Luminescent Platinum(II) Complexes with Stimuli-Responsive Flexible Lewis Pair Ligands: Spectroscopic and Computational Studies.

A series of new luminescent bimetallic platinum(II) complexes with stimuli-responsive flexible Lewis pair (FlexLP) ligands are described. The FlexLP ligands consist of a dimesitylboron Lewis acid and diphenylphosphine oxide Lewis base which are in equilibrium between the unbound open form and the Lewis adduct, controlled by the hydrogen bond donating strength of the solvent. Spectroscopic techniques and density functional theory (DFT) calculations were used to interpret the photophysics of the platinum(II) complexes. All complexes exhibit tunable absorption in the region of 300-500 nm and green to orange photoluminescence, depending on the ratio of weak (THF) to strong (MeOH) hydrogen bond donating solvent employed. Spectroscopic and computational data shows that phosphine and peripheral acetylide ligands on the platinum(II) centers have limited influence on the emission energy, indicating the emission originates from the FlexLP-dominated fluorescence. Using time-resolved transient absorption spectroscopy it is shown that the complexes undergo intersystem crossing (ISC) to the triplet-excited state upon photoexcitation, and the ISC efficiency is affected by the peripheral acetylide ligands. The triplet-excited state lifetime can also be manipulated by the state of the FlexLP ligand, with the closed form complexes having longer lifetimes than the open form complexes.

Downregulation of the metalloproteinases ADAM10 or ADAM17 promotes osteoclast differentiation.

Bone resorption is driven through osteoclast differentiation by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-Β ligand (RANKL). We noted that a disintegrin and metalloproteinase (ADAM) 10 and ADAM17 are downregulated at the expression level during osteoclast differentiation of the murine monocytic cell line RAW264.7 in response to RANKL. Both proteinases are well known to shed a variety of single-pass transmembrane molecules from the cell surface. We further showed that inhibitors of ADAM10 or ADAM17 promote osteoclastic differentiation and furthermore enhance the surface expression of receptors for RANKL and M-CSF on RAW264.7 cells. Using murine bone marrow-derived monocytic cells (BMDMCs), we demonstrated that a genetic deficiency of ADAM17 or its required regulator iRhom2 leads to increased osteoclast development in response to M-CSF and RANKL stimulation. Moreover, ADAM17-deficient osteoclast precursor cells express increased levels of the receptors for RANKL and M-CSF. Thus, ADAM17 negatively regulates osteoclast differentiation, most likely through shedding of these receptors. To assess the time-dependent contribution of ADAM10, we blocked this proteinase by adding a specific inhibitor on day 0 of BMDMC stimulation with M-CSF or on day 7 of subsequent stimulation with RANKL. Only ADAM10 inhibition beginning on day 7 increased the size of developing osteoclasts indicating that ADAM10 suppresses osteoclast differentiation at a later stage. Finally, we could confirm our findings in human peripheral blood mononuclear cells (PBMCs). Thus, downregulation of either ADAM10 or ADAM17 during osteoclast differentiation may represent a novel regulatory mechanism to enhance their differentiation process. Enhanced bone resorption is a critical issue in osteoporosis and is driven through osteoclast differentiation by specific osteogenic mediators. The present study demonstrated that the metalloproteinases ADAM17 and ADAM10 critically suppress osteoclast development. This was observed for a murine cell line, for isolated murine bone marrow cells and for human blood cells by either preferential inhibition of the proteinases or by gene knockout. As a possible mechanism, we studied the surface expression of critical receptors for osteogenic mediators on developing osteoclasts. Our findings revealed that the suppressive effects of ADAM17 and ADAM10 on osteoclastogenesis can be explained in part by the proteolytic cleavage of surface receptors by ADAM10 and ADAM17, which reduces the sensitivity of these cells to osteogenic mediators. We also observed that osteoclast differentiation was associated with the downregulation of ADAM10 and ADAM17, which reduced their suppressive effects. We therefore propose that this downregulation serves as a feedback loop for enhancing osteoclast development.

Perceptions, beliefs, attitudes, and knowledge of US Latino adults pertaining to dementia and brain health: a systematic review.

