Arteriovenous fistula aneurysmorrhaphy is associated with improved patency and decreased vascular access abandonment.

BACKGROUND: Upper extremity hemodialysis arteriovenous fistulas (AVFs) can become aneurysmal over time due to repeated cannulation and/or outflow steno-occlusive disease. The optimal surgical management of aneurysmal AVFs (aneurysmorrhaphy vs interposition graft) has remained unclear. METHODS: We performed a retrospective review in which current procedural terminology codes were used to screen for patients who had undergone surgical treatment of aneurysmal AVFs between 2016 and 2021 at a single hospital system. The patients were included after a review of the operative reports. The cases were divided by surgical procedure (aneurysmorrhaphy vs interposition graft placement). The patients who had undergone primary AVF ligation or other types of repair were excluded. The primary outcomes were primary assisted and secondary patency, and the secondary outcome was dialysis access abandonment. Multivariable Cox proportional hazards regression was used to test the association between the type of AVF aneurysm repair and the primary and secondary outcomes. RESULTS: From 2016 to 2021, 6951 patients had undergone 16,190 dialysis access procedures. Of these procedures, 381 (2.4%) were related to surgical treatment of an aneurysmal AVF. We excluded 58 primary AVF ligation cases and 20 cases involving other types of repair, leaving 303 cases for analysis. These were divided into two groups: aneurysmorrhaphy (n = 123; 41%) and interposition graft (n = 180; 59%). No differences were found between the groups in male gender (68% vs 63%), hypertension (98% vs 98%), or central stenosis (14% vs 22%). The patients who had undergone aneurysmorrhaphy were younger (median age, 54 years vs 59 years); had had a lower rate of diabetes (41% vs 59%), coronary artery disease (41% vs 58%), and congestive heart failure (41% vs 55%); and were less likely to have undergone upper arm access (72% vs 92%). The median follow-up was 11.1 months (interquartile range, 3.6-25.2 months). No differences were found in the incidence of 30-day wound complications (1% vs 3%) or surgical site infections (4% vs 6%). On multivariable Cox regression, interposition graft placement was associated with the loss of primary assisted patency (adjusted hazard ratio [aHR], 2.42; 95% confidence interval [CI], 1.18-4.95), loss of secondary patency (aHR, 3.10; 95% CI, 1.21-7.94), and abandonment of dialysis access (aHR, 3.07; 95% CI, 1.61-5.87; P < .05 for all) at 2 years. CONCLUSIONS: AVF aneurysmorrhaphy was associated with improved primary assisted and secondary patency and decreased abandonment of dialysis access. We suggest using aneurysmorrhaphy when AVF aneurysms are indicated for repair. However, individual factors such as patient comorbidities, AVF anatomy, remaining dialysis access options, and patient preference should be considered when planning the surgical approach.

Advances in the understanding of trauma-induced coagulopathy.

Ten percent of deaths worldwide are due to trauma, and it is the third most common cause of death in the United States. Despite a profound upregulation in procoagulant mechanisms, one-quarter of trauma patients present with laboratory-based evidence of trauma-induced coagulopathy (TIC), which is associated with poorer outcomes including increased mortality. The most common causes of death after trauma are hemorrhage and traumatic brain injury (TBI). The management of TIC has significant implications in both because many hemorrhagic deaths could be preventable, and TIC is associated with progression of intracranial injury after TBI. This review covers the most recent evidence and advances in our understanding of TIC, including the role of platelet dysfunction, endothelial activation, and fibrinolysis. Trauma induces a plethora of biochemical and physiologic changes, and despite numerous studies reporting differences in coagulation parameters between trauma patients and uninjured controls, it is unclear whether some of these differences may be "normal" after trauma. Comparisons between trauma patients with differing outcomes and use of animal studies have shed some light on this issue, but much of the data continue to be correlative with causative links lacking. In particular, there are little data linking the laboratory-based abnormalities with true clinically evident coagulopathic bleeding. For these reasons, TIC continues to be a significant diagnostic and therapeutic challenge.

