An Integrative Model of Subcortical Auditory Plasticity

In direct conflict with the concept of auditory brainstem nuclei as passive relay stations for behaviorally-relevant signals, recent studies have demonstrated plasticity of the auditory signal in the brainstem. In this paper we provide an overview of the forms of plasticity evidenced in subcortical auditory regions. We posit an integrative model of auditory plasticity, which argues for a continuous, online modulation of bottom-up signals via corticofugal pathways, based on an algorithm that anticipates and updates incoming stimulus regularities. We discuss the negative implications of plasticity in clinical dysfunction and propose novel methods of eliciting brainstem responses that could specify the biological nature of auditory processing deficits.     

Comparative efficacy of first-line ceritinib and crizotinib in advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer: an adjusted indirect comparison with external controls

Objective: In the absence of head-to-head trials, this study indirectly compared progression free survival (PFS) and overall survival (OS) between ceritinib and crizotinib among patients with previously untreated advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).

Methods: A matching-adjusted indirect comparison method was implemented to adjust for cross-trial differences in patient characteristics between ASCEND-4 and PROFILE 1014 trials. Patient-level data from ASCEND-4 and published summary data from PROFILE 1014 were used. Patients in ASCEND-4 were reweighted to match average baseline characteristics (i.e. age, sex, race, tumor histology, ECOG score, smoking status, extent of disease, and presence of brain metastases) reported for PROFILE 1014 patients using propensity score weighting. PFS and OS were then compared between balanced populations.

Results: ASCEND-4 included more current smokers (8.0% vs 4.4%) and fewer patients under the age of 65 years (78.5% vs 84.0%) compared to PROFILE 1014. After matching, these and all other patient characteristics were balanced between the two trial populations. Compared to crizotinib, ceritinib was associated with a significantly longer PFS (hazard ratio [95% confidence interval] (HR [CI])?=?0.64 [0.47–0.87]; median PFS: 25.2 vs 10.8 months, log-rank p-value?=?0.003). OS did not differ significantly, with a HR of 0.82 [0.54–1.27] for ceritinib compared to crizotinib.

Conclusions: In the adjusted indirect comparison with external controls, the second generation ALK inhibitor, ceritinib, was associated with a significantly prolonged PFS compared to crizotinib as first-line treatment for ALK-positive NSCLC.     

Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.     

Which Parameters Affect Biofilm Removal with Acoustic Cavitation? A Review

Bacterial biofilms are a cause of contamination in a wide range of medical and biological areas. Ultrasound is a mechanical energy that can remove these biofilms using cavitation and acoustic streaming, which generate shear forces to disrupt biofilm from a surface. The aim of this narrative review is to investigate the literature on the mechanical removal of biofilm using acoustic cavitation to identify the different operating parameters affecting its removal using this method. The properties of the liquid and the properties of the ultrasound have a large impact on the type of cavitation generated. These include gas content, temperature, surface tension, frequency of ultrasound and acoustic pressure. For many of these parameters, more research is required to understand their mechanisms in the area of ultrasonic biofilm removal, and further research will help to optimise this method for effective removal of biofilms from different surfaces.     

Late-onset cytomegalovirus infection complicated by Guillain–Barre syndrome in a kidney transplant recipient: case report and review of the literature

Cytomegalovirus (CMV) infection remains a common infection after solid-organ transplantation. In the general population CMV disease is associated with Guillain–Barre syndrome (GBS), an autoimmune disease leading to an acute peripheral neuropathy, in 1 of 1000 cases. Interestingly, GBS is a rarely observed complication in solid-organ transplant recipients, possibly related to maintenance immunosuppression. We describe a case of CMV infection complicated by GBS in a kidney transplant recipient and review the literature.     

A contemporary review of Clostridioides difficile infections in patients with haematologic diseases

Clostridioides (Clostridium) difficile (C. difficile) infection is one of the most common causes of increased morbidity and mortality. Approximately 500 000 C. difficile infections (CDIs) occur each year in the United States, and they result in more than 29 000 deaths. Patients with haematologic diseases are at a higher risk for this infection due to frequent hospitalization and exposure to treatment-associated risk factors. Whilst several currently available antimicrobial agents offer resolution, recurrence of infection remains a major concern. Recent advancement in deciphering C. difficile virulence mechanisms and identification of its allies in contributing to the infection has led to the development of alternative treatment strategies. Here, we will provide a contemporary discussion of how major risk factors in haematologic diseases, such as immunosuppression, chemoradiation, use of antibiotic, proton pump inhibitor and opioid, and deficiency in butyrate and antimicrobial peptides contribute to C. difficile infection. Next, we will highlight different approaches to control and mitigate this infection such as antibiotic stewardship and faecal microbiota transplantation. Finally, we will explore several emerging treatments such as use of pre- and probiotics, immunotherapy and microbiome-sparing agents.     

Dental diseases and loss of teeth in a group of Finnish alcoholics: a radiological study

A total of 85 Finnish alcohol-dependent subjects and 53 controls were studied with panoramic radiography. The aim was to study the possible associations between prolonged alcohol consumption and dental health. The mean number of teeth, caries lesions, endodontic treatments, periapical lesions, marginal bone loss, and periodontal infrabony pockets was studied. The subjects met the diagnostic criteria of alcohol dependence as set out in DSM-IV and ICD-10. The control group comprised social drinking volunteers with an AUDIT score &#104 8. For the final results the subjects were divided into groups on the basis of sex and age. The social backgrounds of the subjects were similar, except for employment and smoking. The results show significantly fewer teeth and more caries in the alcoholic group. There was a tendency for the alcoholics <45 years of age to have more endodontically treated teeth than the controls, but no difference in the number of periapical lesions in endodontically treated teeth was found. Horizontal bone loss and the presence of calculus were more frequent in alcoholic men than in alcoholic women. Significantly more horizontal bone loss was observed in the group of alcoholic nonsmokers than in nonalcoholic nonsmokers. In the nonsmoking groups alcoholics had significantly more periodontal destruction than the nonsmoking controls. We conclude that radiological dental health among individuals dependent on alcohol is weakened by more caries, more horizontal bone loss, and more numerous vertical infrabony pockets than social drinkers.