OBJECTIVES: Latinos in the USA are 1.5 times more likely to develop Alzheimer's Disease and Related Dementias (ADRD) than non-Latino Whites. This systematic review aims to summarize current understanding of the perceptions, knowledge, beliefs, and attitudes about ADRD and brain health of Latinos to inform public health efforts addressing disparities. METHODS: Searches were completed across six databases (Medline, PsycINFO, WoS, LILACS, ProQUEST, and CINAHL). Studies were required to capture attitudes and/or knowledge of ADRD or brain health among US-based Latino adults who were not cognitively impaired and were not caregivers or healthcare providers. Results were synthesized narratively. RESULTS: A total of 5528 unique records were identified. Following de-duplication and screening, 24 articles met the inclusion criteria for this review. Overall, knowledge about brain health and ADRD among Latinos is quite mixed. A consistent finding was that participants recognized memory loss as a symptom of cognitive impairment, but demonstrated limited recognition of other signs of impairment. The studies also highlighted variable knowledge of protective factors for maintaining brain health. CONCLUSIONS: Opportunities exist to increase knowledge of ADRD signs and symptoms, and awareness of risk and protective factors. Given the heterogeneity of Latinos in the USA, more research is warranted to better elucidate nuances in conceptualizations of brain health and aging among diverse Latino subgroups.

Identifying Differences in Molecular Characteristics Relevant for Remodeling of Periodontal Ligament Stem Cells from the Upper and Lower Jaw.

Periodontal defects' localization affects wound healing and bone remodeling, with faster healing in the upper jaw compared to the lower jaw. While differences in blood supply, innervation, and odontogenesis contribute, cell-intrinsic variances may exist. Few studies explored cell signaling in periodontal ligament stem cells (PDLSC), overlooking mandible-maxilla disparitiesUsing kinomics technology, we investigated molecular variances in PDLSC. Characterization involved stem cell surface markers, proliferation, and differentiation capacities. Kinase activity was analyzed via multiplex kinase profiling, mapping differential activity in known gene regulatory networks. Upstream kinase analysis identified stronger EphA receptor expression in the mandible, potentially inhibiting osteogenic differentiation. The PI3K-Akt pathway showed higher activity in lower-jaw PDLSC. PDLSC from the upper jaw exhibit superior proliferation and differentiation capabilities. Differential activation of gene regulatory pathways in upper vs. lower-jaw PDLSC suggests implications for regenerative therapies.

Acute Effects of Ketamine on Intracranial Pressure in Children With Severe Traumatic Brain Injury.

OBJECTIVES: The acute cerebral physiologic effects of ketamine in children have been incompletely described. We assessed the acute effects of ketamine on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in children with severe traumatic brain injury (TBI). DESIGN: In this retrospective observational study, patients received bolus doses of ketamine for sedation or as a treatment for ICP crisis (ICP > 20 mm Hg for > 5 min). Administration times were synchronized with ICP and CPP recordings at 1-minute intervals logged in an automated database within the electronic health record. ICP and CPP were each averaged in epochs following drug administration and compared with baseline values. Age-based CPP thresholds were subtracted from CPP recordings and compared with baseline values. Trends in ICP and CPP over time were assessed using generalized least squares regression. SETTING: A 30-bed tertiary care children's hospital PICU. PATIENTS: Children with severe TBI who underwent ICP monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data from 33 patients, ages 1 month to 16 years, 22 of whom received bolus doses of ketamine, with 127 doses analyzed. Demographics, patient, and injury characteristics were similar between patients who did versus did not receive ketamine boluses. In analysis of the subset of ketamine doses used only for sedation, there was no significant difference in ICP or CPP from baseline. Eighteen ketamine doses were given during ICP crises in 11 patients. ICP decreased following these doses and threshold-subtracted CPP rose. CONCLUSIONS: In this retrospective, exploratory study, ICP did not increase following ketamine administration. In the setting of a guidelines-based protocol, ketamine was associated with a reduction in ICP during ICP crises. If these findings are reproduced in a larger study, ketamine may warrant consideration as a treatment for intracranial hypertension in children with severe TBI.

Early COVID-19 Attitudes and Behaviors and Their Associations With Later Infection: A Local Perspective From One U.S. City.

