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Circulation Research Jul 2024PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial...
BACKGROUND
PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, the possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated.
METHOD
We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1).
RESULTS
PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism and resulting glycolytic ATP production, with a concurrent decrease in oxidative phosphorylation, both in vivo and in vitro. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knockdown of PANX1. To investigate nonischemic heart failure and the preceding cardiac hypertrophy, we administered isoproterenol, and we demonstrated that Panx1 mice were protected from systolic and diastolic left ventricle volume increases as a result of cardiomyocyte hypertrophy. Moreover, we found that Panx1 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45), particularly neutrophils (CD11b, Ly6g), to the myocardium.
CONCLUSIONS
Together, these data demonstrate that PANX1 deficiency in cardiomyocytes increases glycolytic metabolism and protects against cardiac hypertrophy in nonischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in patients with heart failure.
PubMed: 38957990
DOI: 10.1161/CIRCRESAHA.124.324650 -
DNA and Cell Biology Jul 2024Skin homeostasis relies on a delicate balance between host proteases and protease inhibitors along with those secreted from microbial communities, as disruption to this... (Review)
Review
Skin homeostasis relies on a delicate balance between host proteases and protease inhibitors along with those secreted from microbial communities, as disruption to this harmony contributes to the pathogenesis of inflammatory skin disorders, including atopic dermatitis and Netherton's syndrome. In addition to being a prominent cause of skin and soft tissue infections, the gram-positive bacterium is a key player in inflammatory skin conditions due to its array of 10 secreted proteases. Herein we review how proteases augment the development of inflammation in skin disorders. These mechanisms include degradation of skin barrier integrity, immune dysregulation and pruritis, and impairment of host defenses. Delineating the diverse roles of proteases has the potential to reveal novel therapeutic strategies, such as inhibitors of proteases or their cognate target, as well as neutralizing vaccines to alleviate the burden of inflammatory skin disorders in patients.
PubMed: 38957987
DOI: 10.1089/dna.2024.0134 -
Arteriosclerosis, Thrombosis, and... Jul 2024Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender... (Review)
Review
Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender disparities were prevalent in many institutions, recent decades have witnessed significant progress in supporting the career advancement of women faculty in science and academic medicine. However, continued advancement is necessary as previously unrecognized needs and new opportunities for improvement emerge. To identify the needs, opportunities, and potential challenges encountered by women faculty, the Women's Leadership Committee of the Arteriosclerosis, Thrombosis, and Vascular Biology Council developed an initiative termed GROWTH (Generating Resources and Opportunities for Women in Technology and Health). The committee designed a survey questionnaire and interviewed 19 leaders with roles and responsibilities in faculty development from a total of 12 institutions across various regions of the United States. The results were compiled, analyzed, and discussed. Based on our interviews and analyses, we present the current status of these representative institutions in supporting faculty development, highlighting efforts specific to women faculty. Through the experiences, insights, and vision of these leaders, we identified success stories, challenges, and future priorities. Our article provides a primer and a snapshot of institutional efforts to support the advancement of women faculty. Importantly, this article can serve as a reference and resource for academic entities seeking ideas to gauge their commitment level to women faculty and to implement new initiatives. Additionally, this article can provide guidance and strategies for women faculty as they seek support and resources from their current or prospective institutions when pursuing new career opportunities.
PubMed: 38957985
DOI: 10.1161/ATVBAHA.124.320910 -
Journal of Burn Care & Research :... Jul 2024Burn injury contributes to significant morbidity and mortality in the United States. Despite an increased focus on racial and ethnic disparities in healthcare, there...
Burn injury contributes to significant morbidity and mortality in the United States. Despite an increased focus on racial and ethnic disparities in healthcare, there remains a critical knowledge gap in our understanding of the effect of these disparities on complications experienced by burn patients. The American Burn Association's National Burn Repository data were reviewed from 2010-2018. Information regarding demographics, burn mechanism and severity, complications, and clinical outcomes were recorded. Data analysis was performed using 1:1 propensity-score-matching and logistic regression modeling. A separate analysis of Hispanic and non-Hispanic patients was performed using Chi squared tests. Among 215,071 patients, racial distribution was 65.16% white, 19.13% black, 2.18% Asian, 0.74% American Indian/Alaskan Native, and 12.78% other. Flame injuries were the most common cause (35.2%), followed by scald burns (23.3%). All comparisons were made in reference to the white population. Black patients were more likely to die (OR: 1.28; 95%CI: 1.17-1.40), experience all (OR: 1.08; 95%CI: 1.03-1.14), cardiovascular (OR: 1.24; 95%CI: 1.08-1.43), or infectious (OR: 1.64; 95%CI: 1.40-1.91) complications, and less likely to experience airway complications (OR: 0.83; 95%CI: 0.74-0.94). American Indian/Alaskan Native patients were more likely to experience any complication (OR: 1.33; 95%CI: 1.05-1.70). All minority groups had increased length of hospital stay. Black, Asian, and other patients had longer length of ICU stay. Black patients had longer ventilator duration. Among 82,775 patients, 24,075 patients were identified as Hispanic and 58,700 as non-Hispanic. Statistically significant differences were noted between groups in age, TBSA, proportion of 2nd degree burn, and proportion of 3rd degree burn (p<0.01). These findings highlight the need for further work to determine the etiology of these disparities to improve burn care for all patients.
