The activity prediction of indole inhibitors against HCV NS5B polymerase

Non‐structural viral protein 5B (NS5B) is a viral protein in hepatitis C virus. Although various inhibitors against NS5B have been found, the activity prediction of similar untested inhibitors is still highly desirable. In this respect, the Tchebichef moments (TMs) calculated from the images of molecular structures were regarded as the independent variables while the inhibitory activity (pIC₅₀) was the dependent variable, and the predictive model was established by means of stepwise regression. The R‐squared of leave‐one‐out cross‐validation (Q²) for the training set and the R‐squared of prediction () for external independent test set were 0.919 and 0.927, respectively. The obtained model was also evaluated strictly. Compared with the multivariate curve resolution with alternating least squares (MCR‐ALS) and the QSAR approaches derived from the literature, the proposed method is more accurate and reliable. This study not only provides an effective approach to predict the biological activity of RNA replication's inhibitors, but also extends the QSAR modeling technique.     

Evolution of the HALT-C Trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was designed to determine whether maintenance interferon therapy could slow disease progression in patients who had failed to eradicate hepatitis C virus (HCV) during prior interferon treatment (nonresponders). Ten clinical sites, a virological testing center, and a data coordinating center (DCC) were selected to collaborate in the design and implementation of the final protocol. Eligible patients had been treated previously with interferon for at least 12 weeks, with or without another antiviral, ribavirin, but still had persistent viremia. Because patients had received a variety of prior treatments, and as a perceived benefit of enrollment, we incorporated a Lead-in period of treatment with long-acting pegylated interferon alfa-2a plus ribavirin into the study design, a combination believed to be more effective but not approved by the Food and Drug Administration at the Trial's inception. If patients failed to achieve clearance of virus from the blood after 20 weeks of this Lead-in therapy, they were entered into the main trial at week 24 and randomized to receive either a lower dose of pegylated interferon weekly alone or no further therapy for an additional 3 1/2 years. The original protocol was amended later in three respects to improve enrollment and to adapt to Food and Drug Administration approval of the Lead-in therapy, including allowing patients to proceed directly to the randomized part of the study if treatment resembling the Lead-in had been completed. The protocol changes enhanced enrollment while upholding the original goals of the study and its integrity.     

Unraveling postoperative alterations after mitral valve replacement with three-dimensional printing

Mitral valve (MV) surgery is the second most performed valve operation in Europe. MV pathology is associated with atrial fibrillation, and, therefore, frequently combined with rhythm surgery and left atrial appendage exclusion (LAAE). Currently, no guidelines exist regarding the follow up after LAAE postoperative. Postoperative imaging with computed tomography (CT), in the absence of complaints, will inherently reveal unsuspected cardiac and noncardiac findings with potential clinical significance. However, poststernotomy alterations are nonspecific and often overlap with normal postoperative changes and could, therefore, not directly be recognized. Virtual three-dimensional (3D) CT reconstructions can help us to visualize 2D structures, especially in areas where structures overlap like coronary arteries or when devices (atrial clip, MV prosthesis) cause scattering artifacts. Advanced imaging reconstructions and 3D printing can enhance understanding of the cardiac anatomy in the postoperative phase and help us to determine follow-up strategies.     

First detection of Theileria parva in cattle from Cameroon in the absence of the main tick vector Rhipicephalus appendiculatus

A major risk factor for the spread of livestock diseases and their vectors is the uncontrolled transboundary movement of live animals for trade and grazing. Such movements constrain effective control of tick‐transmitted pathogens, including Theileria parva. Only limited studies have been undertaken to identify ticks and tick‐borne diseases (TTBDs) affecting cattle in central African countries, including Cameroon. We hereby report the collection of baseline data on the prevalence of T. parva in Cameroon through a countrywide cross‐sectional survey, conducted in 2016, involving collection of blood samples from cattle from 63 sites across the five agro‐ecological zones (AEZs) of the country. ELISA‐based surveillance of infected cattle was performed on 479 randomly selected samples and revealed specific antibodies to T. parva in 22.7% and T. mutans in 41.1% of cattle. Screening of 1,340 representative DNA samples for the presence of T. parva identified 25 (1.86%) positives using a p104 antigen gene‐based nested PCR assay. The positives were distributed across agro‐ecological zones I, II, III and V. None of the p104 positive cattle exhibited clinical symptoms of East Coast fever (ECF). Using reverse line blot (RLB), 58 (4.3%) and 1,139 (85%) of the samples reacted with the T. parva and T. mutans oligonucleotide probes, respectively. This represents the first report of T. parva from Cameroon. Surprisingly, no Rhipicephalus appendiculatus ticks, the main vector of T. parva, were identified in a parallel study involving comprehensive morphological and molecular survey of tick species present in the country. Only two of the 25 p104 positive cattle were PCR‐positive for the CD8+ T‐cell target schizont‐expressed antigen gene Tp1. Cloning and sequencing of Tp1 amplicons revealed sequence identity with the reference T. parva Muguga. This new finding raises serious concerns of a potential spread of ECF into the central African region.     

Tendon Insertion at the Base of the Proximal Phalanx of the Hallux: Surgical Implications

Hallux valgus, limitus, and rigidus are conditions affecting the first metatarsophalangeal joint that can be treated by arthroplasty. Excessive arthroplasty can compromise the insertion of the tendons at the base of the proximal phalanx of the hallux, leading to first metatarsophalangeal joint plantarflexion weakness, cock-up toe deformity, and altered forefoot loading. The present study investigated the anatomic length of insertion of the medial and lateral flexor hallucis brevis, extensor hallucis brevis, abductor hallucis, and adductor hallucis tendons into the base of the hallux proximal phalanx and the amount of bone that can be safely resected without compromising the insertional limits. A total of 43 specimens (22 right and 21 left) from 22 embalmed cadavers (11 male and 11 female) were dissected. The insertion lengths of the 5 tendons were measured, along with the dimensions of the hallux proximal phalanx. No statistically significant differences were found in any proximal phalanx measurements or tendon insertion lengths according to side (p > .05). Significant differences were found between the genders in most dimensions of the hallux proximal phalanx (p < .05). The medial insertion site, where the medial flexor brevis tendon and distal abductor hallucis muscle join, was longer than the lateral site (p < .001). To preserve the tendon’s insertion, hallux proximal phalanx resection should not exceed 3 mm. Resection of the tendons is ensured by removal of more than 7.88 mm and 9.37 mm in females and males, respectively. When performing hallux arthroplasty of the first metatarsophalangeal joint, we recommend calculating the length of the tendon insertions, instead of the length of the hallux proximal phalanx.