BACKGROUND: At the onset of the pandemic, there was poor public awareness and inaction in response to COVID-19; it is less known whether this translated to subsequent infections. OBJECTIVES: To explore whether adults who perceived COVID-19 as less of a threat and who were not taking early actions were more likely to become infected over the following year. RESEARCH DESIGN: Survey data from the ongoing (COVID-19 & Chronic Conditions (C3) anonymized for review) cohort study. PARTICIPANTS: Six hundred forty-two adults with a mean age of 63 and ≥1 chronic condition. MEASURES: Self-reported attitudes and behaviors regarding COVID-19 were assessed from March 13 to April 3, 2020, and COVID-19 infection status was captured between May 2020 and January 2021. Bivariate and multivariable analyses examined associations between early perceptions and behaviors with later infection. RESULTS: Approximately 7% reported infection with COVID-19 (N = 46). Adults who perceived the threat of COVID-19 less seriously at the initial outbreak were more likely to test positive over the following year [odds ratio (OR): 0.81, CI: 0.70-0.94; P = 0.006]. Those who were less likely to believe their actions would affect whether they would become infected were more likely to test positive (OR: 0.87, CI: 0.77-0.99; P = 0.03), as were adults who reported not changing their routines (OR: 0.45; CI: 0.24-0.85; P = 0.01). CONCLUSIONS: Adults with delayed responses in acknowledging the threat of COVID-19 and in changing behaviors were more likely to contract the virus. This investigation provides insight into the consequences of inadequate public understanding and response to COVID-19, and it highlights the importance of promoting early awareness among high-risk groups during public health crises.

Development and Validation of the HL6: a Brief, Technology-Based Remote Measure of Health Literacy.

BACKGROUND: Most health literacy measures require in-person administration or rely upon self-report. OBJECTIVE: We sought to develop and test the feasibility of a brief, objective health literacy measure that could be deployed via text messaging or online survey. DESIGN: Participants were recruited from ongoing NIH studies to complete a phone interview and online survey to test candidate items. Psychometric analyses included parallel analysis for dimensionality and item response theory. After 9 months, participants were randomized to receive the final instrument via text messaging or online survey. PARTICIPANTS: Three hundred six English and Spanish-speaking adults with ≥ 1 chronic condition MAIN MEASURES: Thirty-three candidate items for the new measure and patient-reported physical function, anxiety, depression, and medication adherence. All participants previously completed the Newest Vital Sign (NVS) in parent NIH studies. KEY RESULTS: Participants were older (average 67 years), 69.6% were female, 44.3% were low income, and 22.0% had a high school level of education or less. Candidate items loaded onto a single factor (RMSEA: 0.04, CFI: 0.99, TLI: 0.98, all loadings >.59). Six items were chosen for the final measure, named the HL6. Items demonstrated acceptable internal consistency (α=0.73) and did not display differential item functioning by language. Higher HL6 scores were significantly associated with greater educational attainment (r=0.41), higher NVS scores (r=0.55), greater physical functioning (r=0.26), fewer depressive symptoms (r=-0.20), fewer anxiety symptoms (r=-0.15), and fewer barriers to medication adherence (r=-0.30; all p<.01). In feasibility testing, 75.2% of participants in the text messaging arm completed the HL6 versus 66.2% in the online survey arm (p=0.09). Socioeconomic disparities in completion were more common in the online survey arm. CONCLUSIONS: The HL6 demonstrates adequate reliability and validity in both English and Spanish. This performance-based assessment can be administered remotely using commonly available technologies with fewer logistical challenges than assessments requiring in-person administration.

Rhenium(I) Complexes with Sulfur-Bridged Dipyridyl Ligands: Structural, Photophysical, and Computational Studies.

A series of six new rhenium(I) tricarbonyl complexes [Re(CO)3(N-N)Br] bearing sulfur-bridged dipyridyl (N-N) ligands with three different oxidation states (sulfide (S), sulfoxide (SO), and sulfone (SO2)) are described. Spectroscopic studies show that changing the oxidation state of the ligands influences the photophysical properties of the complexes, with complexes 3 and 6 containing the sulfone ligand exhibiting a lower energy MLCT absorption band tailing into the visible region. Solution-state emission measurements show that these complexes exhibit readily tunable emission energies from 480 to 610 nm, depending on the oxidation state of the sulfur bridge and the presence of substituents on the pyridyl rings. Solid-state emission measurements show that the emission is significantly red-shifted upon oxidation of the sulfur bridge to sulfone with enhanced photoluminescence quantum yield.

Restricted rotation and tunable fluorescence in atropisomeric naphthyl pyridine chromophores.

