Current immunotherapeutic approaches to diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour that occurs in the pons of the brainstem and accounts for over 80% of all brainstem gliomas. The median age at diagnosis is 6-7 years old, with less than 10% overall survival 2 years after diagnosis and less than 1% after 5 years. DIPGs are surgically inaccessible, and radiation therapy provides only transient benefit, with death ensuing from relentless local tumour infiltration. DIPGs are now the leading cause of brain tumour deaths in children, with a societal cancer burden in years of life lost (YLL) of more than 67 per individual, versus approximately 14 and 16 YLL for lung and breast cancer respectively. More than 95 clinical drug trials have been conducted on children with DIPGs, and all have failed to improve survival. No single or combination chemotherapeutic strategy has been successful to date because of our inability to identify targeted drugs for this disease and to deliver these drugs across an intact blood-brain barrier (BBB). Accordingly, there has been an increased focus on immunotherapy research in DIPG, with explorations into treatments such as chimeric antigen receptor T (CAR-T) cells, immune checkpoint blockades, cancer vaccines, and autologous cell transfer therapy. Here, we review the most recent advances in identifying genetic factors influencing the development of immunotherapy for DIPG. Additionally, we explore emerging technologies such as Magnetic Resonance-guided Focused Ultrasound (MRgFUS) in potential combinatorial approaches to treat DIPG.

The outcomes of concomitant catheter ablation in non-mitral valve cardiac surgery-a systematic review and meta-analysis of the literature.

Background: Atrial fibrillation (AF) is the most common form of cardiac arrythmia, with a key importance in the perioperative setting of cardiac surgery. In recent years, the question as to whether pre-existent AF should be treated concomitantly when undergoing cardiac surgery has been heatedly debated. This systematic review and meta-analysis sought to delineate the outcomes of patients undergoing concomitant AF ablation procedures alongside cardiac surgery. Methods: The methods for this systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Four databases were searched, ultimately yielding 22 papers for inclusion, using appropriate search terminology. Meta-analysis using proportions or means, as appropriate, were applied. Kaplan-Meier curves were digitized and aggregated using previously reported and validated techniques. Results: A total of 9,428 patients (67% male) were identified across the study period as having received non-mitral cardiac surgery and concomitant AF ablation procedures. On actuarial assessment, freedom from AF was found to be 93%, 88%, 85%, 82%, and 79% at 1 through to 5 years, respectively. Freedom from mortality was found to be 94%, 93%, 91%, 90%, and 87% at 1 through to 5 years, respectively. Conclusions: This review demonstrated excellent freedom from AF out to a long-term follow-up of 5 years. Freedom from mortality was also encouraging. Emerging data are increasingly illustrating that in this patient cohort, concurrent treatment of pre-existent AF with cardiac and/or valvular disease at the point of operation should be the standard of care. Robust data in the form of randomized control trials will hopefully solidify this assertion.

The characteristics and predictors of mortality in periprosthetic fractures around the knee.

Aims: Periprosthetic fractures (PPFs) around the knee are challenging injuries. This study aims to describe the characteristics of knee PPFs and the impact of patient demographics, fracture types, and management modalities on in-hospital mortality. Methods: Using a multicentre study design, independent of registry data, we included adult patients sustaining a PPF around a knee arthroplasty between 1 January 2010 and 31 December 2019. Univariate, then multivariable, logistic regression analyses were performed to study the impact of patient, fracture, and treatment on mortality. Results: Out of a total of 1,667 patients in the PPF study database, 420 patients were included. The in-hospital mortality rate was 6.4%. Multivariable analyses suggested that American Society of Anesthesiologists (ASA) grade, history of peripheral vascular disease (PVD), history of rheumatic disease, fracture around a loose implant, and cerebrovascular accident (CVA) during hospital stay were each independently associated with mortality. Each point increase in ASA grade independently correlated with a four-fold greater mortality risk (odds ratio (OR) 4.1 (95% confidence interval (CI) 1.19 to 14.06); p = 0.026). Patients with PVD have a nine-fold increase in mortality risk (OR 9.1 (95% CI 1.25 to 66.47); p = 0.030) and patients with rheumatic disease have a 6.8-fold increase in mortality risk (OR 6.8 (95% CI 1.32 to 34.68); p = 0.022). Patients with a fracture around a loose implant (Unified Classification System (UCS) B2) have a 20-fold increase in mortality, compared to UCS A1 (OR 20.9 (95% CI 1.61 to 271.38); p = 0.020). Mode of management was not a significant predictor of mortality. Patients managed with revision arthroplasty had a significantly longer length of stay (median 16 days; p = 0.029) and higher rates of return to theatre, compared to patients treated nonoperatively or with fixation. Conclusion: The mortality rate in PPFs around the knee is similar to that for native distal femur and neck of femur fragility fractures. Patients with certain modifiable risk factors should be optimized. A national PPF database and standardized management guidelines are currently required to understand these complex injuries and to improve patient outcomes.

