Emerging Gene Therapies for Alzheimer's and Parkinson's Diseases: An Overview of Clinical Trials and Promising Candidates.

Gene therapy as a disease-modifying therapeutic approach for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), is a promising avenue. Promising results in the preclinical studies involving rodents and nonhuman primates utilizing gene therapy have led to multiple clinical trials evaluating various genes of interest for AD and PD. In AD, clinical trials are assessing gene therapy involving brain-derived neurotrophic factor (BDNF) and other targets such as apolipoprotein E2 (APOE2) and human telomerase reverse transcriptase (hTERT). In PD, clinical trials are evaluating gene therapy delivering neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF). Additionally, gene therapy delivering enzymes aromatic L-amino acid decarboxylase (AADC) and glutamic acid decarboxylase (GAD) are also being evaluated for PD. All these trials primarily utilized adeno-associated virus (AAV) to deliver the above transgene of interest. This review summarizes the current clinical trials involving gene therapy for AD and PD. It also discusses the challenges and opportunities associated with the gene therapy approach in AD and PD and ongoing developments related to increasing the safety and efficacy of the gene therapy for long-term outcomes, which include evaluation of various serotypes and administration routes. This comprehensive review emphasizes translating preclinical findings into clinical trials, further directions, and the potential for this promising therapeutic approach to alleviate neurodegenerative disease.

Using Acidosis as a Surrogate for or Supplement to the Bedside Index of Severity in Acute Pancreatitis Scoring Prediction System Has a Nonsignificant Effect.

Currently, risk stratification calculators for acute pancreatitis (AP) can at best predict acute pancreatitis mortality at 12 hours from the presentation. Given the severe morbidity associated with AP, the identification of additional prognostic indicators, which may afford earlier prediction in length of stay (LOS) and mortality, is desired. Metabolic acidosis can be a prognostic marker for the severity of AP, and venous bicarbonate can reliably and accurately be substituted for arterial base deficit to detect metabolic acidosis. Since serum bicarbonate, anion gap (AG), and corrected AG (CAG) are routinely obtained upon presentation to the emergency department and often daily in the hospital, we conducted a retrospective analysis of 443 patients, evaluating if venous bicarbonate could predict the severity of pancreatitis as well as mortality, admission to the ICU, ICU LOS, and hospital LOS. The inclusion of venous bicarbonate, AG, and CAG in the first 12 hours only slightly improved the predictive capabilities of the Bedside Index for Severity in Acute Pancreatitis (BISAP) score for these secondary outcomes. None of our incorporations of acidemia improved severity predictions more than the BISAP alone. Adding CAG to BISAP scoring had the largest effect on predicting ICU admission and hospital LOS (area under the curve (AUC): 1.12 (confidence interval (CI) 95%: 1.06-1.19), p <.001 and AUC 1.02 (CI 95% 1.01-1.04), p <.001; respectively). ICU LOS was not impacted by the addition of AG, CAG, or venous bicarbonate. In-hospital death (n=12) was too small to be determined.

The Effectiveness of Albumin-to-Globulin Ratio as a Prognostic Biomarker in Primary Gastrointestinal Cancer: A Systematic Review and Meta-Analysis.

Albumin-to-globulin ratio (AGR) is a cheap, widely accessible component of common blood work that has been implicated in the prognosis of various cancers. This effect is attributed to the cooperative relationship between albumin reflecting the body's nutritional status and globulin serving as an indicator of immune status. With the high morbidity and mortality associated with gastrointestinal cancer and the increasing necessity for cost-effective health care, research into AGR's potential as an indicator of prognosis is warranted. A database search, including key terms between AGR and gastrointestinal cancer, was performed. Random-effects meta-analysis was completed on extracted hazard ratios with two-sided p-values <0.05 being deemed significant. A total of 8,384 patients with gastrointestinal cancer were included. A low AGR was found to be associated with increased risk for reduced overall survival in cancer of the primary GI tract (HR: 1.82, 1.35-2.45, p < 0.001), esophageal cancer (HR: 1.57, 1.19-2.06, p < 0.001), colon cancer (HR: 3.36, 2.02-5.58, p < 0.001), and colorectal cancer (HR: 2.27, 1.15-4.48, p = 0.02) populations. A low AGR is significantly associated with increased risk for reduced overall survival in primary gastrointestinal cancer. Due to the ease of access and low cost to physicians and patients, incorporation of AGR into clinical evaluation of prognosis in these cancers should prove beneficial to patient outcomes.