Enhanced fluorescence quantum yields are enabled by simple reactions at the heterocyclic nitrogen in naphthyl-pyridine chromophores in which the electronic properties can be tuned through protonation, oxidation, and alkylation at the nitrogen center. Fluorescence quantum yield is increased by reacting the pyridine lone pair with either a proton or an alkyl group. Restricted intramolecular rotation (RIR) was observed upon alkylation, as evidenced by the presence of atropisomers. These simple structural changes allow application-driven tuning of electronic properties.

Mediterranean diet component oleic acid increases protective lipid mediators and improves trabecular bone in a Porphyromonas gingivalis inoculation model.

AIM: Therapeutic modulation of bacterial-induced inflammatory host response is being investigated in gingival inflammation and periodontal disease pathology. Therefore, dietary intake of the monounsaturated fatty acid (FA) oleic acid (OA (C18:1)), which is the main component of Mediterranean-style diets, and saturated FA palmitic acid (PA (C16:0)), which is a component of Western-style diets, was investigated for their modifying potential in an oral inoculation model of Porphyromonas gingivalis. MATERIALS AND METHODS: Normal-weight C57BL/6-mice received OA- or PA-enriched diets (PA-ED, OA-ED, PA/OA-ED) or normal standard diet for 16 weeks and were inoculated with P. gingivalis/placebo (n = 12/group). Gingival inflammation, alveolar bone structure, circulating lipid mediators, and in vitro cellular response were determined. RESULTS: FA treatment of P. gingivalis-lipopolysaccharide-incubated gingival fibroblasts (GFbs) modified inflammatory activation, which only PA exacerbated with concomitant TNF-α stimulation. Mice exhibited no signs of acute inflammation in gingiva or serum and no inoculation- or nutrition-associated changes of the crestal alveolar bone. However, following P. gingivalis inoculation, OA-ED improved oral trabecular bone micro-architecture and enhanced circulating pro-resolving mediators resolvin D4 (RvD4) and 4-hydroxydocosahexaenoic acid (4-HDHA), whereas PA-ED did not. In vitro experiments demonstrated significantly improved differentiation in RvD4- and 4-HDHA-treated primary osteoblast cultures and reduced the expression of osteoclastogenic factors in GF. Further, P. gingivalis infection of OA-ED animals led to a serum composition that suppressed osteoclastic differentiation in vitro. CONCLUSIONS: Our results underline the preventive impact of Mediterranean-style OA-EDs by indicating their pro-resolving nature beyond anti-inflammatory properties.

Durable Vascular Access in Neonates in the Cardiac ICU: A Novel Technique for Tunneled Femoral Central Venous Catheters.

OBJECTIVES: There is an ongoing need for a method of obtaining long-term venous access in critically ill pediatric patients that can be completed at the bedside and results in a durable, highly functional device. We designed a novel technique for tunneled femoral access to address this need. Herein, we describe the procedure and review the outcomes at our institution. DESIGN: A single-center retrospective chart review identifying patients who underwent tunneled femoral central venous catheter (tfCVC) placement between 2017 and 2021 using a two-puncture technique developed by our team. SETTING: Academic, Quaternary Children's Hospital with a dedicated pediatric cardiac ICU (CICU). PATIENTS: Patients in our pediatric CICU who underwent this procedure. INTERVENTIONS: Tunneled femoral central line placement. MEASUREMENTS AND MAIN RESULTS: One hundred eighty-two encounters were identified in 161 patients. The median age and weight at the time of catheter placement was 22 days and 3.2 kg. The median duration of the line was 22 days. The central line-associated bloodstream infection (CLABSI) rate was 0.75 per 1,000-line days. The prevalence rate of thrombi necessitating pharmacologic treatment was 2.0 thrombi per 1,000-line days. There was no significant difference in CLABSI rate per 1,000-line days between the tfCVC and nontunneled peripherally inserted central catheters placed over the same period in a similar population (-0.40 [95% CI, -1.61 to 0.82; p = 0.52]) and no difference in thrombus rates per 1,000-line days (1.37 [95% CI, -0.15 to 2.89; p = 0.081]). CONCLUSIONS: tfCVCs can be placed by the intensivist team using a two-puncture technique at the bedside with a high-rate of procedural success and low rate of complications. Advantages of this novel technique of obtaining vascular access include a low rate of CLABSIs, the ability to place it at the bedside, and preservation of the upper extremity vasculature.

Mental well-being and patient activation during the first eight months of the COVID-19 pandemic in Denmark - a cohort study among 710 Danish adults with chronic conditions.