Surgical ablation of atrial fibrillation during mitral valve surgery: a systematic review and meta-analysis.

Background: Atrial fibrillation (AF) is a common tachyarrhythmia, affecting approximately 33 million people worldwide, and is frequently associated with mitral valve disease. Surgical ablation during mitral valve surgery provides an opportune circumstance for arrhythmia correction. The results of recent randomized trial data are promising, demonstrating both safety and efficacy. The aim of this systematic review is to report the efficacy and morbidity of concomitant surgical ablation for AF during mitral valve surgery. Methods: Five electronic databases were searched from inception to March 2023. All studies reporting the primary outcome, freedom from AF (FFAF), for patients with a history of AF undergoing concomitant mitral valve surgery were identified. Studies with patient cohorts less than 100 were excluded. Relevant data were extracted and a meta-analysis of proportions was conducted using a random-effects model. Survival data were pooled from original Kaplan-Meier curves and reconstructed, reporting aggregate FFAF and survival. Results: Thirty-six studies with a total of 8,340 patients were included in the systematic review. All 36 papers reported postoperative FFAF with a pooled result of 76.9% [95% confidence interval (CI): 73.8-79.9%] at a weighted mean follow-up of 40.2 months, however this result was associated with significant heterogeneity (I2=89%). A total of 31 studies reported postoperative short-term mortality, with a pooled result of 1.68% (95% CI: 1.15-2.29%). Aggregate survival at 1 to 5 years was 93.7%, 92.5%, 91.3%, 89.4%, and 87%, respectively, and aggregate FFAF for 1 to 5 years was 90.2%, 83.5%, 79.5%, 76.4% and 73.2%, respectively. Conclusions: Evaluation of the evidence suggests that concomitant ablation for AF during mitral valve surgery is both safe and efficacious. The results were associated with significant heterogeneity, reflective of variable institutional protocols, patient characteristics, and lesion sets. Randomized data with longer term follow-up would help validate these results.

Mid-to-long-term recurrence of atrial fibrillation in surgical treatment vs. catheter ablation: a meta-analysis using aggregated survival data.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia and leading cardiac cause of stroke. Catheter and surgical ablation are two techniques used currently to resolve prolonged disease by limiting the excitatory potential of specific areas of myocardium in the atria of the heart. The aim of this systematic review and meta-analysis was to provide a graphical amalgamation of mid-to-long-term rhythm outcomes following transcatheter and surgical intervention, whether primary or concomitant ablation. Methods: Three electronic databases were selected to complete the initial literature search from inception of records until April 2023. Primary outcomes were freedom from AF at 12 months, as well as long term time-to-event recurrence data. These data were calculated using aggregated Kaplan-Meier curves according to established methods. The secondary outcome was procedural time for each ablation method. Results: Following independent screening, 36 studies were included for analysis. A total of 6,700 patients were followed, of whom 4,863 (72.6%) were male. Freedom from AF recurrence at 1, 3 and 5 years for the surgical cohort was 71.7%, 57.6% and 47.6%, respectively. Comparatively, the recurrence rates of the catheter ablation cohort at 1, 3 and 5 years were 71.5%, 56.5% and 50.3%, respectively. Conclusions: Despite potentially more complex diseases, surgical ablation patients have non-inferior long-term AF recurrence when compared to those undergoing catheter ablation. Recurrence at 12 months as well as procedural time are also similar between these groups. Ultimately, both ablation methods were able to prevent recurrence of AF in approximately 50% of patients at five years following the procedure.

