Effect of the anther-smut fungus Microbotryum on the juvenile growth of its host Silene latifolia.

PREMISE OF THE STUDY: Plant pathogens that form persistent systemic infections within plants have the potential to affect multiple plant life history traits, yet we tend to focus only on visible symptoms. Anther smut of Silene latifolia caused by the fungus Microbotryum lychnidis-dioicae induces the anthers of its host to support fungal spore production instead of pollen, and the pathogen is primarily transmitted among flowering plants by pollinators. Nevertheless, most of its life cycle is spent in the asymptomatic vegetative phase, and spores falling on seedlings or nonflowering plants can also infect the host. The purpose of this study was to ask whether the fungus also had an effect on its host plant in the juvenile vegetative phase before flowering as this is important for the disease dynamics in species where infection of seedlings is commonplace. METHODS: Leaf length and leaf number of inoculated and uninoculated juvenile plants were compared in greenhouse experiments, and in one experiment, disease status of the plants at flowering was determined. KEY RESULTS: Inoculated plants had shorter but more leaves, and reduced root mass at the early juvenile (preflowering) stage. Some of these effects were detectable in plants that were inoculated but showed no disease symptoms at flowering. CONCLUSIONS: These results show that pathogenic fungi can have endophyte-like effects even in the total absence of their typical and more charismatic symptoms, and conversely that the assessment of endophyte effects on the fitness of their hosts should include all stages of the host life cycle.

Carbazole-containing amides and ureas: Discovery of cryptochrome modulators as antihyperglycemic agents.

A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.

Carbazole-containing sulfonamides and sulfamides: Discovery of cryptochrome modulators as antidiabetic agents.

A series of novel carbazole-containing sulfonamides and sulfamides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the results of efficacy studies in diet-induced obese (DIO) mice, and the desired pharmacokinetic parameters, compound 41 was selected for further profiling.

Emergence of Atrial Fibrillation and Flutter in COVID-19 Patients: A Retrospective Cohort Study.

COVID-19 is associated with various cardiovascular complications, including arrhythmias. This study investigated the incidence of new-onset atrial fibrillation (AFB) and atrial flutter (AFL) in COVID-19 patients and identified potential risk factors. We conducted a retrospective cohort study at a tertiary-care safety-net community hospital including 647 patients diagnosed with COVID-19 from March 2020 to March 2021. Patients with a prior history of AFB or AFL were excluded. Data on demographics, clinical characteristics, and outcomes were collected and analyzed using chi-square tests, t-tests, and binary logistic regression. We found that 69 patients (10.66%) developed AFB or AFL, with 41 patients (6.34%) experiencing new-onset arrhythmias. The incidence rates for new-onset AFB and AFL were 5.4% and 0.9%, respectively. Older age (≥65 years) was significantly associated with new-onset AFB/AFL (OR: 5.43; 95% CI: 2.31-12.77; p < 0.001), as was the development of sepsis (OR: 2.73; 95% CI: 1.31-5.70; p = 0.008). No significant association was found with patient sex. Our findings indicate that new-onset atrial arrhythmias are a significant complication in COVID-19 patients, particularly among the elderly and those with sepsis. This highlights the need for targeted monitoring and management strategies to mitigate the burden of atrial arrhythmias in high-risk populations during COVID-19 infection.

Left subclavian artery coverage during endovascular repair of thoracic aorta injury in trauma and non-trauma patients.

