 6-month effectiveness of ixekizumab was impacted by prior biologic class. METHODS: We included CorEvitas Psoriasis Registry patients who initiated ixekizumab after discontinuing another biologic therapy and had a corresponding 6-month follow-up visit following ixekizumab initiation (N = 743, 2016-2023). Immediate prior biologic class was categorized as tumor necrosis factor inhibitor (TNFi) or interleukin-12/23 inhibitors (IL-12/23i, n = 405), non-ixekizumab interleukin-17i (IL-17i, n = 237), or IL-23i (n = 101). Adjusted mean changes in body surface area (BSA), Dermatology Life Quality Index (DLQI), itch, and skin pain were calculated for prior biologic class groups using analysis of covariance (ANCOVA). Proportions achieving ≥ 75%, ≥ 90%, and ≥ 100% improvement in Psoriasis Area and Severity Index (PASI75, PASI90, and PASI100, respectively), Investigator's Global Assessment (IGA) 0/1, and DLQI 0/1 were calculated for all patients and compared among prior biologic classes via relative risks (RRs) and 95% confidence intervals (CIs) using multivariable modified Poisson regression. RESULTS: Mean improvements in BSA, DLQI, itch, and skin pain, were 7.6, 3.6, 23.3, and 16.7, respectively, for ixekizumab patients who switched from TNFi or IL-12/23i (all p < 0.05); 6.8, 3.3, 19.6, and 14.1, respectively, for those who switched from non-ixekizumab IL-17i (all p < 0.05); and 7.8, 3.4, 22.2, and 12.8, respectively, for those who switched from IL-23i (all p < 0.05). Overall, 54%, 41%, and 31% of ixekizumab initiators achieved PASI75, PASI90, and PASI100, respectively, 50% maintained or achieved IGA 0/1, and 48% maintained or achieved DLQI 0/1. The prior TNFi or IL-12/23i group was 31% more likely to achieve PASI100 (RR = 1.31, 95% CI 1.01, 1.69) and 32% more likely to maintain or achieve IGA 0/1 (RR = 1.32, 95% CI 1.11, 1.57), but not significantly more likely to achieve PASI90. The prior IL-23i group was 45% more likely to achieve PASI90 (RR = 1.45, 95% CI 1.10, 1.91), 55% more likely to achieve PASI100 (RR = 1.55, 95% CI 1.12, 2.13), and 39% more likely to maintain or achieve IGA 0/1 (RR = 1.39, 95% CI 1.12, 1.73) compared to the prior non-ixekizumab IL-17i group. Achievement of PASI75 and DLQI 0/1 was consistent across the prior TNFi or IL-12/23i, IL-23i, and non-ixekizumab IL-17i groups. CONCLUSIONS: These updated findings with IL-23i data reaffirm that patients with psoriasis who switch to ixekizumab after discontinuing another biologic demonstrate improvement in disease severity and patient-reported outcomes at 6 months in real-world settings. Compared to patients who switched from another IL-17i, patients who switched class from a TNFi or IL-12/23i were more likely to achieve PASI100 and IGA 0/1, and patients who switched class from an IL-23i were more likely to achieve PASI90 in addition to PASI100 and IGA 0/1.

Visit-to-visit variability in multiple biological measurements and cognitive performance and risk of cardiovascular disease: A cohort study.

Background: Visit-to-visit variability in single biological measurements has been associated with cognitive decline and an elevated risk of cardiovascular diseases (CVD). However, the effect of visit-to-visit variability in multiple biological measures is underexplored. We investigated the effect of visit-to-visit variability in blood pressure (BP), heart rate (HR), weight, fasting plasma glucose, cholesterol, and triglycerides on cognitive performance and CVD. Methods: Data on BP, HR, weight, glucose, cholesterol, and triglycerides from study visits in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were used to estimate the association between visit-to-visit variability, cognitive performance (Mini Mental State Examination (MMSE) score) and CVD (non-fatal stroke, non-fatal myocardial infarction, or cardiovascular death). Visit-to-visit variation for each measurement was estimated by calculating each individuals visit-to-visit standard deviation for that measurement. Participants whose standard deviation was in the highest quarter were classified as having high variation. Participants were grouped into those having 0, 1, 2, 3, or ≥ 4 high variation measurements. Regression and survival models were used to estimate the association between biological measures with MMSE and CVD with adjustment for confounders and mean measurement value. Results: After adjustment for covariates, higher visit-to-visit variability in BP, HR, weight, and FPG were associated with poorer MMSE and a higher risk of CVD. Effect sizes did not vary greatly by measurement. The effects of high visit-to-visit variability were additive; compared to participants who had no measurements with high visit-to-visit variability, those who had high visit-to-visit variability in ≥4 measurements had poorer MMSE scores (-0.63 (95 % CI -0.96 to -0·31). Participants with ≥4 measurements with high visit-to-visit variability compared to participants with none had higher risk of CVD (hazard ratio 2.46 (95 % CI 1.63 to 3.70). Conclusion: Visit-to-visit variability in several measurements were associated with cumulatively poorer cognitive performance and a greater risk of CVD.