Chemical Catalysis Guides Structural Identification for the Major In Vivo Metabolite of the BET Inhibitor JQ1.

The bromodomain inhibitor (+)-JQ1 is a highly validated chemical probe; however, it exhibits poor in vivo pharmacokinetics. To guide efforts toward improving its pharmacological properties, we identified the (+)-JQ1 primary metabolite using chemical catalysis methods. Treatment of (+)-JQ1 with tetrabutylammonium decatungstate under photochemical conditions resulted in selective formation of an aldehyde at the 2-position of the thiophene ring [(+)-JQ1-CHO], which was further reduced to the 2-hydroxymethyl analog [(+)-JQ1-OH]. Comparative LC/MS analysis of (+)-JQ1-OH to the product obtained from liver microsomes suggested (+)-JQ1-OH as the major metabolite of (+)-JQ1. The 2-thienyl position was then substituted to generate a trideuterated (-CD3, (+)-JQ1-D) analog having half-lives that were 1.8- and 2.8-fold longer in mouse and human liver microsomes, respectively. This result unambiguously confirmed (+)-JQ1-OH as the major metabolite of (+)-JQ1. These studies demonstrate an efficient process for studying drug metabolism and identifying the metabolic soft spots of bioactive compounds.

Hip Arthroscopy for Femoroacetabular Impingement Is Associated With Improved Sexual Function And Quality of Life.

PURPOSE: The purpose of this study was to investigate changes in sexual function and activity after arthroscopic hip surgery for femoroacetabular impingement using the United Kingdom Non-Arthroplasty Hip Registry dataset. Subanalyses were performed between males and females, and patients over 40 and under 40 years old. METHODS: Patients who had arthroscopic hip surgery between January 1, 2012, and October 31, 2020, were aged over 16, and completed the relevant patient-reported outcome measures were included. Question 9 of the International Hip Outcome Tool-12 (sexual activity question [SAQ]) refers to problems with sexual activity, and responses to this were compared before surgery and at 6 and 12 months after surgery. Subanalyses were also performed, including SAQ scores by patients' sex or age. SAQ scores were correlated with Euroqol-5 dimension-5 level self-reporting tool (EQ-5D-5L) scores using Spearman's rank coefficient. RESULTS: SAQ was answered by 2,547 patients before and at 6 months after surgery (62.3% female, median age = 36.2, interquartile range [IQR] = 29-44 years) and by 2,314 at 12 months (61.9% female, median age = 36.2, IQR = 29-44 years). Scores for sexual activity increased from 35.0 before surgery to 70.0 at 6 months (P < .001) and were maintained at 12 months (P < .001). Female patients demonstrated a significantly greater improvement in their scores for sexual function from before surgery (median = 30.0, IQR = 14-50) to 6 months (median = 60, IQR = 28-86, P < .001) and 12 months (median = 62.0, IQR = 29-90, P < .001), compared to male patients (preoperative median = 50.0, IQR 25-84; 6-month median = 80, IQR = 45-97; 12-month median = 80, IQR = 41-98). The effect of age on improvements in sexual function did not demonstrate a significant difference. A significant positive correlation was found between improvements in sexual function and quality of life, as measured by the EQ-5D-5L, at 6 and 12 months (P < .001). CONCLUSION: Hip arthroscopy for symptomatic femoroacetabular impingement produces an improvement in sexual function and activity. Scores for sexual function improved regardless of patient age or sex; however, female patients experienced a greater improvement in sexual function than males. LEVEL OF EVIDENCE: Level III (Retrospective cohort study).

Predictors of mortality in periprosthetic fractures of the hip: Results from the national PPF study.