Inferior Pancreaticoduodenal Artery Pseudoaneurysm Causing Biliary Obstruction: A Case Report.

Introduction: Visceral arterial aneurysms and pseudoaneurysms are rare but dangerous pathologies, with reported incidence of 0.01-0.2% of the worldwide population, as found on autopsy. Pancreaticoduodenal artery pathology accounts for approximately 2% of all visceral aneurysms; it is commonly caused by chronic inflammatory processes, such as pancreatitis or adjacent pseudocysts. Morbidity and mortality commonly result from rupture of the aneurysm itself, leading to life-threatening hemorrhage into the peritoneum or gastrointestinal tract. Case Report: Here we present the case of a 64-year-old male patient with previous history of alcohol use disorder leading to chronic pancreatitis and prior embolization of an inferior pancreaticoduodenal pseudoaneurysm, who presented to the emergency department (ED) with abdominal pain, nausea, and vomiting, and was found to have a large recurrent inferior pancreaticoduodenal pseudoaneurysm with associated obstructive cholangitis and pancreatitis via contrast-enhanced computed tomography (CT) of the abdomen and pelvis. The patient was managed emergently by interventional radiology angiography with embolic coiling and percutaneous biliary catheter placement, and he subsequently underwent biliary duct stenting with gastroenterology. The patient was successfully discharged after a brief hospitalization after resolution of his pancreatitis and associated hyperbilirubinemia. Conclusion: Pancreaticoduodenal artery aneurysms and pseudoaneurysms are rare and dangerous visceral pathologies. Patients can be diagnosed rapidly in the ED with CT imaging and need urgent endovascular management to prevent morbidity and mortality.

Newly Recognized Spotted Fever Group Rickettsia as Cause of Severe Rocky Mountain Spotted Fever-Like Illness, Northern California, USA.

The incidence of spotted fever group (SFG) rickettsioses in the United States has tripled since 2010. Rocky Mountain spotted fever, the most severe SFG rickettsiosis, is caused by Rickettsia rickettsii. The lack of species-specific confirmatory testing obfuscates the relative contribution of R. rickettsii and other SFG Rickettsia to this increase. We report a newly recognized rickettsial pathogen, Rickettsia sp. CA6269, as the cause of severe Rocky Mountain spotted fever-like illness in 2 case-patients residing in northern California. Multilocus sequence typing supported the recognition of this pathogen as a novel Rickettsia genotype most closely related to R. rickettsii. Cross-reactivity observed for an established molecular diagnostic test indicated that Rickettsia sp. CA6269 might be misidentified as R. rickettsii. We developed a Rickettsia sp. CA6269-specific real-time PCR to help resolve this diagnostic challenge and better characterize the spectrum of clinical disease and ecologic epidemiology of this pathogen.

Unexpected Airway Collapse: A Rare Case of Spontaneous Postoperative Tracheobronchomalacia in the Absence of Identifiable Risk Factors.

We report the case of a 53-year-old female who developed tracheobronchomalacia immediately following an uncomplicated robotic hysterectomy with bilateral salpingo-oophorectomy to treat postmenopausal bleeding. Induction of anesthesia was notable for moderately difficult intubation, managed with applied cricothyroid pressure and a small 6.5 endotracheal tube placement via GlideScope. The surgical course was uneventful. The patient remained intubated in the post-anesthesia care unit but was not providing end-tidal volumes. Attempts to replace the endotracheal tube with a larger tube were unsuccessful and the patient was temporarily unable to ventilate. Rapid troubleshooting discovered that a laryngeal mask airway (LMA) could sufficiently ventilate the patient. An otolaryngologist was able to perform direct bronchoscopy, which revealed more than 50% dynamic anterior-posterior collapse of the trachea and bronchi. The patient was subsequently awakened from anesthesia and monitored in the intensive care unit, ventilating with an LMA. After a couple of hours, it was determined that the patient's airway was protected, and the LMA was removed.

The Efficacy of Metformin as a Therapeutic Agent in the Treatment of Acne Vulgaris: A Systematic Review.