PubMed: 38957983
DOI: 10.1093/jbcr/irae126 -
Annals of Surgery Jul 2024A recent study of 21 institutions noted significant differences between number of cases reported during general surgery residency by trainees who are Underrepresented in...
OBJECTIVES
A recent study of 21 institutions noted significant differences between number of cases reported during general surgery residency by trainees who are Underrepresented in Medicine (URiM) versus trainees who are not Underrepresented in Medicine (non-URiM). This study also identified differences between female residents and male residents. We partnered with the Accreditation Council for Graduate Medical Education to examine case logs reported from all accredited general surgery programs in the United States. This is the first time this data has been examined nationally.
METHODS
We examined total case logs submitted by graduating residents between 2017 and 2022. Group differences in mean reported case logs were examined using paired t- tests for female versus male and URiM versus non- URiM overall case numbers.
RESULTS
A total of 6,458 residents submitted case logs from 319 accredited programs. Eight-hundred and fifty-four (13%) were URiM and 5,604 (87%) were non-URiM. Over the 5-year study period, URM residents submitted 1096.95 (SD +/- 160.57) major cases versus 1115.96 (+/- 160.53) for non-URiM residents (difference =19 cases, P=0.001). Case logs were submitted by 3,833 (60.1%) male residents and 2,625 (39.9%) female residents over the five-year study period. Male residents reported 1128.56 (SD +/- 168.32) cases versus 1091.38 (+/- 145.98) cases reported by females (difference=37.18, P<0.001). When looking at Surgeon Chief and Teaching Assistant cases, there was no significant difference noted between cases submitted by URiM versus non- URiM residents. However, male residents reported significantly more in both categories than their female peers (P<0.001).
CONCLUSIONS
Overall, URiM residents submitted fewer cases in the five- year study period than their non-URiM peers. The gap in submitted cases between male and female residents was more pronounced, with male residents submitting significantly more cases than their female counterparts. This finding was consistent and statistically significant throughout the entire study period, in most case categories, and without narrowing of difference over time. A difference of 30-40 cases can amount to 1-3 months of surgical training and is a concerning national trend deserving the attention of every training program and our governing institutions.
PubMed: 38957982
DOI: 10.1097/SLA.0000000000006373 -
Headache Jul 2024The small molecule calcitonin gene-related peptide receptor antagonists (gepants) are the only drug class with medicines indicated for both the acute and preventive...
The small molecule calcitonin gene-related peptide receptor antagonists (gepants) are the only drug class with medicines indicated for both the acute and preventive treatment of migraine. Given this dual capacity to both treat and prevent, along with their favorable tolerability profiles and lack of an association with medication-overuse headache, headache specialists have begun to use gepants in ways that transcend the traditional categories of acute and preventive treatment. One approach, called situational prevention, directs patients to treat during the interictal phase, before symptoms develop, in situations of increased risk for migraine attacks. Herein, we present three patients to illustrate scenarios of gepant use for situational prevention. In each case, a gepant was started in anticipation of a period of increased headache probability (vulnerability) and continued for a duration of 1 day to 5 consecutive days. Although this approach may expose patients to medication when headache may not have developed, the tolerability and safety profile and preventive effect of gepants may represent a feasible approach for some patients. Situational prevention is an emerging strategy for managing migraine before symptoms develop in individuals who can identify periods when the probability of headache is high. This paper is intended to increase awareness of this strategy and stimulate future randomized, placebo-controlled trials to rigorously assess this strategy.
PubMed: 38957980
DOI: 10.1111/head.14775 -
British Journal of Clinical Pharmacology Jul 2024The management of patients treated with direct oral anticoagulants (DOACs) during hospitalization is a common challenge in clinical practice. Although bridging is...
AIMS
The management of patients treated with direct oral anticoagulants (DOACs) during hospitalization is a common challenge in clinical practice. Although bridging is generally not recommended, too often DOACs are switched to parenteral therapy with low molecular weight heparins. Our objectives were to update a local guideline for perioperative DOAC management and to develop a guideline for the anticoagulation management in non-surgical patients regarding temporary DOAC discontinuation.
METHODS
We executed a two-step modified Delphi study in a 1000-bed university hospital in Belgium. The Delphi questionnaires were developed based on a literature review and a telephone survey of prescribers. Two expert panels were established: one dedicated to perioperative DOAC management and the other to DOAC management in non-surgical patients. Both panels completed two rounds, commencing with an individual and online round, followed by a face-to-face group session.
RESULTS
After the two-round Delphi process, the updated perioperative guideline on DOAC management included reasons for delaying the resumption of DOACs following surgery, such as oral intake not possible, the probability of re-intervention within 3 days, and insufficient haemostasis (e.g. active clinically significant haematoma, haemorrhagic drains or wounds). Furthermore, a guideline for non-surgical hospitalized patients was developed, outlining possible reasons for interrupting DOAC therapy. Both guidelines offer clear anticoagulation therapy strategies corresponding to the identified scenarios.