INTRODUCTION: Periprosthetic fractures (PPFs) around the hip joint are increasing in prevalence. In this collaborative study, we aimed to investigate the impact of patient demographics, fracture characteristics, and modes of management on in-hospital mortality of PPFs involving the hip. METHODS: Using a multi-centre cohort study design, we retrospectively identified adults presenting with a PPF around the hip over a 10-year period. Univariate and multivariable logistic regression analyses were performed to study the independent correlation between patient, fracture, and treatment factors on mortality. RESULTS: A total of 1,109 patients were included. The in-hospital mortality rate was 5.3%. Multivariable analyses suggested that age, male sex, abbreviated mental test score (AMTS), pneumonia, renal failure, history of peripheral vascular disease (PVD) and deep surgical site infection were each independently associated with mortality. Each yearly increase in age independently correlates with a 7% increase in mortality (OR 1.07, p=0.019). The odds of mortality was 2.99 times higher for patients diagnosed with pneumonia during their hospital stay [OR 2.99 (95% CI 1.07-8.37) p=0.037], and 7.25 times higher for patients that developed renal failure during their stay [OR 7.25 (95% CI 1.85-28.47) p=0.005]. Patients with history of PVD have a six-fold greater mortality risk (OR 6.06, p=0.003). Mode of treatment was not a significant predictor of mortality. CONCLUSION: The in-hospital mortality rate of PPFs around the hip exceeds 5%. The fracture subtype and mode of management are not independent predictors of mortality, while patient factors such as age, AMTS, history of PVD, pneumonia, and renal failure can independently predict mortality. Peri-operative optimisation of modifiable risk factors such as lung and kidney function in patients with PPFs around the hip during their hospital stay is of utmost importance.

High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion dynamics.

DNA looping is vital for establishing many enhancer-promoter interactions. While CTCF is known to anchor many cohesin-mediated loops, the looped chromatin fiber appears to predominantly exist in a poorly characterized actively extruding state. To better characterize extruding chromatin loop structures, we used CTCF MNase HiChIP data to determine both CTCF binding at high resolution and 3D contact information. Here we present FactorFinder, a tool that identifies CTCF binding sites at near base-pair resolution. We leverage this substantial advance in resolution to determine that the fully extruded (CTCF-CTCF) state is rare genome-wide with locus-specific variation from ~1-10%. We further investigate the impact of chromatin state on loop extrusion dynamics, and find that active enhancers and RNA Pol II impede cohesin extrusion, facilitating an enrichment of enhancer-promoter contacts in the partially extruded loop state. We propose a model of topological regulation whereby the transient, partially extruded states play active roles in transcription.

Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers.

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs.

Dishevelled Has Anti-Viral Activity in Rift Valley Fever Virus Infected Aedes aegypti.

Mosquitoes in the genera Aedes and Culex are vectors of Rift Valley fever virus (RVFV), which emerges in periodic epidemics in Africa and Saudi Arabia. Factors that influence the transmission dynamics of RVFV are not well characterized. To address this, we interrogated mosquito host-signaling responses through analysis of differentially expressed genes (DEGs) in two mosquito species with marked differences in RVFV vector competence: Aedes aegypti (Aae, low competence) and Culex tarsalis (Cxt, high competence). Mosquito-host transcripts related to three different signaling pathways were investigated. Selected genes from the Wingless (Wg, WNT-beta-catenin) pathway, which is a conserved regulator of cell proliferation and differentiation, were assessed. One of these, dishevelled (DSH), differentially regulates progression/inhibition of the WNT and JNK (c-Jun N-terminal Kinase) pathways. A negative regulator of the JNK-signaling pathway, puckered, was also assessed. Lastly, Janus kinase/signal transducers and activators of transcription (JAK-STAT) are important for innate immunity; in this context, we tested domeless levels. Here, individual Aae and Cxt were exposed to RVFV MP-12 via oral bloodmeals and held for 14 days. Robust decreases in DEGs in both Aae and Cxt were observed. In particular, Aae DSH expression, but not Cxt DSH, was correlated to the presence/absence of viral RNA at 14 days post-challenge (dpc). Moreover, there was an inverse relationship between the viral copy number and aaeDSH expression. DSH silencing resulted in increased viral copy numbers compared to controls at 3 dpc, consistent with a role for aaeDSH in antiviral immunity. Analysis of cis-regulatory regions for the genes of interest revealed clues to upstream regulation of these pathways.

Integrative PTEN Enhancer Discovery Reveals a New Model of Enhancer Organization.