A large portion of the world's population is affected by acne vulgaris (AV), with many of these individuals being adolescents. The underlying mechanism of AV is hyperkeratinization and Cutibacterium acnes infection of the pilosebaceous follicle secondary to excessive stimulation of sebaceous glands by androgens. Metformin is a biguanide medication primarily used in efforts to lower patients' sugar levels in the management of type 2 diabetes. It has been proven to reduce levels of circulating androgens in patients with insulin resistance, indicating its potential for treating AV. A search strategy was developed and performed using the databases Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Controlled Register of Trials (CENTRAL), and Web of Science. The keywords "metformin" and "acne" were searched, along with related Medical Subject Headings (MeSH) and other subject headings. Studies that met the inclusion criteria were controlled trials, published after 2010, and in the English language. Participants with and without comorbidities such as polycystic ovary syndrome (PCOS) were considered. Two independent reviewers screened studies based on predefined criteria and extracted data from each study, which were quantitatively combined. A total of 15 studies were included in this systematic review. Across the 15 studies, there were 1,046 participants, with 13 studies looking exclusively at women with PCOS. Of the remaining two studies, one examined males with altered metabolic profiles, while the other included men and women with moderate AV. Notable risks of bias included studies that did not exclusively state the blindness of the study. Of the studies that were examined, 13 showed that metformin reduces AV, with seven studies showing statistical significance. Acne vulgaris is an inflammatory condition that has plagued patients for years due to the limited treatment options available. The hyperglycemic medication metformin, used in the management of type 2 diabetes, is being explored as a novel therapeutic that can possibly be repurposed for the treatment of AV. The use of metformin in AV is hypothesized to disrupt the proposed linkage between insulin resistance and AV proliferation. This proposed research could offer physicians a new option for the treatment of AV as well as render an alternative AV treatment for patients.

Percutaneous kidney biopsy trends in the Medicare population by specialty from 2011 to 2021: implications for nephrology training requirements and radiology referral patterns.

PURPOSE: To study trends in volume and reimbursement for percutaneous kidney biopsy (PKB) by physicians and advanced practice providers (APPs) for Medicare enrollees from 2011-2021. METHODS: Claims from the Medicare Part B Physician/Supplier Procedure Master File (a national Medicare database) for 2011-2021 were extracted using Current Procedural Terminology codes for PKB. Total volumes were compared by provider specialty. Non-facility reimbursement, work Relative Value Unit (RVU) non-facility practice expense RVU, and malpractice RVU were compared. RESULTS: Between 2011 and 2021, total volume of PKB by physicians and APPs increased from 30,753 to 34,090 (10.9%), with a peak of 37,882 in 2019 prior to the COVID 19 pandemic. Radiology performed the majority of procedures during the study period. Relative share for radiology increased from 67.6% to 81.1% while the relative share for internal medicine/nephrology decreased from 24.3% to 14.3%, accelerating between 2019 and 2020. Volume and relative share for APPs marginally increased (from 0.9% to 1.2%). Non-facility reimbursement decreased from $578.96 in 2010 to $568.76 in 2021 (1.7%), work RVU decreased from 2.63 to 2.38 (9.5%), non-facility practice expense RVU decreased from 14.10 to 13.71 (2.8%), and malpractice RVU decreased from 0.31 to 0.21 (32.3%). CONCLUSION: Volume and total share of PKB performed by radiology increased over the study period. Conversely, internal medicine/nephrology performed fewer kidney biopsies. Despite the expanding role for APPs in other image-guided procedures, very few PKBs were performed by APPs throughout the study period. Reimbursement and RVU for PKB declined over the study period.

Host interactions of novel Crassvirales species belonging to multiple families infecting bacterial host, Bacteroides cellulosilyticus WH2.