PURPOSE: In thoracic endovascular aortic repair (TEVAR), the left subclavian artery (LSA) is often occluded. Although most patients tolerate this, some develop ischemic symptoms to the brain or left upper extremity (LUE). A revascularization procedure may be associated with significant complications. The purpose of this review was to assess the incidence of LSA occlusion, resulting ischemic symptoms, and complications related to revascularization operations in trauma patients compared to non-trauma patients. METHODS: Studies from 2010 to 2020 were fully reviewed if they discussed incidence of LSA coverage, LUE ischemia, carotid-subclavian bypass, or complications associated with carotid-subclavian bypass. RESULTS: Seventeen articles were included in this analysis. A total of 167 patients were identified as trauma cases. Incidence of LSA occlusion in trauma was 91/167 (54%) compared to 281/1446 (19%) in the population exclusive of trauma (p < 0.001). Following LSA occlusion, the rate of LUE claudication/ischemia was 21/56 (38%) for trauma, compared to 12/193 (6%) in non-trauma cases (p < 0.001). The overall complication rate after carotid-subclavian rescue bypass was 29.2% (33/112), with phrenic nerve palsy (24%), recurrent laryngeal nerve palsy (5%), and pseudoaneurysm (1.7%) being the most common. CONCLUSION: LSA coverage following TEVAR is common and associated with significant complications, often requiring operative management. The incidence of ischemic complications after occlusion of the LSA is significantly higher in the trauma population. Revascularization procedures to correct the occlusion have a high rate of complications.

Targeting CD73 with AB680 (Quemliclustat), a Novel and Potent Small-Molecule CD73 Inhibitor, Restores Immune Functionality and Facilitates Antitumor Immunity.

T cells play a critical role in the control of cancer. The development of immune checkpoint blockers (ICB) aimed at enhancing antitumor T-cell responses has revolutionized cancer treatment. However, durable clinical benefit is observed in only a subset of patients, prompting research efforts to focus on strategies that target multiple inhibitory signals within the tumor microenvironment (TME) to limit tumor evasion and improve patient outcomes. Adenosine has emerged as a potent immune suppressant within the TME, and CD73 is the major enzyme responsible for its extracellular production. CD73 can be co-opted within the TME to impair T-cell-mediated antitumor immunity and promote tumor growth. To target this pathway and block the formation of adenosine, we designed a novel, selective, and potent class of small-molecule inhibitors of CD73, including AB680 (quemliclustat), which is currently being tested in patients with cancer. AB680 effectively restored T-cell proliferation, cytokine secretion, and cytotoxicity that were dampened by the formation of immunosuppressive adenosine by CD73. Furthermore, in an allogeneic mixed lymphocyte reaction where CD73-derived adenosine had a dominant suppressive effect in the presence of PD-1 blockade, AB680 restored T-cell activation and function. Finally, in a preclinical mouse model of melanoma, AB680 inhibited CD73 in the TME and increased the antitumor activity of PD-1 blockade. Collectively, these data provide a rationale for the inhibition of CD73 with AB680 in combination with ICB, such as anti-PD-1, to improve cancer patient outcomes.

Concomitant angiotensin AT1 receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal plasma extravasation in the rat.

Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy but cause high incidence of angioedema. We examined whether dual inhibition of angiotensin AT1 receptor (ARB) and NEP (ARB-NEPI, valsartan-candoxatril) provides similar efficacy to omapatrilat without the risk of angioedema. Activity of test compounds at the targets was assayed using fluorescence-based enzyme assays (ACE, NEP, aminopeptidase P) or competition binding assays (AT1). Target engagement in vivo (ACE, AT1, and NEP) was quantified by measuring inhibition of angiotensin-pressor responses and potentiation of atrial natriuretic peptide-induced urinary cyclic guanosine monophosphate (cGMP) output in rats. Tracheal plasma extravasation (TPE) was used as a surrogate to assess propensity of compounds to promote upper airway angioedema. Antihypertensive efficacy in renin-dependent and -independent states was measured in spontaneously hypertensive rats and deoxycorticosterone acetate salt hypertensive rats, respectively. Administration of omapatrilat and coadministration of valsartan and candoxatril blocked angiotensin induced vasopressor responses and potentiated atrial natriuretic peptide-induced increase in urinary cGMP output. In spontaneously hypertensive rats, valsartan, omapatrilat, and valsartan-candoxatril combination all produced reduction in blood pressure to a similar extent, whereas candoxatril was ineffective. In deoxycorticosterone acetate rats, omapatrilat, candoxatril, and valsartan-candoxatril combination but not valsartan produced reduction in blood pressure. Antihypertensive doses of omapatrilat produced robust increases in TPE; by contrast, valsartan, candoxatril, or their combination did not increase TPE. Pretreatment with icatibant, a bradykinin B2 antagonist, abolished omapatrilat-induced TPE but not its antihypertensive effects. On the background of NEP inhibition, suppression of the renin-angiotensin system through ARB and ACE inhibition shows a similar antihypertensive efficacy but exerts differential effects on bradykinin metabolism and TPE indicative of reduced risk of angioedema. Thus, dual AT1 receptor blockade and NEP inhibition is potentially an attractive approach to retain the excellent antihypertensive effects of omapatrilat but with a superior safety profile.