Enhancers possess both structural elements mediating promoter looping and functional elements mediating gene expression. Traditional models of enhancer-mediated gene regulation imply genomic overlap or immediate adjacency of these elements. We test this model by combining densely-tiled CRISPRa screening with nucleosome-resolution Region Capture Micro-C topology analysis. Using this integrated approach, we comprehensively define the cis-regulatory landscape for the tumor suppressor PTEN, identifying and validating 10 distinct enhancers and defining their 3D spatial organization. Unexpectedly, we identify several long-range functional enhancers whose promoter proximity is facilitated by chromatin loop anchors several kilobases away, and demonstrate that accounting for this spatial separation improves the computational prediction of validated enhancers. Thus, we propose a new model of enhancer organization incorporating spatial separation of essential functional and structural components.

Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.

Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long-proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

The outcomes of three decades of the David and Yacoub procedures in bicuspid aortic valve patients-a systematic review and meta-analysis.

Background: Valve-sparing aortic procedures, including the David and Yacoub procedures, have emerged as the dominant approaches in aortic aneurysm surgery, preserving the native aortic valve and thereby conferring significant prognostic benefits to the patient. Over the years, these procedures have also shown promise in patients with bicuspid valve-related aortopathy. This systematic review and meta-analysis presents the most up-to-date data on perioperative outcomes, freedom from secondary reoperation, and freedom from mortality for bicuspid valve patients undergoing valve-sparing aortic operations. Methods: The methods for this systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Four databases were searched, ultimately yielding 19 papers for inclusion, using appropriate search terminology. Meta-analysis using proportions or means, as appropriate, were applied. Kaplan-Meier curves were digitized and aggregated using previously validated techniques. Results: A total of 1,159 patients were included. Males accounted for 87.4% of the cohort. The mean age of the cohort was 44.9 years. The mean aortic root diameter was estimated to be 46.3 mm, with an estimated range from 38 to 54 mm. Thirty-day mortality rate was estimated to be 1.7%. Eighty-five percent of patients in this series received the David approach, with the remainder receiving the Yacoub approach. Overall, there was low heterogeneity observed for the mean length of intensive care stay, while high heterogeneity was observed for the other remaining variables of interest. Kaplan-Meier survival estimation at 5, 10, and 15 years was 96%, 90%, and 87%, respectively. Kaplan-Meier freedom from secondary reoperation at 5, 10, and 15 years was 96%, 91%, and 88%, respectively. Conclusions: This review demonstrates the durability and safety of the David and Yacoub valve-sparing procedures across long-term follow-up in bicuspid aortic valve patients. These procedures offer significant freedom from mortality and secondary reoperations on the aorta and valve and will likely continue to demonstrate excellent results into the future. There is a clear transition towards the David procedure, with the bulk of contemporary literature publishing on this technique.

Species which may act as vectors or reservoirs of diseases covered by the Animal Health Law: Listed pathogens of molluscs.

Vector or reservoir species of five mollusc diseases listed in the Animal Health Law were identified, based on evidence generated through an extensive literature review, to support a possible updating of Regulation (EU) 2018/1882. Mollusc species on or in which Mikrocytos mackini, Perkinsus marinus, Bonamia exitiosa, Bonamia ostreae and Marteilia refringens were detected, in the field or during experiments, were classified as reservoir species with different levels of certainty depending on the diagnostic tests used. Where experimental evidence indicated transmission of the pathogen from a studied species to another known susceptible species, this studied species was classified as a vector species. Although the quantification of the risk of spread of the pathogens by the vectors or reservoir species was not part of the terms of reference, such risks do exist for the vector species, since transmission from infected vector species to susceptible species was proven. Where evidence for transmission from infected molluscs was not found, these were defined as reservoir. Nonetheless, the risk of the spread of the pathogens from infected reservoir species cannot be excluded. Evidence identifying conditions that may prevent transmission by vectors or reservoir mollusc species during transport was collected from scientific literature. It was concluded that it is very likely to almost certain (90-100%) that M. mackini, P. marinus, B. exitiosa B. ostreae and M. refringens will remain infective at any possible transport condition. Therefore, vector or reservoir species that may have been exposed to these pathogens in an affected area in the wild or at aquaculture establishments or through contaminated water supply can possibly transmit these pathogens. For transmission of M. refringens, the presence of an intermediate host, a copepod, is necessary.

Species which may act as vectors or reservoirs of diseases covered by the Animal Health Law: Listed pathogens of crustaceans.