Bacteroides, the prominent bacteria in the human gut, play a crucial role in degrading complex polysaccharides. Their abundance is influenced by phages belonging to the Crassvirales order. Despite identifying over 600 Crassvirales genomes computationally, only few have been successfully isolated. Continued efforts in isolation of more Crassvirales genomes can provide insights into phage-host-evolution and infection mechanisms. We focused on wastewater samples, as potential sources of phages infecting various Bacteroides hosts. Sequencing, assembly, and characterization of isolated phages revealed 14 complete genomes belonging to three novel Crassvirales species infecting Bacteroides cellulosilyticus WH2. These species, Kehishuvirus sp. 'tikkala' strain Bc01, Kolpuevirus sp. 'frurule' strain Bc03, and 'Rudgehvirus jaberico' strain Bc11, spanned two families, and three genera, displaying a broad range of virion productions. Upon testing all successfully cultured Crassvirales species and their respective bacterial hosts, we discovered that they do not exhibit co-evolutionary patterns with their bacterial hosts. Furthermore, we observed variations in gene similarity, with greater shared similarity observed within genera. However, despite belonging to different genera, the three novel species shared a unique structural gene that encodes the tail spike protein. When investigating the relationship between this gene and host interaction, we discovered evidence of purifying selection, indicating its functional importance. Moreover, our analysis demonstrated that this tail spike protein binds to the TonB-dependent receptors present on the bacterial host surface. Combining these observations, our findings provide insights into phage-host interactions and present three Crassvirales species as an ideal system for controlled infectivity experiments on one of the most dominant members of the human enteric virome.

The efficacy of albumin-globulin ratio to predict prognosis in cancer patients.

The goal of this systematic review was to identify all of the research within the last 10 years that investigated both the Albumin-Globulin Ratio (AGR) and outcomes of solid tumor cancer patients via quantitative prognostic variables. Multiple scientific databases were researched for journal articles that included keywords relating AGR to prognosis. Once isolated from the databases, the articles were de-duplicated and manually screened based on standardized inclusion/exclusion criteria in a blind format via Rayyan. The collective data were sorted by cancer type, corrected for population size, and used to calculate the average cut-off values for the most popular prognostic variables. In total, 18 independent types of cancer have been evaluated to see if AGR is a prognostic indicator based on multivariate analyses. The average cut-off value for AGR in overall survival was 1.356, while the average cut-off value for AGR in progression free survival was 1.292. AGR was found to be significantly associated with at least one prognostic variable in every type of cancer evaluated based on multivariate analyses. The ease of access and affordability of AGR makes it an invaluable tool applicable to nearly all patients. Overall, AGR is a proven prognostic variable that should always be considered in the evaluation of a solid tumor cancer patient's prognosis. Further research needs to be conducted studying the potential prognostic effect in more types of solid tumors.

Extreme Concentrations of Nitric Oxide Control Daytime Oxidation and Quench Nocturnal Oxidation Chemistry in Delhi during Highly Polluted Episodes.

Delhi, India, suffers from periods of very poor air quality, but little is known about the chemical production of secondary pollutants in this highly polluted environment. During the postmonsoon period in 2018, extremely high nighttime concentrations of NOx (NO and NO2) and volatile organic compounds (VOCs) were observed, with median NOx mixing ratios of ∼200 ppbV (maximum of ∼700 ppbV). A detailed chemical box model constrained to a comprehensive suite of speciated VOC and NOx measurements revealed very low nighttime concentrations of oxidants, NO3, O3, and OH, driven by high nighttime NO concentrations. This results in an atypical NO3 diel profile, not previously reported in other highly polluted urban environments, significantly perturbing nighttime radical oxidation chemistry. Low concentrations of oxidants and high nocturnal primary emissions coupled with a shallow boundary layer led to enhanced early morning photo-oxidation chemistry. This results in a temporal shift in peak O3 concentrations when compared to the premonsoon period (12:00 and 15:00 local time, respectively). This shift will likely have important implications on local air quality, and effective urban air quality management should consider the impacts of nighttime emission sources during the postmonsoon period.

Host interactions of novel Crassvirales species belonging to multiple families infecting bacterial host, Bacteroides cellulosilyticus WH2.

