Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKÆ´ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Longitudinal Lower Airway Microbial Signatures of Acute Cellular Rejection in Lung Transplantation.

Rationale: Acute cellular rejection (ACR) after lung transplant is a leading risk factor for chronic lung allograft dysfunction. Prior studies have demonstrated dynamic microbial changes occurring within the allograft and gut that influence local adaptive and innate immune responses. However, the lung microbiome's overall impact on ACR risk remains poorly understood. Objectives: To evaluate whether temporal changes in microbial signatures were associated with the development of ACR. Methods: We performed cross-sectional and longitudinal analyses (joint modeling of longitudinal and time-to-event data and trajectory comparisons) of 16S rRNA gene sequencing results derived from lung transplant recipient lower airway samples collected at multiple time points. Measurements and Main Results: Among 103 lung transplant recipients, 25 (24.3%) developed ACR. In comparing samples acquired 1 month after transplant, subjects who never developed ACR demonstrated lower airway enrichment with several oral commensals (e.g., Prevotella and Veillonella spp.) than those with current or future (beyond 1 mo) ACR. However, a subgroup analysis of those who developed ACR beyond 1 month revealed delayed enrichment with oral commensals occurring at the time of ACR diagnosis compared with baseline, when enrichment with more traditionally pathogenic taxa was present. In longitudinal models, dynamic changes in α-diversity (characterized by an initial decrease and a subsequent increase) and in the taxonomic trajectories of numerous oral commensals were more commonly observed in subjects with ACR. Conclusions: Dynamic changes in the lower airway microbiota are associated with the development of ACR, supporting its potential role as a useful biomarker or in ACR pathogenesis.

Cost-effectiveness of MRE versus VCTE in staging fibrosis for nonalcoholic fatty liver disease (NAFLD) patients with advanced fibrosis.

INTRODUCTION: NAFLD is a common cause of liver disease. To determine the optimal testing strategy for NAFLD patients with advanced fibrosis, several factors such as diagnostic accuracy, failure rates, costs of examinations, and potential treatment options need to be considered. The purpose of this study was to determine the cost-effectiveness of combination testing involving vibration-controlled transient elastography (VCTE) versus magnetic resonance elastography (MRE) as a frontline imaging strategy for NAFLD patients with advanced fibrosis. METHODS: A Markov model was developed from the US perspective. The base-case scenario in this model included patients aged 50 years with a Fibrosis-4 score of ≥2.67 and suspected advanced fibrosis. The model included a decision tree and a Markov state-transition model including 5 health states: fibrosis stage 1-2, advanced fibrosis, compensated cirrhosis, decompensated cirrhosis, and death. Both deterministic and probabilistic sensitivity analyses were performed. RESULTS: Staging fibrosis with MRE cost $8388 more than VCTE but led to an additional 1.19 Quality-adjusted life years (QALYs) with the incremental cost-effectiveness ratio of $7048/QALY. The cost-effectiveness analysis of the 5 strategies revealed that MRE+biopsy and VCTE+MRE+biopsy were the most cost-effective with the incremental cost-effectiveness ratios of $8054/QALY and $8241/QALY, respectively. Furthermore, sensitivity analyses indicated that MRE remained cost-effective with a sensitivity of ≥0.77, whereas VCTE became cost-effective with a sensitivity of ≥0.82. CONCLUSIONS: MRE was not only cost-effective than VCTE as the frontline modality for staging NAFLD patients with Fibrosis-4 ≥2.67 with incremental cost-effectiveness ratio of $7048/QALY but also remained cost-effective when used as a follow-up in instances of VCTE failure to diagnose.

Single center utilization and post-transplant outcomes of thoracoabdominal normothermic regional perfusion deceased cardiac donor organs.