Vector or reservoir species of three diseases of crustaceans listed in the Animal Health Law were identified based on evidence generated through an extensive literature review, to support a possible updating of Regulation (EU) 2018/1882. Crustacean species on or in which Taura syndrome virus (TSV), Yellow head virus (YHV) or White spot syndrome virus (WSSV) were identified, in the field or during experiments, were classified as reservoir species with different levels of certainty depending on the diagnostic tests used. Where experimental evidence indicated transmission of the pathogen from a studied species to another known susceptible species, the studied species was classified as vector species. Although the quantification of the risk of spread of the pathogens by the vectors or reservoir species was not part of the terms of reference, such risks do exist for the vector species, since transmission from infected vector species to susceptible species was proven. Where evidence for transmission from infected crustaceans was not found, these were defined as reservoirs. Nonetheless, the risk of the spread of the pathogens from infected reservoir species cannot be excluded. Evidence identifying conditions that may prevent transmission by vectors during transport was collected from scientific literature. It was concluded that it is very likely to almost certain (90-100%) that WSSV, TSV and YHV will remain infective at any possible transport condition. Therefore, vector or reservoir species that may have been exposed to these pathogens in an affected area in the wild or aquaculture establishments or by water supply can possibly transmit WSSV, TSV and YHV.

Species which may act as vectors or reservoirs of diseases covered by the Animal Health Law: Listed pathogens of fish.

Vector or reservoir species of five fish diseases listed in the Animal Health Law were identified, based on evidence generated through an extensive literature review (ELR), to support a possible updating of Regulation (EU) 2018/1882. Fish species on or in which highly polymorphic region-deleted infectious salmon anaemia virus (HPR∆ ISAV), Koi herpes virus (KHV), epizootic haematopoietic necrosis virus (EHNV), infectious haematopoietic necrosis virus (IHNV) or viral haemorrhagic septicaemia virus (VHSV) were detected, in the field or during experiments, were classified as reservoir species with different levels of certainty depending on the diagnostic tests used. Where experimental evidence indicated transmission of the pathogen from a studied species to another known susceptible species, the studied species was classified as a vector species. Although the quantification of the risk of spread of the pathogens by the vectors or reservoir species was not part of the terms or reference, such risks do exist for the vector species, since transmission from infected vector species to susceptible species was proven. Where evidence for transmission from infected fish was not found, these were defined as reservoirs. Nonetheless, the risk of the spread of the pathogens from infected reservoir species cannot be excluded. Evidence identifying conditions that may prevent transmission by vectors or reservoir fish species during transport was collected from scientific literature. For VHSV, IHNV or HPR∆ ISAV, it was concluded that under transport conditions at temperatures below 25°C, it is likely (66-90%) they will remain infective. Therefore, vector or reservoir species that may have been exposed to these pathogens in an affected area in the wild, aquaculture establishments or through water supply can possibly transmit VHSV, IHNV or HPR∆ ISAV into a non-affected area when transported at a temperature below 25°C. The conclusion was the same for EHN and KHV; however, they are likely to remain infective under all transport temperatures.

The perioperative outcomes of uniportal robotic-assisted thoracic surgeries-a systematic review and meta-analysis of surgical cohort studies and case reports.