Bacteroides, the prominent bacteria in the human gut, play a crucial role in degrading complex polysaccharides. Their abundance is influenced by phages belonging to the Crassvirales order. Despite identifying over 600 Crassvirales genomes computationally, only few have been successfully isolated. Continued efforts in isolation of more Crassvirales genomes can provide insights into phage-host-evolution and infection mechanisms. We focused on wastewater samples, as potential sources of phages infecting various Bacteroides hosts. Sequencing, assembly, and characterization of isolated phages revealed 14 complete genomes belonging to three novel Crassvirales species infecting Bacteroides cellulosilyticus WH2. These species, Kehishuvirus sp. 'tikkala' strain Bc01, Kolpuevirus sp. 'frurule' strain Bc03, and 'Rudgehvirus jaberico' strain Bc11, spanned two families, and three genera, displaying a broad range of virion productions. Upon testing all successfully cultured Crassvirales species and their respective bacterial hosts, we discovered that they do not exhibit co-evolutionary patterns with their bacterial hosts. Furthermore, we observed variations in gene similarity, with greater shared similarity observed within genera. However, despite belonging to different genera, the three novel species shared a unique structural gene that encodes the tail spike protein. When investigating the relationship between this gene and host interaction, we discovered evidence of purifying selection, indicating its functional importance. Moreover, our analysis demonstrated that this tail spike protein binds to the TonB-dependent receptors present on the bacterial host surface. Combining these observations, our findings provide insights into phage-host interactions and present three Crassvirales species as an ideal system for controlled infectivity experiments on one of the most dominant members of the human enteric virome. Impact statement: Bacteriophages play a crucial role in shaping microbial communities within the human gut. Among the most dominant bacteriophages in the human gut microbiome are Crassvirales phages, which infect Bacteroides. Despite being widely distributed, only a few Crassvirales genomes have been isolated, leading to a limited understanding of their biology, ecology, and evolution. This study isolated and characterized three novel Crassvirales genomes belonging to two different families, and three genera, but infecting one bacterial host, Bacteroides cellulosilyticus WH2. Notably, the observation confirmed the phages are not co-evolving with their bacterial hosts, rather have a shared ability to exploit similar features in their bacterial host. Additionally, the identification of a critical viral protein undergoing purifying selection and interacting with the bacterial receptors opens doors to targeted therapies against bacterial infections. Given Bacteroides role in polysaccharide degradation in the human gut, our findings advance our understanding of the phage-host interactions and could have important implications for the development of phage-based therapies. These discoveries may hold implications for improving gut health and metabolism to support overall well-being. Data summary: The genomes used in this research are available on Sequence Read Archive (SRA) within the project, PRJNA737576. Bacteroides cellulosilyticus WH2, Kehishuvirus sp. 'tikkala' strain Bc01, Kolpuevirus sp. ' frurule' strain Bc03, and 'Rudgehvirus jaberico' strain Bc11 are all available on GenBank with accessions NZ_CP072251.1 ( B. cellulosilyticus WH2), QQ198717 (Bc01), QQ198718 (Bc03), and QQ198719 (Bc11), and we are working on making the strains available through ATCC. The 3D protein structures for the three Crassvirales genomes are available to download at doi.org/10.25451/flinders.21946034.

Reductions in Reimbursement and Relative Value Units for Interventional Radiology Procedures: Trends from 2011 to 2021 Compared with Those for Other Physician Specialties.

PURPOSE: To compare recent trends in Medicare reimbursement and relative value units (RVUs) for interventional radiology (IR) procedures similar to those performed by non-IR specialties. MATERIALS AND METHODS: Data from the Centers for Medicare and Medicaid Services Physician Fee Schedule for facility reimbursement and RVU component values for 23 commonly performed single Current Procedural Terminology IR procedures were compared with similar procedures or procedures for similar indications performed by non-IR specialties between 2011 and 2021. RESULTS: The work RVU component decreased in 18 of 23 (78.3%) IR procedures compared with 6 of 23 (26.1%) similar procedures performed by non-IR specialties. The largest change in single RVU component was a 19.2% reduction in practice expense RVU for IR compared with a 16.5% reduction for similar procedures performed by non-IR specialties. CONCLUSIONS: As a specialty, IR experienced a disproportionately greater reduction in reimbursement and RVU valuation for a range of comparable procedures performed by non-IR specialties.

Growth in Thoracentesis and Paracentesis Performed by Radiology and Advanced Practice Providers: Medicare Volume and Reimbursement Trends From 2012 to 2018.

