Anaplasma capra in sheep and goats on Corsica Island,France: A European lineage within A. capra clade II?

Anaplasmosis is a tick-transmitted disease due to several species of the genus Anaplasma. In 2019, we demonstrated the presence of Anaplasma capra in two deer species at a zoological park in mainland France. As we suspected its presence in Corsica, we surveyed 11 geographically distant sheep or goat farms. Using molecular tools such as nested PCR targeting 16S ribosomal RNA (rRNA), citrate synthase (gltA) and heat-shock protein (groEL) genes, we detected the presence of A. capra on 5/11 farms, in 26/108 blood samples (24%), in sheep as well as in goats. Genotyping and phylogenetic analysis of A. capra revealed that isolates from Corsica island grouped closely with A. capra isolates reported in red deer and swamp deer from a zoological reserve in mainland France, as well as in roe deer from Spain, in a separate and well supported clade within A. capra clade II. This third report of the tick-borne bacterium A. capra in Europe suggests a potentially larger presence of this pathogen on the European continent, on domestic, native as well as wild ruminants, a broad host range already described in Asian countries for this species.     

Prognostic models to predict survival in patients with pancreatic cancer: a systematic review

BackgroundPancreatic ductal adenocarcinoma (PDAC) has poor survival. Current treatments offer little likelihood of cure or long-term survival. This systematic review evaluates prognostic models predicting overall survival in patients diagnosed with PDAC.MethodsWe conducted a comprehensive search of eight electronic databases from their date of inception through to December 2019. Studies that published models predicting survival in patients with PDAC were identified.Results3297 studies were identified; 187 full-text articles were retrieved and 54 studies of 49 unique prognostic models were included. Of these, 28 (57.1%) were conducted in patients with advanced disease, 17 (34.7%) with resectable disease, and four (8.2%) in all patients. 34 (69.4%) models were validated, and 35 (71.4%) reported model discrimination, with only five models reporting values >0.70 in both derivation and validation cohorts. Many (n = 27) had a moderate to high risk of bias and most (n = 33) were developed using retrospective data. No variables were unanimously found to be predictive of survival when included in more than one study.ConclusionMost prognostic models were developed using retrospective data and performed poorly. Future research should validate instruments performing well locally in international cohorts and investigate other potential predictors of survival.     

Novel pathogenic variants in an Indian cohort with epidermolysis bullosa: Expanding the genotypic spectrum

BackgroundEpidermolysis bullosa (EB) is a genodermatosis characterized by skin fragility and blisters with variable severity. Patients with Dystrophic EB (DEB) or Junctional EB (JEB) mainly present to clinic due to greater functional impairment. Pathogenic sequence variations in COL7A1 are implicated in DEB.ObjectiveWe have tried to decipher the molecular spectrum and genotype phenotype correlation of 21 Indian patients with EB.MethodsNext generation sequencing (NGS) was performed to determine the pathogenic variants. Sanger sequencing was also done for validation of the variants in eleven individuals.ResultsPathogenic variants were detected in 20 individuals (diagnostic yield of 95%). Majority of them (90%) had sequence variation in COL7A1 while two had pathogenic variants in ITGB4 and KRT14 respectively. Out of the 18 patients confirmed to have DEB, 3 had Dominant DEB (DDEB) whereas 15 patients had Recessive DEB (RDEB). Amongst 23 sequence variations identified, 12 were found to be novel (3 were missense, 5 were premature termination codon variants while 4 were splice-site changes).ConclusionGenotype phenotype correlation was noted with milder manifestations in those with dominant inheritance types. Exact molecular diagnosis can be ascertained by NGS in majority of cases.     

Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

Removing the complexity from wide complex tachycardia

Correctly diagnosing the cause of wide QRS tachycardias remain an area of difficulty for many clinicians. The authors provide a concise update to the different ECG algorithms that have been developed as well as caveats in their application.     

A comprehensive method for calculating total body irradiation

PurposeTo provide means for calculating the dose received by various tissues of the patient, calculate lung shield, and verify received dose using a phantom as a tool for quality assurance for a planned Total Body Irradiation (TBI) procedure in radiotherapy.MethodUsing Microsoft Visual Basic, MATLAB, and Python, a program for Total Body Irradiation Calculation in Radiotherapy (TBICR) is constructed. It uses patient translation and beam zone method for total body irradiation calculations to compute the proper dose received by the patient and determine the lung shield thickness. There are three main user-friendly interfaces in the application. The first one allows the user to upload the TBI topography and estimate the distances needed for TBI calculations. The second one enables the user to count the number of beam zones needed for each point and estimate the effective area (A_eff) for each level. The third interface estimates the velocity required to deliver the relative dose depending on patient separation, Monitor Units (MU), couch speed and travel distance. It allows the user to compute the required lung shield thickness, read any patient's CT DICOM file and acquire dose in any distinct location using machine learning model to predict the dose.ResultsThe TBICR software has been successfully validated by reproducing all of the manual calculations in an exact and timely manner. TBICR generated more accurate results and confirmed the absorbed dose to patient through measurements on Anderson phantom.ConclusionsA computer program for the calculation of total body irradiation (TBI) is described in full. The dose received at each point on the patient, the calculation of lung shield and the determination of the velocity and time required for the couch movement are all made possible using the software. The ease of use, precision, data storage and printing are some important features of the present software.     

Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d₉-methadone.The pharmacokinetic profiles of d₉-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d₉-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD₅₀ value for a single intravenous dose of d₉-methadone was 2.1-fold higher than that for methadone. Moreover, d₉-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.     

Feasibility and Clinical Utility of a Workflow Interfacing Radiation Oncology Lung Stereotactic Body Radiation Therapy Treatment Planning and Diagnostic Radiology

Stereotactic body radiation therapy (SBRT) is commonly used to treat early-stage non-small cell lung cancer. Beam arrangements for SBRT include multiple entry and exit pathways resulting in irregular low-dose distributions within normal lung parenchyma. An improved understanding of posttreatment radiographic changes may improve the ability to predict clinical complications including radiation pneumonitis as well as assist in early detection of local failures. Radiation treatment planning is conducted using software systems separate from diagnostic radiology, often not accessible to the diagnostic radiologist. We developed a workflow for interfacing radiation dose information from lung SBRT treatments with a diagnostic radiology picture archiving and communication system (PACS). In an anonymized PACS study folder, SBRT dose maps depicting high-dose, low-dose, and nonirradiated lung volumes were viewable side by side with pretreatment and follow-up diagnostic computed tomography scans. Clinical utility was evaluated by 2 thoracic diagnostic radiologists reviewing posttreatment diagnostic follow-up scans in the PACS both with and without radiation dose maps available. The addition of the biologically effective dose map did not significantly change identification rates of radiation induced lung injury) (92% vs 95%; P = .32) but did significantly decrease radiologic suspicion for local recurrence (22% vs 8%; P = .003). The addition of biologically effective dose maps significantly increased confidence in identifying radiation induced lung injury (7.75 vs 8.82; P = .004) and local recurrence (5.5 vs 6.6; P = .005). The recommendation for additional workup was not significantly different (10% vs 7%; P = .41). We demonstrated the feasibility and clinical utility of a workflow generating simplified radiation dose maps that are viewable within a PACS for diagnostic radiology review.