Corrigendum to "Association of state-level factors with rate of firearm-related deaths" [Surg. Open Sci. vol. 14 (2023) 114-119].

[This corrects the article DOI: 10.1016/j.sopen.2023.07.011.].

Association of state-level factors with rate of firearm-related deaths.

Background: Over 48,000 people died by firearm in the United States in 2021. Firearm violence has many inciting factors, but the full breadth of associations has not been characterized. We explored several state-level factors including factors not previously studied or insufficiently studied, to determine their association with state firearm-related death rates. Methods: Several state-level factors, including firearm open carry (OC) and concealed carry (CC) laws, state rank, partisan lean, urbanization, poverty rate, anger index, and proportion of college-educated adults, were assessed for association with total firearm-related death rates (TFDR). Secondary outcomes were firearm homicide (FHR) and firearm suicide rates (FSR). Exploratory data analysis with correlation plots and ANOVA was performed. Univariable and multivariable linear regression on the rate of firearm-related deaths was also performed. Results: All 50 states were included. TFDR and FSR were higher in permitless OC and permitless CC states. FHR did not differ based on OC or CC category. Open carry and CC were eliminated in all three regression models due to a lack of significance. Significant factors for each model were: 1) TFDR - partisan lean, urbanization, poverty rate, and state ranking; 2) FHR - poverty rate; 3) FSR - partisan lean and urbanization. Conclusions: Neither open nor concealed carry is associated with firearm-related death rates when socioeconomic factors are concurrently considered. Factors associated with firearm homicide and suicide differ and will likely require separate interventions to reduce firearm-related deaths. Key message: Neither open carry nor concealed carry law are associated with total firearm-related death rate, but poverty rate, urbanization, partisan lean, and state ranking are associated. When analyzing firearm homicide and suicide rates separately, poverty rate is strongly associated with firearm homicide rate, while urbanization and partisan lean are associated with firearm suicide rate.

Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock.

Systemic concentrations of chemokine CCL2, an agonist at chemokine receptors CCR2/3/5, have been associated with hemodynamic instability after traumatic-hemorrhagic shock. We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 30min of hemorrhagic shock (HS), whereas the CCR5 antagonist Maraviroc was ineffective. The effects of CCR3 blockade after HS are unknown and information on the therapeutic potential of INCB3284 after longer periods of HS and in HS models in the absence of fluid resuscitation (FR) is lacking. The aims of the present study were to assess the effects of CCR3 blockade with SB328437 and to further define the therapeutic efficacy of INCB3284. In series 1-3, Sprague-Dawley rats were hemorrhaged to a mean arterial blood pressure (MAP) of 30mmHg, followed by FR to MAP of 60mmHg or systolic blood pressure of 90mmHg. Series 1: 30min HS and FR until t = 90min. SB328437 at t = 30min dose-dependently reduced fluid requirements by >60%. Series 2: 60min HS and FR until t = 300min. INCB3284 and SB328437 at t = 60min reduced fluid requirements by more than 65% (p<0.05 vs. vehicle) and 25% (p>0.05 vs. vehicle), respectively, until t = 220min. Thereafter, all animals developed a steep increase in fluid requirements. Median survival time was 290min with SB328437 and >300min after vehicle and INCB3284 treatment (p<0.05). Series 3: HS/FR as in series 2. INCB3284 at t = 60min and t = 200min reduced fluid requirements by 75% until t = 300min (p<0.05 vs. vehicle). Mortality was 70% with vehicle and zero with INCB3284 treatment (p<0.05). Series 4: INCB3284 and SB328437 did not affect survival time in a lethal HS model without FR. Our findings further support the assumption that blockade of the major CCL2 receptor CCR2 is a promising approach to improve FR after HS and document that the dosing of INCB3284 can be optimized.

α1-adrenoceptor ligands inhibit chemokine receptor heteromerization partners of α1B/D-adrenoceptors via interference with heteromer formation.

We reported previously that α1-adrenoceptor (α1-AR) ligands inhibit chemokine receptor (CR) heteromerization partners of α1B/D-AR. The underlying mechanisms are unknown and in vivo evidence for such effects is missing. Utilizing CCR2 and α1B-AR as prototypical partners, we observed in recombinant systems and THP-1 cells that α1B-AR enhanced whereas its absence inhibited Gαi signaling of CCR2. Phenylephrine and phentolamine reduced the CCR2:α1B-AR heteromerization propensity and inhibited Gαi signaling of CCR2. Phenylephrine cross-recruited ß-arrestin-2 to CCR2, and reduced expression of α1B/D-AR, CR partners (CCR1/2, CXCR4) and corresponding heteromers. Phentolamine reduced CR:α1B/D-AR heteromers without affecting ß-arrestin-2 recruitment or receptor expression. Phenylephrine/phentolamine prevented leukocyte infiltration mediated via CR heteromerization partners in a murine air pouch model. Our findings document that α1-AR ligands inhibit leukocyte migration mediated by CR heteromerization partners in vivo and suggest interference with α1B-AR:CR heteromerization as a mechanism by which CR partners are inhibited. These findings provide new insights into the pharmacology of GPCR heteromers and indicate that an agonist and antagonist at one GPCR can act as antagonists at heteromerization partners of their target receptors.