PURPOSE: To study trends in volume and reimbursement for paracentesis and thoracentesis by physicians and advanced practice providers (APPs) after the introduction of discreet Current Procedural Terminology codes for image guidance. METHODS: Medicare claims for 2012 to 2018 (paracentesis) and 2013 to 2018 (thoracentesis) were extracted using Current Procedural Terminology codes for blind and image-guided paracentesis and thoracentesis. Total volumes were analyzed by provider specialty. Nonfacility reimbursement and relative value units were compared. RESULTS: For blind paracentesis, volume decreased from 17,393 to 12,226 procedures from 2012 to 2018. Conversely, volume of image-guided paracentesis increased from 171,631 to 253,834 procedures. Radiology performed the majority of image-guide paracentesis (83.9% in 2012 and 77.1% in 2018). Volume and relative share for APPs dramatically increased (from 10.2% to 15.8%). For blind thoracentesis, volume decreased from 26,716 to 15,075 procedures from 2013 to 2018. Conversely, volume of image-guided thoracentesis increased from 187,168 to 222,673 procedures. Radiology performed the majority of image-guided thoracentesis (73.6% in 2013 and 66.2% in 2018). Volume and relative share for APPs dramatically increased (from 7.7% to 12.9%). Although reimbursement for both image-guided paracentesis and thoracentesis decreased, their reimbursement remained higher than that of blind paracentesis and thoracentesis throughout the study period. CONCLUSION: A higher percentage of these procedures are being performed using image guidance; radiologists performed a growing number but declining percentage of image-guided paracentesis and thoracentesis. APPs are playing an increasing role, particularly using image guidance. Given decreasing reimbursement for these procedures, APPs can provide a large cost advantage in procedural radiology practices.

Percutaneous ablation of renal tumors versus surgical ablation and partial nephrectomy: Medicare trends and reimbursement cost comparison from 2010 to 2018.

PURPOSE: The purpose of this study is to analyze trends in Medicare volume and reimbursement for percutaneous and surgical ablation as well as laparoscopic and open partial nephrectomy for treatment of small renal tumors from 2010 to 2018. METHODS: Claims from the Medicare Part B Physician/Supplier Procedure Summary from 2010 to 2018 were extracted using CPT codes for percutaneous and surgical renal ablation and surgical and laparoscopic partial nephrectomy. Facility reimbursement and relative value units (RVUs) were obtained using the Centers for Medicare & Medicaid Services physician fee schedule look-up tool. RESULTS: Volume of percutaneous ablation increased from 2539 to 4571 procedures (80.0%). Specifically, percutaneous cryoablation became the dominant technique, increasing from 1434 to 2981 procedures (107.9%). Overall, volume of partial nephrectomy also increased by 40.4%, driven by an increase in laparoscopic partial nephrectomy from 3227 to 7770 procedures (140.8%) with a decrease in open partial nephrectomy from 3489 to 1661 (- 52.4%). Volume of surgical ablations also decreased 72.7% from 1260 to 344 procedures. In 2018, reimbursement was $358.56 for percutaneous radiofrequency ablation, $481.32 for percutaneous cryoablation, $1216.43 for surgical radiofrequency ablation, $1269.35 for surgical cryoablation, $1381.67 for open partial nephrectomy, and $1552.66 for laparoscopic partial nephrectomy. CONCLUSION: There has been a trend toward minimally invasive techniques for treatment of small renal tumors among Medicare patients. Laparoscopic partial nephrectomy has become the dominant treatment. In the setting of evidence showing comparable outcomes with surgery as well as lower costs to insurers, the volume of percutaneous ablation has also markedly increased.

Incursions of divergent genotypes, evolution of virulence and host jumps shape a continental clonal population of the stripe rust pathogen Puccinia striiformis.