BACKGROUND: COVID-19 has highlighted the importance of patient activation in managing chronic conditions and promoting resilience during times of crisis. Patient activation refers to an individual's knowledge, skills, and confidence in managing their own health and healthcare. Previous research has shown that people with higher levels of patient activation are better prepared to navigate the challenges of chronic illness and are more likely to engage in healthy behaviors. However, the impact of patient activation on COVID-19-related concerns and mental well-being among people with chronic conditions during the pandemic remains unclear. This study aims to investigate the possible role of patient activation in shaping COVID-19-related concerns and to describe changes in mental well-being among Danish adults with one or more chronic conditions during the early months of the pandemic. METHODS: Danish adults with chronic conditions (e.g. diabetes, coronary heart disease, obstructive pulmonary lung disease, cancer) who had participated in a municipal health education program prior to the COVID-19 outbreak were asked to participate in this prospective questionnaire study in May 2020 and November 2020. Sociodemographic (sex, age, living status, educational attainment, employment status) and disease-related information (diagnosis, one or more chronic conditions) along with the Patient Activation Measure were collected before the outbreak and were obtained from a clinical database used for monitoring and evaluation of municipal health education programs. In contrast, the two questionnaires collected six months apart consisted of single items related to concerns about COVID-19 and the WHO-5 well-being index. RESULTS: A total of 710 people with chronic conditions (mean age 60.9 years; 55.8% female) participated at both time points. In bivariate analyses, patient activation was associated with COVID-19-related concern and well-being. At follow-up, participants experienced a significant decrease in well-being. The decrease was associated with poorer well-being measured six months earlier, a greater perception that it had become more challenging to take care of one's health due to the pandemic, and finally, feeling lonely. The association between patient activation and well-being ceased to be significant in the multivariate regression model. CONCLUSIONS: A considerable proportion of people with chronic conditions participating in this study have been mentally burdened during COVID-19. Although lower levels of patient activation were associated with greater COVID-19-related concerns, it did not have a significant impact on mental well-being over time.

How I Do It: Ureteroscopy and high-power holmium laser lithotripsy to treat renal stones.

In North America, ureteroscopy has become the most popular treatment modality for upper urinary tract urinary calculi. Herein we describe our technique for the treatment of renal stones with flexible ureteroscopy and high-power holmium laser lithotripsy. We discuss preoperative planning, intraoperative strategies, and laser settings for a high-frequency dusting technique with the goal to provide optimal patient outcomes.

Development and Validation of COVID-19 Vaccine Messaging Materials for Latinx Communities.

With pervasive health misinformation and mistrust, many of those at greatest risk from COVID-19 have demonstrated lower vaccine acceptance. In Chicago, IL, surveillance data has revealed lower rates of vaccine uptake among Black and Latinx individuals compared with others. We partnered with two local federally qualified health centers (FQHCs) to develop and implement language-concordant, low literacy patient education materials to promote COVID-19 vaccine knowledge, acceptance, and uptake. Our multi-phase study included: 1) iterative content generation and refinement by health literacy experts, health center providers and staff, and community-dwelling adults; and 2) materials testing via a two-arm randomized experiment among adults from Latinx communities in the Chicagoland area. Results indicate that our English and Spanish-language COVID-19 Fact Sheets increase knowledge about COVID-19 vaccination. These materials are publicly available and can be used by health centers or community organizations to promote COVID-19 vaccination among diverse populations.

Early Functional Status Change After Cardiopulmonary Resuscitation in a Pediatric Heart Center: A Single-Center Retrospective Study.

Children with cardiac disease are at significantly higher risk for in-hospital cardiac arrest (CA) compared with those admitted without cardiac disease. CA occurs in 2-6% of patients admitted to a pediatric intensive care unit (ICU) and 4-6% of children admitted to the pediatric cardiac-ICU. Treatment of in-hospital CA with cardiopulmonary resuscitation (CPR) results in return of spontaneous circulation in 43-64% of patients and survival rate that varies from 20 to 51%. We aimed to investigate the change in functional status of survivors who experienced an in-hospital CA using the functional status scale (FSS) in our heart center by conducting a retrospective study of all patients 0-18 years who experienced CA between June 2015 and December 2020 in a free-standing university-affiliated quaternary children's hospital. Of the 165 CA patients, 61% (n = 100) survived to hospital discharge. The non-survivors had longer length from admission to CA, higher serum lactate levels peri-CA, and received higher number of epinephrine doses. Using FSS, of the survivors, 26% developed new morbidity, and 9% developed unfavorable outcomes. There was an association of unfavorable outcomes with longer CICU-LOS and number of epinephrine doses given. Sixty-one-percent of CA patients survived to hospital discharge. Of the survivors, 26% developed new morbidity and 91% had favorable outcomes. Future multicenter studies are needed to help better identify modifiable risk factors for development of poor outcomes and help improve outcomes of this fragile patient population.