Genome-wide family-based study in torus palatinus affected individuals.

OBJECTIVE: Tori or exostoses are bony growths that appear in different oral regions. Torus palatinus, more specifically, develop in the palate midline and can impair proper word pronunciation and hinder the fabrication and use of dentures. Even though a multifactorial inheritance model has been suggested for torus palatinus appearance, precise genetic factors involved in its etiology remain unclear. Hence, in this study we aimed to identify variants across the genome of individuals from 46 Filipino families that associate with torus palatinus. DESIGN: All families were composed of fishermen or landless rural dwellers who provided blood samples for DNA extraction and genotyping. A total of 3519 single nucleotide polymorphisms (SNPs) were analyzed through a transmission disequilibrium test in individuals affected by torus palatinus and their unaffected family members. RESULTS: Fourteen SNPs showed trends for associations to the level of p < .005 threshold and several others were nominally (p < .05) associated with torus palatinus. We highlight SNP rs6582285, which is located in the CAPS2 gene, being the C allele less transmitted than the T allele in our sample. The C allele of CAPS2 rs6582285 protects from having torus palatinus whereas the other associations found were linked to an increased risk of developing the condition. CONCLUSIONS: Trends for associations were identified for several markers across the genome, supporting the hypothesis that torus palatinus has a multifactorial mode of inheritance. We hope that our study contributes to a better understanding of torus palatinus etiology and helps guide future research in examining genes for this often-overlooked condition in different populations.

Nationwide Analysis of Dog Bite Injuries: Different Age Groups, Different Injury Patterns.

BACKGROUND: As the number of households with dogs in the United States has increased, so has the incidence of dog bites. Contemporary analysis of nationwide epidemiological data regarding such injuries is scarce. The purpose of this study is to describe dog bite injury patterns and related surgical interventions with a focus on differences between pediatric and adult age groups. STUDY DESIGN: This is a retrospective study (2015-2017) using the National Trauma Data Bank. 10 569 patients were included. RESULTS: Of these, 4729 (44.7%) qualified as pediatric (age ≤ 12 years) and 5840 (55.3%) qualified as adults (age ≥ 13 years). Pediatric patients were more frequently admitted with facial injuries (78.1% vs. 29.3%, P < .01) and facial fractures (4.8% vs. 2.5%, P < .01), and had a higher incidence of facial bone surgical procedures (1.3% vs. .5%, P < .01). Adult patients were more frequently admitted with upper extremity injuries (65.8% vs. 21.2%, P < .01) and upper extremity vascular arterial injuries (2.3% vs. .2%, P < .01) with a higher incidence of upper extremity arterial procedures (1.3% vs. .2%, P < .01). CONCLUSION: This study demonstrates the contrast in injury patterns from dog bite between adults and children. These findings can dictate injury prevention policies and prepare clinicians to treat dog bite victims.

Discovery of Potent and Selective 7-Azaindole Isoindolinone-Based PI3Kγ Inhibitors.

The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγ offers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγ inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγ inhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγ inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.

Primary breast leiomyosarcoma with metastases to the lung in a young adult: Case report and literature review.