Controlled cell proliferation and immortalization of human dental pulp stem cells with a doxycycline-inducible expression system.

Human dental pulp stem cells are a potentially useful resource for cell-based therapies and tissue repair in dental and medical applications. However, the primary culture of isolated dental pulp stem cells has notably been limited. A major requirement of an ideal human dental pulp stem cell culture system is the preservation of efficient proliferation and innate stemness over prolonged passaging, while also ensuring ease of handling through standard, user-friendly culture methods. In this study, we have engineered a novel human dental pulp stem cell line, distinguished by the constitutive expression of telomerase reverse transcriptase (TERT), and the conditional expression of the R24C mutant cyclin-dependent kinase 4 (CDK4R24C) and Cyclin D1. We have named this cell line Tet-off K4DT hDPSCs. Furthermore, we have conducted a comprehensive comparative analysis of their biological attributes in relation to a previously immortalized human dental pulp stem cells, hDPSC-K4DT, which were immortalized by the constitutive expression of CDK4R24C, Cyclin D1 and TERT. In Tet-off K4DT cells, the expression of the K4D genes can be precisely suppressed by the inclusion of doxycycline. Remarkably, Tet-off K4DT cells demonstrated an extended cellular lifespan, increased proliferative capacity, and enhanced osteogenic differentiation potential when compared to K4DT cells. Moreover, Tet-off K4DT cells had no observable genomic aberrations and also displayed a sustained expression of stem cell markers even at relatively advanced passages. Taken together, the establishment of this new cell line holds immense promise as powerful experimental tool for both fundamental and applied research involving dental pulp stem cells.

The circulating proteome and brain health: Mendelian randomisation and cross-sectional analyses.

Decline in cognitive function is the most feared aspect of ageing. Poorer midlife cognitive function is associated with increased dementia and stroke risk. The mechanisms underlying variation in cognitive function are uncertain. Here, we assessed associations between 1160 proteins' plasma levels and two measures of cognitive function, the digit symbol substitution test (DSST) and the Montreal Cognitive Assessment in 1198 PURE-MIND participants. We identified five DSST performance-associated proteins (NCAN, BCAN, CA14, MOG, CDCP1), with NCAN and CDCP1 showing replicated association in an independent cohort, GS (N = 1053). MRI-assessed structural brain phenotypes partially mediated (8-19%) associations between NCAN, BCAN, and MOG, and DSST performance. Mendelian randomisation analyses suggested higher CA14 levels might cause larger hippocampal volume and increased stroke risk, whilst higher CDCP1 levels might increase intracranial aneurysm risk. Our findings highlight candidates for further study and the potential for drug repurposing to reduce the risk of stroke and cognitive decline.

The Variability of MCID, SCB, PASS, and MOI Thresholds for PROMs in the Reverse Total Shoulder Arthroplasty Literature: A Systematic Review.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) is a common procedure utilized to address degenerative pathologies of the glenohumeral joint and rotator cuff. Increased reliance on patient-reported outcome measures (PROMs) has placed emphasis on the utilization of the minimum clinically important difference (MCID), substantial clinical benefit (SCB), patient acceptable symptom state (PASS), and maximal outcome improvement (MOI) thresholds to assess the clinical efficacy of RTSA. In this study, we systematically reviewed the MCID, SCB, PASS, and MOI thresholds reported for PROMs following RTSA. METHODS: PubMed, Embase, MEDLINE, Cochrane Library, and Google Scholar were queried for articles from Jan. 1, 2000-Aug. 31, 2023 reporting MCID, SCB, PASS, or MOI values for PROMs following RTSA. Patient demographic data, study characteristics, MCID/SCB/PASS/MOI thresholds, and threshold calculation methods were extracted. RESULTS: 141 articles were screened with 39 ultimately included, comprising 11,984 total patients that underwent RTSA. 34 (87%) studies reported MCID thresholds, 20 (51%) reported SCB, 5 (13%) reported PASS, and 2 (5%) reported MOI. 25/39 (64%) studies referenced a previous study when reporting MCID, SCB, PASS, or MOI values, 11 (28%) used an anchor-based method to calculate threshold values, 1 (3%) used a distribution-based method, and 2 (5%) used both anchor and distribution methods. There were 19 newly calculated MCID (11), SCB (5), PASS (1), and MOI (2) thresholds. For five of the six most utilized PROMs (ASES, SST, Constant, UCLA, SPADI), the range of reported MCID values exceeded 50% of the most common threshold. For three of the six, the range of SCB values exceeded 25% of the most common threshold. CONCLUSION: There is substantial variability in the MCID and SCB threshold values reported in the RTSA literature. Standardizing the methodologic calculation and utilization of MCID, SCB, PASS, and MOI thresholds for RTSA may allow for improved assessment of PROMs.