INTRODUCTION: Thoracoabdominal normothermic regional perfusion (TA-NRP) following cardiac death is an emerging multivisceral organ procurement technique. Recent national studies on outcomes of presumptive TA-NRP-procured organs are limited by potential misclassification since TA-NRP is not differentiated from donation after cardiac death (DCD) in registry data. METHODS: We studied 22 donors whose designees consented to TA-NRP and organ procurement performed at our institution between January 20, 2020 and July 3, 2022. We identified these donors in SRTR to describe organ utilization and recipient outcomes and compared them to recipients of traditional DCD (tDCD) and donation after brain death (DBD) organs during the same timeframe. RESULTS: All 22 donors progressed to cardiac arrest and underwent TA-NRP followed by heart, lung, kidney, and/or liver procurement. Median donor age was 41 years, 55% had anoxic brain injury, 45% were hypertensive, 0% were diabetic, and median kidney donor profile index was 40%. TA-NRP utilization was high across all organ types (88%-100%), with a higher percentage of kidneys procured via TA-NRP compared to tDCD (88% vs. 72%, p = .02). Recipient and graft survival ranged from 89% to 100% and were comparable to tDCD and DBD recipients (p ≥ .2). Delayed graft function was lower for kidneys procured from TA-NRP compared to tDCD donors (27% vs. 44%, p = .045). CONCLUSION: Procurement from TA-NRP donors yielded high organ utilization, with outcomes comparable to tDCD and DBD recipients across organ types. Further large-scale study of TA-NRP donors, facilitated by its capture in the national registry, will be critical to fully understand its impact as an organ procurement technique.

Biodistribution of lentiviral transduced adipose-derived stem cells for "ex-vivo" regional gene therapy for bone repair.

Ex-vivo gene therapy has been shown to be an effective method for treating bone defects in pre-clinical models. As gene therapy is explored as a potential treatment option in humans, an assessment of the safety profile becomes an important next step. The purpose of this study was to evaluate the biodistribution of viral particles at the defect site and various internal organs in a rat femoral defect model after implantation of human ASCs transduced with lentivirus (LV) with two-step transcriptional activation (TSTA) of bone morphogenetic protein-2 (LV-TSTA-BMP-2). Animals were sacrificed at 4-, 14-, 56-, and 84-days post implantation. The defects were treated with either a standard dose (SD) of 5 million cells or a high dose (HD) of 15 million cells to simulate a supratherapeutic dose. Treatment groups included (1) SD LV-TSTA-BMP-2 (2) HD LV-TSTA-BMP-2, (3) SD LV-TSTA-GFP (4) HD LV-TSTA-GFP and (5) SD nontransduced cells. The viral load at the defect site and ten organs was assessed at each timepoint. Histology of all organs, ipsilateral tibia, and femur were evaluated at each timepoint. There were nearly undetectable levels of LV-TSTA-BMP-2 transduced cells at the defect site at 84-days and no pathologic changes in any organ at all timepoints. In conclusion, human ASCs transduced with a lentiviral vector were both safe and effective in treating critical size bone defects in a pre-clinical model. These results suggest that regional gene therapy using lentiviral vector to treat bone defects has the potential to be a safe and effective treatment in humans.

Influence of donor age and comorbidities on transduced human adipose-derived stem cell in vitro osteogenic potential.

Human adipose-derived mesenchymal stem cells (ASCs) transduced with a lentiviral vector system to express bone morphogenetic protein 2 (LV-BMP-2) have been shown to reliably heal bone defects in animal models. However, the influence of donor characteristics such as age, sex, race, and medical co-morbidities on ASC yield, growth and bone regenerative capacity, while critical to the successful clinical translation of stem cell-based therapies, are not well understood. Human ASCs isolated from the infrapatellar fat pads in 122 ASC donors were evaluated for cell growth characteristics; 44 underwent additional analyses to evaluate in vitro osteogenic potential, with and without LV-BMP-2 transduction. We found that while female donors demonstrated significantly higher cell yield and ASC growth rates, age, race, and the presence of co-morbid conditions were not associated with differences in proliferation. Donor demographics or the presence of comorbidities were not associated with differences in in vitro osteogenic potential or stem cell differentiation, except that transduced ASCs from healthy donors produced more BMP-2 at day 2. Overall, donor age, sex, race, and the presence of co-morbid conditions had a limited influence on cell yield, proliferation, self-renewal capacity, and osteogenic potential for non-transduced and transduced (LV-BMP-2) ASCs. These results suggest that ASCs are a promising resource for both autologous and allogeneic cell-based gene therapy applications.