Survival of patients undergoing cardiac resynchronization therapy with or without defibrillator: the RESET-CRT project.

AIMS: Cardiac resynchronization therapy (CRT) is an established treatment for heart failure. There is contradictory evidence whether defibrillator capability improves prognosis in patients receiving CRT. We compared the survival of patients undergoing de novo implantation of a CRT with defibrillator (CRT-D) option and CRT with pacemaker (CRT-P) in a large health claims database. METHODS AND RESULTS: Using health claims data of a major German statutory health insurance, we analysed patients with de novo CRT implantation from 2014 to 2019 without indication for defibrillator implantation for secondary prevention of sudden cardiac death. We performed age-adjusted Cox proportional hazard regression and entropy balancing to calculate weights to control for baseline imbalances. The analysis comprised 847 CRT-P and 2722 CRT-D patients. Overall, 714 deaths were recorded during a median follow-up of 2.35 years. A higher cumulative incidence of all-cause death was observed in the initial unadjusted Kaplan-Meier time-to-event analysis [hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.38-1.92]. After adjustment for age, HR was 1.13 (95% CI: 0.95-1.35) and after entropy balancing 0.99 (95% CI: 0.81-1.20). No survival differences were found in different age groups. The results were robust in sensitivity analyses. CONCLUSION: In a large health claims database of CRT implantations performed in a contemporary setting, CRT-P treatment was not associated with inferior survival compared with CRT-D. Age differences accounted for the greatest part of the survival difference that was observed in the initial unadjusted analysis.

Evaluation of an artificial intelligence-based algorithm for automated localization of craniofacial landmarks.

OBJECTIVES: Due to advancing digitalisation, it is of interest to develop standardised and reproducible fully automated analysis methods of cranial structures in order to reduce the workload in diagnosis and treatment planning and to generate objectifiable data. The aim of this study was to train and evaluate an algorithm based on deep learning methods for fully automated detection of craniofacial landmarks in cone-beam computed tomography (CBCT) in terms of accuracy, speed, and reproducibility. MATERIALS AND METHODS: A total of 931 CBCTs were used to train the algorithm. To test the algorithm, 35 landmarks were located manually by three experts and automatically by the algorithm in 114 CBCTs. The time and distance between the measured values and the ground truth previously determined by an orthodontist were analyzed. Intraindividual variations in manual localization of landmarks were determined using 50 CBCTs analyzed twice. RESULTS: The results showed no statistically significant difference between the two measurement methods. Overall, with a mean error of 2.73 mm, the AI was 2.12% better and 95% faster than the experts. In the area of bilateral cranial structures, the AI was able to achieve better results than the experts on average. CONCLUSION: The achieved accuracy of automatic landmark detection was in a clinically acceptable range, is comparable in precision to manual landmark determination, and requires less time. CLINICAL RELEVANCE: Further enlargement of the database and continued development and optimization of the algorithm may lead to ubiquitous fully automated localization and analysis of CBCT datasets in future routine clinical practice.