Remote Damage Control Resuscitation in Austere Environments.

Hemorrhage is the leading cause of preventable military and civilian trauma death. Damage control resuscitation with concomitant mechanical hemorrhage control has become the preferred in-hospital treatment of hemorrhagic shock. In particular, plasma-based resuscitation with decreased volumes of crystalloids and artificial colloids as part of damage control resuscitation has improved outcomes in the military and civilian sectors. However, translation of these principles and techniques to the prehospital, remote, and austere environments, known as remote damage control resuscitation, is challenging given the resource limitations in these settings. Rapid administration of tranexamic acid and reconstituted freeze-dried (lyophilized) plasma as early as the point of injury are feasible and likely beneficial, but comparative studies in the literature are lacking. Whole blood is likely the best fluid therapy for traumatic hemorrhagic shock, but logistical hurdles need to be addressed. Rapid control of external hemorrhage with hemostatic dressings and extremity tourniquets are proven therapies, but control of noncompressible hemorrhage (ie, torso hemorrhage) remains a significant challenge.

Potent, selective and orally bioavailable leucine-rich repeat kinase 2 (LRRK2) inhibitors.

Familial Parkinson's disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection. Initial SAR studies around the core established the series as a tractable small molecule lead series of LRRK2 inhibitors for potential treatment of Parkinson's disease. It was also found that incorporation of a lactam into the core drastically improved the CNS and DMPK properties of these small molecules.

Mandarin Tone and Vowel Recognition in Cochlear Implant Users: Effects of Talker Variability and Bimodal Hearing.

OBJECTIVES: For cochlear implant (CI) users with residual low-frequency acoustic hearing in the nonimplanted ear, bimodal hearing combining the use of a CI and a contralateral hearing aid (HA) may provide more salient talker voice cues than CI alone to handle the variability of talker identity across trials. This study tested the effects of talker variability, bimodal hearing, and their interaction on response accuracy and time of CI users' Mandarin tone, vowel, and syllable recognition (i.e., combined Mandarin tone and vowel recognition in this study). DESIGN: Fifteen prelingually deafened native Mandarin-speaking CI users (at age 20 or lower) participated in this study. Four talkers each produced six Mandarin single-vowel syllables in four lexical tones. The stimuli were presented in quiet via a single loudspeaker. To study the effects of talker variability, Mandarin tone, vowel, and syllable recognition was tested in two presentation conditions: with stimuli blocked according to talker (blocked-talker condition) or mixed across talkers from trial to trial (mixed-talker condition). To explore the effects of bimodal hearing, two processor conditions were tested: CI alone or CI + HA. The cumulative response time was recorded as an indirect indicator of the cognitive load or listening effort in each condition. The correlations were computed between demographic/hearing factors (e.g., hearing thresholds in the nonimplanted ear) and bimodal performance/benefits (where bimodal benefits refer to the performance differences between CI alone and CI + HA). RESULTS: Mandarin tone recognition with both CI alone and CI + HA was significantly poorer in the mixed-talker condition than in the blocked-talker condition, while vowel recognition was comparable in the two presentation conditions. Bimodal hearing significantly improved Mandarin tone recognition but not vowel recognition. Mandarin syllable recognition was significantly affected by both talker variability and bimodal hearing. The cumulative response time significantly reduced with CI + HA compared with CI alone, but remained invariant with respect to talker variability. There was no interaction between talker variability and bimodal hearing for any performance measure adopted in this study. Correlation analyses revealed that the bimodal performance and benefits in Mandarin tone, vowel, and syllable recognition could not be predicted by the hearing thresholds in the nonimplanted ear or by the demographic factors of the participants. CONCLUSIONS: Talker variability from trial to trial significantly degraded Mandarin tone and syllable recognition performance in both the CI alone and CI + HA conditions. While bimodal hearing did not reduce the talker variability effects on Mandarin tone and syllable recognition, generally better Mandarin tone and syllable recognition performance with shorter response time (an indicator of less listening effort) was observed when a contralateral HA was used in conjunction with the CI. On the other hand, vowel recognition was not significantly affected by either talker variability or bimodal hearing, because ceiling effects could not be counted out of the vowel recognition results.