Association between Endometriosis and Surgical Complications among Benign Hysterectomies.

STUDY OBJECTIVE: To investigate the effect of endometriosis on perioperative outcomes in patients undergoing hysterectomy for benign disease. DESIGN: A retrospective cohort study. SETTING: The American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS: A total of 127 556 hysterectomies performed for benign gynecologic indications INTERVENTIONS: Differences in the primary outcomes were compared between patients with and without endometriosis after adjustment for group differences in covariates using inverse probability of treatment weighting approach. MEASURES AND MAIN RESULTS: Of the 127 556 hysterectomies identified, 19 618 (15.4%) had a diagnosis of endometriosis. Patients with endometriosis were younger with a lower prevalence of chronic comorbidities but had higher rates of concurrent pelvic inflammatory disease and previous abdominal operations. The incidence of postoperative complications was higher in patients with endometriosis (9.9% vs 8.1%; odds ratio [OR], 1.25; 95% confidence interval [CI], 1.17-1.34). The incidence of 30-day mortality (0.1% vs 0.03%; OR, 1.98; 95% CI, 0.69-5.65) and reoperations (1.50% vs 1.36%; OR, 1.18; 95% CI, 0.98-1.42) were not different in patients with and without endometriosis. CONCLUSION: Postoperative complications are more likely in hysterectomies involving endometriosis than those without endometriosis, likely owing to anatomic distortion incurring increased surgical complexity. Patients and surgeons should be aware of the increased risk of complications and plan for mitigating these increased risks before and during surgery for suspected endometriosis.

Ice-POP: Ice Packs for Postoperative Pain: A Randomized Controlled Trial.

STUDY OBJECTIVE: To evaluate the benefit of ice packs as a supplement to standard pain management following laparoscopic hysterectomy (LH). DESIGN: This Institutional Review Board-approved randomized controlled trial involved patients undergoing LH for benign conditions. Subjects were randomized to receive standard enhanced recovery after surgery pain management or standard enhanced recovery after surgery plus ice packs. SETTING: Two academic tertiary care centers PATIENTS: Patients undergoing planned outpatient LH with the minimally invasive gynecologic surgery team between February 2019 and November 2020 were considered. Patients with chronic pain, current opioid use ≥1 week, or planned overnight hospitalizations were excluded. Primary outcome data were available for 51 subjects (24 control, 27 intervention). INTERVENTIONS: Ice packs were placed on the abdomen in the operating room. MEASUREMENTS AND MAIN RESULTS: Pain was assessed at multiple time points throughout the study using a visual analogue scale (VAS). Opioid requirement was assessed using morphine milligram equivalent. There was no difference between the groups on any demographic variables. Morphine milligram equivalent requirements were also not different between the groups (p = .63). Postoperative day 1 (POD#1) VAS scores were not different (p = .89). Eighty-five percent of subjects reported feeling that their pain was controlled. Subjects who reported that they did not feel their pain was controlled did not use more opioids on POD#1 (p = .37), nor did they have higher POD#1 VAS scores (p = .55). Eighty-seven percent of the intervention subjects said they would use ice again, and 82.6% of them said they would recommend ice to others. There were no adverse events related to ice. All subjects were prescribed 20 tablets oxycodone and averaged 2.9 (SD 3.4) tablets used after discharge. CONCLUSION: Ice packs are an acceptable supplement for postoperative pain control, but they do not reduce postoperative pain or opioid usage compared to standard pain management without ice packs.

A Framework for the Development of Living Practice Guidelines in Health Care.

BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.

Modeling economic impacts of mobility restriction policy during the COVID-19 pandemic.

The economic impacts of pandemics can be enormous. However, lockdown and human mobility restrictions are effective policies for containing the spread of the disease. This study proposes a framework for assessing the economic impact of varying degrees of movement restrictions and examines the effectiveness of this framework in a case study examining COVID-19 control measures in Japan. First, mobile network operators data and total employment statistics on a 500-meter grid scale are used to determine the status of mobility restrictions and impacts on consumption in 30 industrial sectors. Next, the economic impacts are assessed using a spatial computable general equilibrium (CGE) model, proven to yield valuable insights into the total economic impacts of natural disasters. In sectors that implement telework and e-commerce-wholesale/retail, finance/insurance, and communication sectors-estimates of production and GDP are obtained that are close to the actual figures. The current case study is limited to Japan, but similar analysis can be conducted by using the CGE model for each country and open mobility data. Thus, the framework has potential to serve as an effective tool for assessing trade-offs between infection risks and economic impacts to inform policy-making by combining with findings from epidemiology.

Development of Psychiatric Residents as Psychotherapists: Effectiveness of a Psychotherapy Pathway.

OBJECTIVE: This study aimed to assess the effectiveness and impact of participation by psychiatric residents in an academic institution's tiered psychotherapy pathway. METHODS: The authors invited pathway graduates who earned an area of distinction between 2013 and 2020 (N=22) to complete an anonymous online survey about their pathway experiences. RESULTS: Thirteen graduates (59%) responded to the survey. Most respondents (92%) agreed that participating in the pathway exposed them to many psychotherapy modalities, and most (92%) agreed that their participation facilitated an in-depth understanding of one or more psychotherapy modalities of personal interest. In written comments, respondents practicing across different settings noted that pathway participation had positively influenced their career development. CONCLUSIONS: The survey results highlight the educational and professional benefits of developing a psychotherapy pathway for psychiatric residents with varying career plans.

Cefepime Versus Piperacillin-Tazobactam for the Treatment of Intra-Abdominal Infections Secondary to Potential AmpC Beta-Lactamase-Producing Organisms.

Background: Recent studies have established cefepime as an effective treatment option for AmpC beta-lactamase (AmpC) Enterobacterales; however, the efficacy of beta-lactam/beta-lactamase inhibitors is unclear. Objective: The objective of this study was to determine if piperacillintazobactamis an appropriate alternative to cefepime for the treatment of intra-abdominal infections (IAIs) secondary to AmpC-producing organisms. Methods: This multicenter, retrospective cohort study was conducted in hospitalized adults with an IAI caused by an AmpC-producing organism and received either cefepime or piperacillin-tazobactam for definitive treatment after a source control procedure. The primary outcome was a composite of surgical site infections, recurrent IAIs, or in-hospital mortality. Secondary outcomes included the individual components of the composite outcome, hospital length of stay (LOS), microbiologic failure, study antibiotic duration, time to clinical resolution, and incidence of Clostridioides difficile infection (CDI). Results: This study included 119 patients. There was no difference in the primary outcome between the cefepime and piperacillin-tazobactam groups (35% vs 27%, P = 0.14). Microbiological failure was the only secondary outcome with an observed difference between groups (17% vs 0%, P = 0.01): hospital LOS (15 vs 13 days, P = 0.09), days of therapy (7 vs 7 days, P = 0.87), time to clinical resolution (7 vs 4 days, P = 0.30), and CDI (1% vs 2%, P = 0.58) were all similar.

Multimodal opioid-sparing pain management after lung transplantation and the impact of liposomal bupivacaine intercostal nerve block.