Association between medication regimen complexity and glycemic control among patients with type 2 diabetes.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) and comorbid conditions require patients to take complex medication regimens. Greater regimen complexity has been associated with poorer T2DM management; however, the relationship between overall regimen complexity and glycemic control is unclear. OBJECTIVES: Our objectives were: (1) to examine associations between regimen complexity (with the Medication Regimen Complexity Index [MRCI]) and glycemic control (A1C), and (2) to compare overall MRCI with other measures of regimen complexity (overall and diabetes-specific medication count) and diabetes-specific MRCI. METHODS: This was a secondary data analysis of cross-sectional data from a parent trial. Participants were patients with T2DM taking at least 3 chronic medications followed in safety net clinics in the Chicago area. The MRCI measures complexity based on dosing frequency, route of administration, and special instructions for prescribed medications. MRCI scores were created for overall regimens and diabetes-specific medications. Sociodemographics and outpatient visit utilization were included in models as covariates. Linear regression was used to examine the associations between variables of interest and hemoglobin A1C. RESULTS: Participants (N = 432) had a mean age of 56.9 years, most were female (66.0%), and Hispanic or Latino (73.3%). Regimen complexity was high based on overall medications (mean = 6.6 medications, SD: 3.09) and MRCI (mean = 21.4, SD: 11.3). Higher diabetes-specific MRCI was associated with higher A1C in bivariate and multivariable models. In multivariable models, overall MRCI greater than 14, fewer outpatient health care visits, male gender, and absence of health insurance were independently associated with higher A1C. The variance in A1C explained by MRCI was higher compared to medication count for overall and diabetes-specific regimen complexity. CONCLUSIONS: More complex regimens are associated with worse A1C and measuring complexity with MRCI may have advantages. Deprescribing, increasing insurance coverage, and promoting engagement in health care may improve A1C among underserved populations with complex regimens.

Development, Establishment, and Validation of a Model for the Mineralization of Periodontium Remodelling Cells: Cementoblasts.

Chronic kidney disease (CKD) patients undergoing dialysis are at high risk of bone fractures. CKD-induced mineral and bone disorder is extended to periodontal disease due to changes in the ionic composition of saliva in CKD patients, dysregulating mineralization, hindering regeneration and thereby promoting the progression of dental complications. Despite the importance of cementum for overall oral health, the mechanisms that regulate its development and regeneration are not well comprehended, and a lack of sufficient in vitro experimental models has hindered research progress. In this study, the impact of experimental conditions on the calcification of cementoblasts was systematically investigated, aimed at establishing a standardized and validated model for the calcification of cementoblasts. The effects of phosphate, calcium, ascorbic acid, ß-glycerolphosphate, dexamethasone, and fetal calf serum on the calcification process of cementoblasts were analyzed over a wide range of concentrations and time points by investigating calcium content, cell viability, gene expression and kinase activity. Cementoblasts calcified in a concentration- and time-dependent manner with higher concentrations of supplements cause a higher degree of calcification but decreased cell viability. Phosphate and calcium have a significantly stronger effect on cementoblast calcification processes compared to osteogenic supplements: ascorbic acid, ß-glycerolphosphate, and dexamethasone induce calcification over a wide range of osteogenic signalling pathways, with osteopontin being a central target of gene regulation. Conversely, treatment with ascorbic acid, ß-glycerolphosphate, and dexamethasone leads to activating only selected pathways, especially promoting bone sialoprotein expression. The developed and validated cementoblast calcification protocol, incubating up to 60% confluent cementoblasts with 1.9 mmol L-1 of phosphate supplementation for a reasonable, multi-pathway calcification induction and 10 mmol L-1 ß-glycerolphosphate, 75 µmol L-1 ascorbic acid and 10 nmol L-1 dexamethasone for a reasonable osteogenic differentiation-based calcification induction, provides standard in vitro experimental models for better understanding cementoblast function and regeneration.

The Contribution of the Nrf2/ARE System to Mechanotransduction in Musculoskeletal and Periodontal Tissues.

Mechanosensing plays an essential role in maintaining tissue functions. Across the human body, several tissues (i.e., striated muscles, bones, tendons, ligaments, as well as cartilage) require mechanical loading to exert their physiological functions. Contrary, mechanical unloading triggers pathological remodeling of these tissues and, consequently, human body dysfunctions. At the cellular level, both mechanical loading and unloading regulate a wide spectrum of cellular pathways. Among those, pathways regulated by oxidants such as reactive oxygen species (ROS) represent an essential node critically controlling tissue organization and function. Hence, a sensitive balance between the generation and elimination of oxidants keeps them within a physiological range. Here, the Nuclear Factor-E2-related factor 2/Antioxidant response element (Nrf2/ARE) system plays an essential role as it constitutes the major cellular regulation against exogenous and endogenous oxidative stresses. Dysregulations of this system advance, i.a., liver, neurodegenerative, and cancer diseases. Herein, we extend our comprehension of the Nrf2 system to the aforementioned mechanically sensitive tissues to explore its role in their physiology and pathology. We demonstrate the relevance of it for the tissues' functionality and highlight the imperative to further explore the Nrf2 system to understand the physiology and pathology of mechanically sensitive tissues in the context of redox biology.