INTRODUCTION: Primary leiomyosarcomas of the breast are extremely rare. Because of this rarity, only a small number of studies have been published about the disease; diagnosis, treatment, and prognosis are not well-described. Our work has been reported in line with the SCARE criteria. PRESENTATION OF CASE: We present a 20-year-old female with primary breast leiomyosarcoma who despite mastectomy, developed lung metastases three years later. DISCUSSION: We discuss the rarity of breast leiomyosarcoma and risk of metastatic disease even with treatment. We review the literature and provide an outline of available data to shed light on the best strategies to manage this aggressive disease. CONCLUSION: Physicians and surgeons treating breast leiomyosarcoma must be vigilant of potential lung metastases in order to optimize short- and long-term oncologic outcomes.

Resuscitative endovascular balloon occlusion of the aorta (REBOA): Comparison with immediate transfusion following massive hemorrhage in swine.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is less invasive than emergency department thoracotomy for the treatment of massive hemorrhage. We evaluated the effects of REBOA on carotid blood flow (Qcarotid) in a porcine model of massive hemorrhage. We hypothesized that REBOA restores Qcarotid faster than reinfusion of blood. METHODS: Spontaneously breathing sedated Sinclair pigs underwent exponential hemorrhage of 65% total blood volume in 1 hour. They were randomized into three groups. Positive control (PC, n = 7) underwent immediate transfusion of shed blood. REBOA (n = 21) received a novel 7 Fr ER-REBOA catheter (Pryor Medical, Arvada, CO) placed into aortic Zone 1 via a femoral artery introducer for 30 minutes or 60 minutes, with transfusion either after deflation or midway through inflation. Negative control (n = 7) received no resuscitation. Qcarotid was recorded continuously using an ultrasonic flow probe. Survival and time between Qcarotid, min and both a stable maximal value (Qcarotid, max) and restoration of baseline flow (Qcarotid, new BL) were compared by Kaplan-Meier analysis. RESULTS: Median time to Qcarotid, max was 3.0 minutes in the REBOA group versus 9.6 minutes in the control group (p = 0.006). Median time to Qcarotid, new BL was 6.0 minutes in the REBOA group versus 20.5 minutes in the PC group (p = 0.11). Slope of the linear regression between Qcarotid, min and Qcarotid, new BL was 16.7 in REBOA and 10.4 in PC (p = 0.31). Four-hour survival was 95% (20 of 21) in the REBOA group versus 71% (5 of 7) in the PC group (p = 0.06) and 0% in the negative control group. CONCLUSION: REBOA resulted in the restoration of Qcarotid ("cerebrovascular resuscitation") at least as rapidly as retransfusion of shed blood, with equivalent 4-hour survival. Further studies of REBOA, to include mitigation of end-organ effects and longer follow-up, are needed.

Automated inhaled nitric oxide alerts for adult extracorporeal membrane oxygenation patient identification.

BACKGROUND: Recently, automated alerts have been used to identify patients with respiratory failure based on set criteria, which can be gleaned from the electronic medical record (EMR). Such an approach may also be useful for identifying patients with severe adult respiratory distress syndrome (ARDS) who may benefit from extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide (iNO) is a common rescue therapy for severe ARDS which can be easily tracked in the EMR, and some patients started on iNO may have indications for initiating ECMO. This case series summarizes our experience with using automated electronic alerts for ECMO team activation focused particularly on an alert triggered by the initiation of iNO. METHODS: After a brief trial evaluation, our Smart Alert system generated an automated page and e-mail alert to ECMO team members whenever a nonzero value for iNO appeared in the respiratory care section of our EMR. If iNO was initiated for severe respiratory failure, a detailed evaluation by the ECMO team determined if ECMO was indicated. For those patients managed with ECMO, we tabulated baseline characteristics, indication for ECMO, and outcomes. RESULTS: From September 2012 to July 2013, 45 iNO alerts were generated on 42 unique patients. Six patients (14%) met criteria for ECMO. Of these, four were identified exclusively by the iNO alert. At the time of the alert, the median PaO2-to-FIO2 ratio was 64 mm Hg (range, 55-107 mm Hg), the median age-adjusted oxygenation index was 73 (range, 51-96), and the median Murray score was 3.4 (range, 3-3.75), indicating severe respiratory failure. Median time from iNO alert to ECMO initiation was 81 hours (range, -2-292 hours). Survival to hospital discharge was 83% in those managed with ECMO. CONCLUSION: Automated alerts may be useful for identifying patients with severe ARDS who may be ECMO candidates. LEVEL OF EVIDENCE: Diagnostic test, level V.

Low-volume resuscitation for severe intraoperative hemorrhage: a step in the right direction.

The impact on outcomes resulting from crystalloids used with hemostatic close ratio resuscitation (HCRR) in intraoperative hemorrhage (IOH) has not been analyzed. We hypothesize a survival advantage in patients with IOH managed with a low-volume resuscitation (LVR) protocol during HCRR. A 4-year case-control study was conducted to determine the impact on mortality of LVR versus conventional resuscitation efforts (CRE) during HCRR. A total of 45 patients managed with a HCRR + LVR protocol (combination Hextend® and 3% hypertonic saline) and 55 historical cohorts managed with HCRR + CRE (lactated Ringer's) were included. Patient demographics, number of intraoperative units of packed red blood cells (PRBCs) and fresh-frozen plasma (FFP) received, and FFP:PRBC ratio were similar between groups. The mean intraoperative fluid volume was 0.76 L in the HCRR + LVR group versus 4.7 L in the HCRR + CRE group (P = 0.003). In a linear regression model HCRR + LVR versus HCRR + CRE, mean trauma intensive care unit length of stay was 6 versus 11 days (P = 0.009); 30-day overall mortality was 11.1 versus 32.7 per cent (P = 0.009); perioperative mortality was 2.2 to 10.9 per cent (P = 0.13); and intensive care unit mortality 8.8 to 21.8 per cent (P = 0.07). LVR protocol conveyed a survival benefit to patients undergoing HCRR (odds ratio for mortality, 0.07 [95% confidence interval 0.07-0.54]). This is the first civilian study to analyze the impact of LVR in patients managed with HCRR during IOH. Patients with IOH managed with HCRR and a predefined LVR protocol with Hextend® and 3 per cent hypertonic saline had an overall survival advantage and shorter trauma intensive care unit length of stay. LVR can be an effective alternative to CRE when used in combination with HCRR in patients with IOH.

Efficiency analysis for organic agricultural producers: the role of soil-improving inputs.

Greater emphasis is being placed on indicators of agri-environmental efficiency of organic production systems. Linking environmental measures with profitability measures based on net income is the only way to develop such indicators. A stochastic production frontier model that explicitly incorporates farm decisions about acquiring and managing organic soil-improving inputs is used to measure efficiency. The results confirm that on-farm self-sufficiency in soil-improving inputs is positively related to farm-level efficiency.

Valuing snorkeling visits to the Florida Keys with stated and revealed preference models.

Coastal coral reefs, especially in the Florida Keys, are declining at a disturbing rate. Marine ecologists and reef scientists have emphasized the importance of establishing nonmarket values of coral reefs to assess the cost effectiveness of coral reef management and remediation programs. The purpose of this paper is to develop a travel cost-contingent valuation model of demand for trips to the Florida Keys focusing on willingness to pay (WTP) to preserve the current water quality and health of the coral reefs. The stated and revealed preference models allow the marginal valuation of recreationists to adjust depending on current and planned trip commitments in valuing nonmarginal policy changes in recreational opportunities. The integrated model incorporates key factors for establishing baseline amenity values for tourist dive sites, including perceptions of reef quality and dive conditions, the role of substitute sites, and the quality and availability of tourist facilities and recreation opportunities. The travel cost and WTP model differ in identifying critical variables and provide insight into the adjustment of trip decisions across alternative destination sites and the valuation of trips. In contrast to the travel cost model, a measure of the availability of substitute sites and total recreation activities does not have a significant impact on WTP valuations reported by snorkelers. Snorkelers engage in a relatively focused set of activities, suggesting that these recreationists may not shift expenditures to other sites or other recreation activities in the Florida Keys when confronted with increased access costs for the snorkeling experience.