Opioid analgesics are commonly used post-lung transplant, but have many side effects and are associated with worse outcomes. We conducted a retrospective review of all lung transplant recipients who were treated with a multimodal opioid-sparing pain protocol. The use of liposomal bupivacaine intercostal nerve block was variable due to hospital restrictions. The primary objective was to describe opioid requirements and patient-reported pain scores early post-lung transplant and to assess the impact of intraoperative liposomal bupivacaine intercostal nerve block. We treated 64 lung transplant recipients with our protocol. Opioid utilization decreased to a mean of 43 milligram oral morphine equivalents by postoperative day 4. Median pain scores peaked at 4 on postoperative day 1 and decreased thereafter. Only three patients were discharged home with opioids, all of whom were taking opioid agonist therapy pre-transplant for opioid use disorder. Patients who received liposomal bupivacaine intercostal nerve block in the operating room had a significant reduction in opioid consumption over postoperative day 1 through 4 (228 mg vs. 517 mg, P= .032). A multimodal opioid-sparing pain management protocol is feasible and resulted in weaning of opioids prior to hospital discharge.

One-year immunologic outcomes of lung transplantation utilizing hepatitis C-viremic donors.

Little is known about the effects of hepatitis C viremia on immunologic outcomes in the era of direct-acting antivirals. We conducted a prospective, single-arm trial of lung transplantation from hepatitis C-infected donors into hepatitis C-naïve recipients (n = 21). Recipients were initiated on glecaprevir-pibrentasvir immediately post-transplant and were continued on therapy for a total of 8 weeks. A control group of recipients of hepatitis C-negative lungs were matched 1:1 on baseline variables (n = 21). The primary outcome was the frequency of acute cellular rejection over 1-year post-transplant. Treatment with glecaprevir-pibrentasvir was well tolerated and resulted in viremia clearance after a median of 16 days of therapy (IQR 10-24 days). At one year, there was no difference in incidence of acute cellular rejection (71.4% vs. 85.7%, P = .17) or rejection requiring treatment (33.3% vs. 57.1%, P = .12). Mean cumulative acute rejection scores were similar between groups (.46 [SD ± .53] vs. .52 [SD ± .37], P = .67). Receipt of HCV+ organs was not associated with acute rejection on unadjusted Cox regression analysis (HR .55, 95% CI .28-1.11, P = .09), or when adjusted for risk factors known to be associated with acute rejection (HR .57, 95% CI .27-1.21, P = .14). Utilization of hepatitis C infected lungs with immediate treatment leads to equivalent immunologic outcomes at 1 year.

Rapidly Growing Mycobacterium tuberculosis in the Form of Empyema Necessitans: A Case Report.

We present a case of rapidly growing disseminated Mycobacterium tuberculosis (MTB) that presented as an empyema necessitans (EN) in a 65-year-old woman with a single right lung transplant admitted for progressive dyspnea. While hospitalized, she had daily fevers and was found to have a right-sided chest wall abscess and pleural effusion. Acid-fast bacilli cultures from the abscess and pleural fluid grew MTB within 4 and 6 days, respectively. Blood cultures later grew MTB as well. Upon initiation of rifampin, isoniazid, pyrazinamide, and ethambutol, she developed hemorrhagic pancreatitis and distributive shock secondary to antituberculosis medications and disseminated MTB. Noteworthy features of this case include the rapid rate of MTB culture growth in less than a week, the development of a likely donor-derived MTB EN, and the clinical challenges of MTB screening and MTB infection management in a solid organ transplant recipient.

Comparison of the effect of sedation and general anesthesia on pattern and flash visual evoked potentials in normal dogs.

BACKGROUND: Visual evoked potentials (VEPs) can provide objective functional assessment of the post-retinal visual pathway. This study compared the effects of sedation (butorphanol and dexmedetomidine) and general anesthesia (propofol and sevoflurane) on pattern and flash VEPs. Dogs (n = 13) underwent sedation or anesthesia and VEPs were obtained from 3 subcutaneous recording electrodes placed on the head (O1, Oz, O2). RESULTS: Pattern VEPs could only be recorded under sedation and a maximum of 3 peaks were identified (N75, P100, N135). Flash VEPs could be recorded under both sedation and anesthesia and a maximum of 5 peaks were identified (N1, P1, N2, P2, N3). The latency of the N1 peak and the baseline-N1 amplitude were significantly longer under general anesthesia. CONCLUSION: Visual evoked potentials should be preferentially recorded in dogs sedated with dexmedetomidine and butorphanol, regardless of the stimulus.