CONCLUSIONS
We have updated and developed guidelines for DOAC management in surgical and non-surgical patients during hospitalization, which aim to support prescribers and to enhance targeted prescription review by hospital pharmacists.
PubMed: 38957976
DOI: 10.1111/bcp.16159 -
Hypertension (Dallas, Tex. : 1979) Jul 2024Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who...
BACKGROUND
Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets.
METHODS
In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories.
RESULTS
Over a median follow-up of 5.1 years, 830 of 8111 participants (10.2%) developed MCI or PD. Participants in the highest biomarker category were at higher risk of MCI or PD compared with those in the lowest category (hazard ratio, 1.34 [95% CI, 1.00-1.56]). The effect of intensive treatment on reducing the risk of MCI or PD was greater among participants in the lowest biomarker category (hazard ratio, 0.64 [95% CI, 0.50-0.81]) than those in the intermediate (hazard ratio, 1.01 [95% CI, 0.80-1.28]) or highest categories (hazard ratio, 0.90 [95% CI, 0.72-1.13]; =0.02). The 5-year absolute risk differences in MCI or PD with intensive treatment were -2.9% (-4.4%, -1.3%), -0.2% (-3.0%, 2.6%), and -1.9% (-6.2%, 2.4%) in the lowest, intermediate, and highest biomarker categories, respectively.
CONCLUSIONS
In SPRINT, the relative effect of intensive systolic blood pressure lowering on preventing cognitive impairment appears to be stronger among participants with lower compared with higher cardiac biomarker levels, though the absolute risk reductions were similar.
PubMed: 38957975
DOI: 10.1161/HYPERTENSIONAHA.124.22876 -
Surgical Infections Jul 2024The prophylactic use of antibiotics in parotid region surgery continues to be a subject of debate. The aim of this study is to elucidate the impact of antibiotic...
The prophylactic use of antibiotics in parotid region surgery continues to be a subject of debate. The aim of this study is to elucidate the impact of antibiotic prophylaxis on surgical site infections (SSIs) in parotid region surgery. Patients who received antibiotic prophylaxis during the peri-operative period were designated as group 1, whereas those who did not were categorized into group 2. Group 1 cases were further subdivided into three subgroups based on different antibiotic usage patterns. Patient individual information was collected. Clinical data such as surgical duration, post-operative hospital stay, incision infection status, and antibiotic usage were recorded. All data were compared and analyzed among different groups. A total of 357 patients were included in the study, with no statistically significant differences in baseline characteristics. Pre-operative American Society of Anesthesiologists scores did not significantly differ between groups (p = 0.151), but there was a significant distinction in National Nosocomial Infection Surveillance (NNIS) index values (p = 0.044). Furthermore, surgical duration (p = 0.001) and pathology types (p = 0.016) differed significantly. The post-operative hospital stay in group 1 was longer than that in group 2 (p < 0.01). The post-operative SSI rate in group 1 was lower than that in group 2 without statistical significance (2.55% vs. 5.59%, p = 0.141). The logistic regression analysis showed that malignant tumors, longer surgical durations, and higher NNIS index scores correlated positively with post-operative SSI rates. Meanwhile, compared with non-use, all three different antibiotic use modes correlated negatively with SSI occurrence. Antibiotic prophylaxis in parotid gland surgery shows no significant reduction in SSI occurrence. If there is a compelling reason to administer prophylactic antibiotics, pre-operative single dose may be a relatively feasible measure for preventing SSIs.
PubMed: 38957972
DOI: 10.1089/sur.2024.054 -
American Journal of Epidemiology Jul 2024In longitudinal studies, the devices used to measure exposures can change from visit to visit. Calibration studies, wherein a subset of participants is measured using...
In longitudinal studies, the devices used to measure exposures can change from visit to visit. Calibration studies, wherein a subset of participants is measured using both devices at follow-up, may be used to assess between-device differences (i.e., errors). Then, statistical methods are needed to adjust for between-device differences and the missing measurement data that often appear in calibration studies. Regression calibration and multiple imputation are two possible methods. We compared both methods in linear regression with a simulation study, considering various real-world scenarios for a longitudinal study of pulse wave velocity. Regression calibration and multiple imputation were both essentially unbiased, but correctly estimating the standard errors posed challenges. Multiple imputation with predicted mean matching produced close agreement with the empirical standard error. Fully stochastic multiple imputation underestimated the standard error by up to 50%, and regression calibration with bootstrapped standard errors performed slightly better than fully stochastic multiple imputation. Regression calibration was slightly more efficient than either multiple imputation method. The results suggest use of multiple imputation with predictive mean matching over fully stochastic imputation or regression calibration in longitudinal studies where a new device at follow-up might be error-prone compared to the device used at baseline.
PubMed: 38957970
DOI: 10.1093/aje/kwae169