Long-distance migration and host adaptation by transboundary plant pathogens often brings detrimental effects to important agroecosystems. Efficient surveillance as a basis for responding to the dynamics of such pathogens is often hampered by a lack of information on incursion origin, evolutionary pathways and the genetic basis of rapidly evolving virulence across larger timescales. Here, we studied these genetic features by using historical isolates of the obligate biotrophic pathogen Puccinia striiformis f. sp. tritici (Pst), which causes one of the most widespread and devastating diseases, stripe (yellow) rust, of wheat. Through a combination of genotypic, phenotypic and genomic analyses, we assigned eight Pst isolates representing putative exotic Pst incursions into Australia to four previously defined genetic groups, PstS0, PstS1, PstS10 and PstS13. We showed that isolates of an additional incursion of P. striiformis, known locally as P. striiformis f. sp. pseudo-hordei, had a new and unique multilocus SSR genotype (MLG). We provide results of overall genomic variation of representative Pst isolates from each genetic group by comparative genomic analyses. We showed that isolates within the PstS1 and PstS13 genetic groups are most distinct at the whole-genome variant level from isolates belonging to genetic group PstS0, whereas the isolate from the PstS10 genetic group is intermediate. We further explored variable gene content, including putative effectors, representing both shared but also unique genetic changes that have occurred following introduction, some of which may additionally account for local adaptation of these isolates to triticale. Our genotypic and genomic data revealed new genetic insights into the evolution of diverse phenotypes of rust pathogens following incursion into a geographically isolated continental region.

Percutaneous ablation versus surgical ablation and resection of liver tumors: medicare volume and physician reimbursement trends from 2010 to 2018.

PURPOSE: The purpose of this study is to analyze trends in Medicare volume and physician reimbursement for percutaneous ablation, surgical ablation, and resection of liver tumors from 2010 to 2018. METHODS: Claims from the Medicare Part B PSPSMF for the years 2010 to 2018 were extracted using the CPT codes for percutaneous and surgical ablation of liver tumors and surgical liver resection. Total procedural volume and physician payment were analyzed by procedure and physician specialty. RESULTS: From 2010 to 2018, the volume of percutaneous ablation of liver tumors increased 94.3% from 1630 to 3168 procedures, and the volume of surgical ablations increased 86.2% from 593 to 1104 procedures. In contrast, there was a 16.8% decrease in liver resections from 10,807 to 8994 procedures. Physician reimbursement for percutaneous ablation decreased from $702.41 to $610.11 (- 13.1%). Conversely, reimbursement for resection increased from $849.18 to $1015.06 (19.5%). Reimbursement for surgical ablation also increased from $722.36 to $744.25 (3.0%). In 2018, physician reimbursement for resection and surgical ablation were 66% and 22% more than that for percutaneous ablation. CONCLUSION: An increasing number of patients with liver tumors were treated with percutaneous ablation from 2010 to 2018. Despite higher morbidity, a dwindling set of theoretical advantages over percutaneous ablation, and higher overall costs, the volume of surgical ablation also increased over this time period. The findings of this study suggest that a reevaluation of practice and referral patterns for surgical ablation of liver tumors is warranted in many institutions.

Functional brain imaging in larval zebrafish for characterising the effects of seizurogenic compounds acting via a range of pharmacological mechanisms.

BACKGROUND AND PURPOSE: Functional brain imaging using genetically encoded Ca2+ sensors in larval zebrafish is being developed for studying seizures and epilepsy as a more ethical alternative to rodent models. Despite this, few data have been generated on pharmacological mechanisms of action other than GABAA antagonism. Assessing larval responsiveness across multiple mechanisms is vital to test the translational power of this approach, as well as assessing its validity for detecting unwanted drug-induced seizures and testing antiepileptic drug efficacy. EXPERIMENTAL APPROACH: Using light-sheet imaging, we systematically analysed the responsiveness of 4 days post fertilisation (dpf; which are not considered protected under European animal experiment legislation) transgenic larval zebrafish to treatment with 57 compounds spanning more than 12 drug classes with a link to seizure generation in mammals, alongside eight compounds with no such link. KEY RESULTS: We show 4dpf zebrafish are responsive to a wide range of mechanisms implicated in seizure generation, with cerebellar circuitry activated regardless of the initiating pharmacology. Analysis of functional connectivity revealed compounds targeting cholinergic and monoaminergic reuptake, in particular, showed phenotypic consistency broadly mapping onto what is known about neurotransmitter-specific circuitry in the larval zebrafish brain. Many seizure-associated compounds also exhibited altered whole brain functional connectivity compared with controls. CONCLUSIONS AND IMPLICATIONS: This work represents a significant step forward in understanding the translational power of 4dpf larval zebrafish for use in neuropharmacological studies and for studying the events driving transition from small-scale pharmacological activation of local circuits, to the large network-wide abnormal synchronous activity associated with seizures.