Perioperative risk and complications of revisional bariatric surgery compared to primary Roux-en-Y gastric bypass.

INTRODUCTION: Growing number of patients requires revisional bariatric surgery. This study compares perioperative course and outcomes of revisional versus primary bariatric surgery. METHODS: Patients who underwent revisional bariatric surgery from Jan 1997 to Sept 2012 were reviewed retrospectively. Every revisional patient with BMI >35 and age <70 was matched with a primary Roux-en-Y gastric bypass control patient based on preoperative BMI, age, sex, and year of surgery. Patients' preoperative indications, intraoperative/postoperative course, and complications were analyzed. RESULTS: Two hundred and fifty five patients underwent revisional bariatric surgery with resulting Roux-en-Y gastric bypass anatomy while 1,674 patients underwent primary gastric bypass in the same time interval. Of 255 patients, 172 patients were paired with 172 primary gastric bypass patients. Revisional bariatric group had preoperative BMI 48 ± 9, age 52 ± 9 years, 93 % female, 44 % laparoscopic, 30 % diabetic, 60 % hypertensive. Primary bypass patients had preoperative BMI 49 ± 8, age 52 ± 9 years, 93 % female, 97 % laparoscopic, 49 % diabetic, 67 % hypertensive. Compared to primary bypass patients, revisional patients had significantly higher estimated blood loss (463.7 vs. 113.3 mL), longer operative time (272.5 vs. 175.5 min), greater risk for ICU stay (N = 24, 14 % vs. N = 2, 1 %), and longer hospital stay (5.6 vs. 2.5 days). There were significantly more intraoperative liver (N = 13, 8 % vs. N = 1, 1 %) and spleen (N = 18, 10 % vs. N = 0) injuries, and more enterotomies (N = 9, 5 % vs. N = 0) in the revisional group. There were also significantly more postoperative complications (N = 94, 55 % vs. N = 48, 28 %), readmissions (N = 27, 16 % vs. N = 12, 7 %), and reoperations (N = 16, 9 % vs. N = 3, 2 %) within 30 days of surgery. Mean percentage weight loss at 1 year was significantly less for revisional patients (27 vs. 37 %). There was no significant difference in 30 day mortality between the two groups (N = 6 vs. 0). CONCLUSION: Even in experienced hands, complex revisional bariatric surgery should be approached with significant caution, especially given that weight loss is less substantial.

Incidence, mechanisms, and outcomes of esophageal and gastric perforation during laparoscopic foregut surgery: a retrospective review of 1,223 foregut cases.