Effectiveness and safety of repeated percutaneous intervention in an office-based endovascular center in maintaining hemodialysis access.

OBJECTIVES: Percutaneous dialysis access interventions are routinely used to maintain the patency of dialysis access despite the lack of data regarding their long-term effectiveness. This retrospective study was undertaken to study the effectiveness and safety of percutaneous dialysis access interventions in arm fistulas and bridge grafts in an office-based endovascular center. METHODS: Patients who had a percutaneous dialysis access intervention in their upper extremity access site, performed at a single office-based endovascular center over a nine-year period (2007-2016) were included in this study. The patients' demographic factors, patency, and complications were analyzed. Patients were entered in the study after first percutaneous dialysis access intervention. RESULTS: A total of 298 limbs in 259 patients had 913 procedures carried out over a nine-year period. There were 190 access arteriovenous fistulas and 108 arteriovenous grafts. The two most common arteriovenous fistulas were the brachiocephalic fistula (n = 74, 39%) and radio cephalic fistula (n = 69, 36%). Arteriovenous grafts were most commonly placed in the upper arm (n = 66, 61%) followed by the forearm (n = 42, 39%). The mean overall patency for all limbs was 50.86 months. Arteriovenous fistulas had a significantly longer patency than arteriovenous grafts (51.65 vs. 42.09 months; P = 0.01). In addition, patients with two or more percutaneous dialysis access intervention in their arteriovenous fistula had significantly greater patency than those with only one percutaneous dialysis access intervention (58.5 vs. 7.6 months; hazard ratio 0.41; P = 0.0008). This was not true for the arteriovenous graft group. Women represented 49% of the patient group. Their accesses had shorter patency than men (39.8 vs. 60 months; P = 0.0007). CONCLUSIONS: This data support the use of repeated percutaneous dialysis access intervention to maintain long-term patency of dialysis access sites in an office-based endovascular center. Overall, fistulas have longer patency than grafts and women have poorer outcomes as compared to men.

Comparison of Sedative Effects of Alfaxalone-Ketamine and Alfaxalone-Midazolam Administered Intramuscularly in Chickens.

The objective of this study was to compare the sedative effects of intramuscular alfaxalone combined with either ketamine or midazolam in chickens (Gallus gallus domesticus). A prospective, randomized blinded crossover study design with a 7-day washout period was used. Nine adult layer hens received alfaxalone 15 mg/kg with ketamine 5 mg/kg IM (treatment AK) or alfaxalone 15 mg/kg with midazolam 1 mg/kg IM (treatment AM). Time to lateral recumbency, time to loss of righting reflex, induction quality, duration of loss of righting reflex, time to sternal recumbency or vigorous response to stimulation, and time to standing were recorded. Muscle tone, response to noxious stimulation, heart rate, respiratory rate, and oxygen saturation were monitored once the righting reflex was absent. Induction and recovery times were not different between treatments. Lateral recumbency was induced in 8 of 9 birds receiving AK compared to 6 of 9 birds receiving AM. Righting reflex was absent in 7 of 9 and 5 of 9 chickens administered AK and AM, respectively. Median time to loss of righting reflex for AK and AM were 5.5 (4.3-9.3) minutes and 9.1 (4.8-15.0) minutes, respectively (P = .88). Median duration of loss of righting reflex was 21.6 (16.0-36.9) minutes for AK and 21.1 (11.9-26.4) minutes for AM (P = .38). Alfaxalone-ketamine resulted in moderate excitation during induction. Further investigations are warranted to investigate the effects of alfaxalone and midazolam or ketamine at different doses.