Background: Early results have illustrated the multiportal robotic approach to be safe and oncologically efficacious in the treatment of thoracic malignancies. Industry leaders have improved upon the lessons learned during the early multiportal studies and have now come to establish the feasibility of the biportal, and subsequently the uniportal robotic-assisted approach, all in an effort to offer patients equivalent or better outcomes with less surgical trauma. No current, coherent body of evidence currently exists outlining the early-term outcomes of patients undergoing uniportal robotic-assisted thoracic surgery. This systematic review and meta-analysis sought to clarify the early-phase outcomes of these patients. Methods: An electronic search of four databases was performed to identify relevant studies outlining the immediate post-operative outcomes of patients undergoing uniportal robotic-assisted thoracic surgeries. The primary endpoint was defined as technical success (i.e., no conversion to secondary robotic, video-assisted thoracoscopic, or open approaches). Secondary endpoints of interest included post-operative outcomes and complication rates. A meta-analysis using a random effects model of proportions or means was applied, as appropriate. Results: The search strategy ultimately yielded 12 relevant studies for inclusion. A total of 240 patients (52% male) split across cohort studies and case reports were identified. The mean age of the two groups was 59.7±3.0 and 58.1±6.8 years, respectively. The mean operative time was 133.8±38.2 and 150.0±52.2 minutes, respectively. Length of hospital stay was 4.4±1.6 and 4.3±1.1 days, respectively. The mean blood loss was 80.0±25.1 mL The majority of identified procedures were lobectomies, segmentectomies, and wedge resections, though complex sleeve resections and anterior mediastinal mass resections were also completed. Cumulative technical success was 99.9%. Conclusions: The uniportal robotic-assisted approach, when completed in expert hands, has been illustrated to have exceedingly low rates of conversion to secondary procedures, along with short length of stay (LOS), minimal blood loss, and short procedural times (variable depending on operation type). Current evidence on the feasibility of this approach will be bolstered by upcoming multi-institutional series.

ABL kinases regulate the stabilization of HIF-1α and MYC through CPSF1.

The hypoxia-inducible factor 1-α (HIF-1α) enables cells to adapt and respond to hypoxia (Hx), and the activity of this transcription factor is regulated by several oncogenic signals and cellular stressors. While the pathways controlling normoxic degradation of HIF-1α are well understood, the mechanisms supporting the sustained stabilization and activity of HIF-1α under Hx are less clear. We report that ABL kinase activity protects HIF-1α from proteasomal degradation during Hx. Using a fluorescence-activated cell sorting (FACS)-based CRISPR/Cas9 screen, we identified HIF-1α as a substrate of the cleavage and polyadenylation specificity factor-1 (CPSF1), an E3-ligase which targets HIF-1α for degradation in the presence of an ABL kinase inhibitor in Hx. We show that ABL kinases phosphorylate and interact with CUL4A, a cullin ring ligase adaptor, and compete with CPSF1 for CUL4A binding, leading to increased HIF-1α protein levels. Further, we identified the MYC proto-oncogene protein as a second CPSF1 substrate and show that active ABL kinase protects MYC from CPSF1-mediated degradation. These studies uncover a role for CPSF1 in cancer pathobiology as an E3-ligase antagonizing the expression of the oncogenic transcription factors, HIF-1α and MYC.

The learning curve of the robotic-assisted lobectomy-a systematic review and meta-analysis.

Background: Early studies have illustrated the robotic lobectomy to be safe, oncologically effective, and economically feasible as a therapeutic modality in the treatment of thoracic malignancies. The 'challenging' learning curve seemingly associated with the robotic approach, however, continues to be an often-cited factor to its ongoing uptake, with the overwhelming volume of these surgeries being performed in centers of excellence where extensive experience with minimal access surgery is the norm. An exact quantification of this learning curve challenge, however, has not been made, begging the question of whether this is an outdated assumption, versus fact. This systematic review and meta-analysis sort to clarify the learning curve for robotic-assisted lobectomy based on the existing literature. Methods: An electronic search of four databases was performed to identify relevant studies outlining the learning curve of robotic lobectomy. The primary endpoint was a clear definition of operator learning (e.g., cumulative sum chart, linear regression, outcome-specific analysis, etc.) which could be subsequently aggregated or reported. Secondary endpoints of interest included post-operative outcomes and complication rates. A meta-analysis using a random effects model of proportions or means was applied, as appropriate. Results: The search strategy identified twenty-two studies relevant for inclusion. A total of 3,246 patients (30% male) receiving robotic-assisted thoracic surgery (RATS) were identified. The mean age of the cohort was 65.3±5.0 years. Mean operative, console and dock time was 190.5±53.8, 125.8±33.9 and 10.2±4.0 minutes, respectively. Length of hospital stay was 6.1±4.6 days. Technical proficiency with the robotic-assisted lobectomy was achieved at a mean of 25.3±12.6 cases. Conclusions: The robotic-assisted lobectomy has been illustrated to have a reasonable learning curve profile based on the existing literature. Current evidence on the oncologic efficacy and purported benefits of the robotic approach will be bolstered by the results of upcoming randomized trials, which will be critical in supporting RATS uptake.