BACKGROUND: Intraoperative perforation is a potentially major complication of laparoscopic (lap) foregut surgery. This study analyzed the incidence, mechanism, and outcomes of intraoperative perforations during these procedures in a large institutional experience. METHODS: All patients who underwent lap foregut surgery including laparoscopic antireflux surgery (LARS), paraesophageal hernia (PEH) repair, Heller myotomy, and reoperative hiatal hernia (redo HH) repair at the authors' institution from August 2004 to September 2012 were reviewed retrospectively. Perforation events and postoperative outcomes were analyzed, and complications were graded by the modified Clavien system. All data are expressed as means ± standard deviations or as medians. Statistical analysis was performed using Fisher's exact test and the Mann-Whitney U test. RESULTS: In this study, the repairs for 1,223 patients were analyzed (381 LARS procedures, 379 PEH repairs, 313 Heller myotomies, 150 redo HH repairs). Overall, 51 patients (4.2 %) had 56 perforations resulting from LARS (n = 4, 1 %), PEH repair (n = 7, 1.8 %), Heller myotomy (n = 18, 5.8 %), and redo HH repair (n = 22, 14.6 %). Redo HH was significantly more likely to result in perforations than LARS or PEH repair (p < 0.001). The locations of the perforations were esophageal in 13 patients (23.6 %), gastric in 40 patients (72.7 %), and indeterminate in 2 patients (3.6 %). The most common mechanisms of perforations were suture placement for LARS (75 %) and traction for PEH repair (43 %) and for Heller myotomy during the myotomy (72 %). The most redo HH perforations resulted from dissection/wrap takedown (73 %) and traction (14 %). Perforations were recognized and repaired intraoperatively in 43 cases (84 %) and postoperatively in eight cases (16 %). Perforations discovered postoperatively were more likely to require reoperation (75 vs 2 %; p < 0.001), to require more gastrointestinal and radiologic interventions (50 vs 2 %; p = 0.004), and to have higher morbidity (88 vs 26 %; p = 0.004) than perforations recognized intraoperatively. CONCLUSIONS: In a high-volume center, intraoperative perforations are the most frequent with reoperative HH repair. If perforations are recognized and repaired intraoperatively, they require minimal postoperative intervention. Unrecognized perforations usually require reoperation and result in significantly greater morbidity.

Quinolizidinone carboxylic acid selective M1 allosteric modulators: SAR in the piperidine series.

SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.

Identification of non-amidine inhibitors of acid-sensing ion channel-3 (ASIC3).

A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.

Heterocyclic fused pyridone carboxylic acid M(1) positive allosteric modulators.

The phenyl ring in a series of quinolone carboxylic acid M(1) positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure.

Characteristics of Trauma Mortality in Patients with Aortic Injury in Harris County, Texas.

BACKGROUND: The National Academies of Science have issued a call for zero preventable trauma deaths. The mortality characteristics in all patients with aortic injury are not well described. METHODS: All prehospital and hospital medical examiner records for deaths occurring in Harris County, Texas in 2014 were retrospectively reviewed, and patients with traumatic aortic injury were selected. The level of aortic injury was categorized by zone (0 through 9) and further grouped by aortic region (arch, zones 0 to 2; descending thoracic, zones 3 to 5; visceral abdominal, zones 6 to 8; infrarenal, zone 9). Multiple investigators used standardized criteria to categorize deaths as preventable, potentially preventable, or non-preventable. RESULTS: Of 1848 trauma deaths, 192 (10%) had aortic injury. There were 59 (31%) aortic arch, 144 (75%) descending thoracic, 19 (10%) visceral abdominal, and 20 (10%) infrarenal aortic injuries. There were 178 (93%) non-preventable deaths and 14 (7%) potentially preventable deaths, and none were preventable. Non-preventable deaths were associated with blunt trauma (69%) and the arch or thoracic aorta (93%), whereas potentially preventable deaths were associated with penetrating trauma (93%) and the visceral abdominal or infrarenal aorta (79%) (all p < 0.05). Half of potentially preventable deaths (n = 7) occurred at the scene, and half occurred at a trauma center. CONCLUSION: Potentially preventable deaths after aortic injury were associated with penetrating mechanism and injury to the visceral abdominal and/or infrarenal aorta. Optimal prehospital and ED treatment include temporizing hemorrhage control, hemostatic resuscitation, and faster transport to definitive treatment.

Amiloride derived inhibitors of acid-sensing ion channel-3 (ASIC3).

A series of amiloride derivatives modified at the 5-position of the pyrazine ring were evaluated as inhibitors of acid-sensing ion channel-3 (ASIC3), a novel target for the treatment of chronic pain.

Amidine derived inhibitors of acid-sensing ion channel-3 (ASIC3).

A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.

Too fast, or not fast enough? The FAST exam in patients with non-compressible torso hemorrhage.

BACKGROUND: Focused assessment with sonography for trauma (FAST) performance metrics are unknown in patients with non-compressible torso hemorrhage (NCTH). METHODS: Retrospective review of a dedicated NCTH database from four level 1 trauma centers (2008-2012). NCTH was defined as (1) named axial torso vessel disruption; (2) AIS chest or abdomen >2 with shock (base deficit < -4) or truncal operation in ≤ 90 min; or (3) pelvic fracture with ring disruption. Patients were grouped by cavity of hemorrhage source and by shock (SBP ≤ 90). RESULTS: 274 patients had a FAST prior to diagnosis of NCTH. FAST was positive in 51% of patients with abdominal/pelvic hemorrhage for a false negative rate (FNR) of 49%. FNR was higher for pelvic (61%) versus abdominal (43%) sources (p = 0.02). There was no difference between FAST negative or positive patients for ISS, shock, length of stay, or mortality (all p = NS). FNR was not improved among the subgroup of NCTH patients with shock (p = NS). CONCLUSION: FAST identified abdominal/pelvic hemorrhage in approximately half of NCTH patients, and this was not improved among patients presenting with shock.

Earlier time to hemostasis is associated with decreased mortality and rate of complications: Results from the Pragmatic Randomized Optimal Platelet and Plasma Ratio trial.

BACKDROP: Clinicians intuitively recognize that faster time to hemostasis is important in bleeding trauma patients, but these times are rarely reported. METHODS: Prospectively collected data from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial were analyzed. Hemostasis was predefined as no intraoperative bleeding requiring intervention in the surgical field or resolution of contrast blush on interventional radiology (IR). Patients who underwent an emergent (within 90 minutes) operating room (OR) or IR procedure were included. Mixed-effects Poisson regression with robust error variance (controlling for age, Injury Severity Score, treatment arm, injury mechanism, base excess on admission [missing values estimated by multiple imputation], and time to OR/IR as fixed effects and study site as a random effect) with modified Bonferroni corrections tested the hypothesis that decreased time to hemostasis was associated with decreased mortality and decreased incidence of acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), multiple-organ failure (MOF), sepsis, and venous thromboembolism. RESULTS: Of 680 enrolled patients, 468 (69%) underwent an emergent procedure. Patients with decreased time to hemostasis were less severely injured, had less deranged base excess on admission, and lower incidence of blunt trauma (all p < 0.05). In 408 (87%) patients in whom hemostasis was achieved, every 15-minute decrease in time to hemostasis was associated with decreased 30-day mortality (RR, 0.97; 95% confidence interval [CI], 0.94-0.99), AKI (RR, 0.97; 95% CI, 0.96-0.98), ARDS (RR, 0.98; 95% CI, 0.97-0.99), MOF (RR, 0.94; 95% CI, 0.91-0.97), and sepsis (RR, 0.98; 95% CI, 0.96-0.99), but not venous thromboembolism (RR, 0.99; 95% CI, 0.96-1.03). CONCLUSION: Earlier time to hemostasis was independently associated with decreased incidence of 30-day mortality, AKI, ARDS, MOF, and sepsis in bleeding trauma patients. Time to hemostasis should be considered as an endpoint in trauma studies and as a potential quality indicator. LEVEL OF EVIDENCE: Therapeutic/care management, level III.

A new class of bradykinin B1 receptor antagonists with high oral bioavailability and minimal PXR activity.

The design and synthesis of a novel class of human bradykinin B1 antagonists featuring difluoroethyl ether and isoxazole carboxamide moieties are disclosed. Compound 7g displayed excellent pharmacokinetic properties, efficient ex vivo receptor occupancy, and low potential for P450 induction via PXR activation.

Bradykinin B1 receptor antagonists: an alpha-hydroxy amide with an improved metabolism profile.

A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.

Alpha-hydroxy amides as a novel class of bradykinin B1 selective antagonists.

Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.

Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial.

BACKGROUND: Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis. STUDY DESIGN: We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a value of p < 0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites. RESULTS: We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL [IQR 67 to 336 ng/dL] in those who did (p < 0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, Injury Severity Score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis. CONCLUSIONS: Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis.