Progressive multifocal leukoencephalopathy presenting with acute sensorineural hearing loss in an intestinal transplant recipient

A 20‐year‐old male presented 3.5 years after intestinal transplantation with rapidly progressive sensorineural hearing loss. Initial brain imaging was consistent with inflammation and/or demyelination. Lumbar puncture was initially non‐diagnostic and a broad infectious workup was unrevealing. Three months after presentation, a repeat LP detected JC virus for which tests had not earlier been conducted. He continued to deteriorate despite withdrawal of prior immunosuppression and addition of mirtazapine, maraviroc, and steroids. He died of progressive neurologic decompensation 5 months after his initial presentation. This case highlights progressive multifocal leukoencephalopathy (PML) as a rare complication after solid organ transplantation and acute sensorineural hearing loss as an unusual first presenting symptom of PML. JC virus should be considered in the differential diagnosis of acute sensorineural hearing loss in any immunocompromised patient.     

Humans in the cold: Regulating energy balance

For humans to maintain a stable core temperature in cold environments, an increase in energy expenditure (EE) is required. However, little is known about how cold stimulus impacts energy balance as a whole, as energy intake (EI) has been largely overlooked. This review focuses on the current state of knowledge regarding how cold exposure (CE) impacts both EE and EI, while highlighting key gaps and shortcomings in the literature. Animal models clearly reveal that CE produces large increases in EE, while decreasing environmental temperatures results in a significant negative dose‐response effect in EI (r=‐.787, P<.001), meaning animals eat more as temperature decreases. In humans, multiple methods are used to administer cold stimuli, which result in consistent yet quantitatively small increases in EE. However, only two studies have measured ad libitum food intake in combination with acute CE in humans. Chronic CE (i.e., cold acclimation) studies have been shown to produce minimal changes in body weight, with an average compensation of ~126%. Although more studies are required to investigate how cold impacts EI in humans, results presented in this review warrant caution before presenting or considering CE as a potential adjunct to weight loss strategies.     

Successful weight loss maintenance: A systematic review of weight control registries

Weight loss maintenance is a major challenge for obesity treatment. Weight control registries can be useful in identifying psychological and behavioural factors that could contribute to better long‐term success. The objective of this study is to describe the existing weight control registries and their participants and identify correlates of weight loss maintenance. A comprehensive search of peer‐reviewed articles published until November 2018 was conducted in PubMed, Web of Science, and Scopus. Studies that reported results from weight control registries were considered. Fifty‐two articles, corresponding to five registries (the United States, Portugal, Germany, Finland, and Greece), were included. Registries differed in inclusion criteria and procedures. Of 51 identified weight loss and maintenance strategies, grouped in 14 domains of the Oxford Food and Activity Behaviors taxonomy, the following were the most frequently reported: having healthy foods available at home, regular breakfast intake, increasing vegetable consumption, decreasing sugary and fatty foods, limiting certain foods, and reducing fat in meals. Increased physical activity was the most consistent positive correlate of weight loss maintenance. To our knowledge, this is the first systematic review of information about successful weight loss maintenance obtained from weight control registries. Key common influential characteristics of success were identified, which can inform future prospective studies and weight management initiatives.     

Drugs for hyperlipidaemia may slow down the progression of hearing loss in the elderly: A drug repurposing study

Hearing loss in the elderly causes communication difficulties, decreased quality of life, isolation, loneliness and frustration. The aim of this study was to identify the modifiable variables that may affect the progression of hearing loss in the elderly. A case‐control study was conducted using two data sets. Data were extracted from the health examination survey of Ajou University Hospital (2010‐2014) and the Korea National Health and Nutrition Examination Survey (2009‐2012) data sets. Audiometry data were evaluated according to variables such as age, sex and drug use for underlying diseases. Logistic regression analysis was performed on the entire study population, and middle‐aged and elderly groups using odds ratios (ORs). Factors including older age, female gender and diabetes mellitus were significantly associated with hearing levels in all age groups (OR [95% confidence interval, 95% CI], 0.375 [0.388‐0.415], 1.202 [1.195‐1.208], and 1.427 [1.183‐1.721], respectively). However, when the results from the middle‐aged and elderly groups were compared, medication for hyperlipidaemia had a significantly positive effect on the preservation of hearing in the elderly group (OR [95% CI], 0.713 [0.567‐0.897]), but not in the middle‐aged group (OR [95% CI], 0.967 [0.791‐1.183]). People, especially those in the elderly group, exposed to medication for hyperlipidaemia are likely to have better hearing than those not exposed to such drugs. Thus, drugs prescribed for hyperlipidaemia may maintain hearing in the elderly. However, to overcome potential confounding—by unmeasured variables—that is present in this study, further studies must be performed with more elaborate research design and methodology.     

Bennett acceptance ratio method to calculate the binding free energy of BACE1 inhibitors: Theoretical model and design of new ligands of the enzyme

In recent years, the design, development, and evaluation of several inhibitors of the BACE1 enzyme, as part of Alzheimer's treatment, have gathered the scientific community's interest. Here, a linear regression model was built using binding free energy calculations through the Bennett acceptance ratio method for 20 known inhibitors of the BACE1 enzyme, with a Pearson coefficient of R = 0.88 and R² = 0.78. The validation of this model was verified employing eight additional random inhibitors, which also gave a linear correlation with R = 0.97 and R² = 0.93. Furthermore, this linear regression model was also used for proposing the structure of four potential BACE1 inhibitors, and the most active of them gave a theoretical K_d = 10 nM. However, these molecules have not been synthesized yet. Our team used a total time of more than 800 ns for the Molecular Dynamics to carry out this study, and all the software used were freely available.     

Noteworthy effect of slight variation in aliphatic chain length of trisubstituted imidazole inhibitors against epidermal growth factor receptor L858R/T790M/C797S mutant in cancer therapy

11h is a very potent inhibitor against epidermal growth factor receptor triple mutation L858R/T790M/C797S (EGFR^TM) with 13‐fold stronger potency than the FDA‐approved osimertinib. Recently, two new EGFR^TM inhibitors, 11d and 11e , were reported which revealed 2.8‐ and 2.3‐fold stronger potency than 11h , respectively. 11h , 11d, and 11e have the same structures but differ only in their aliphatic chain length. However, the exact effects of differential aliphatic chain length on the inhibitory potencies of these compounds require further elaboration at the atomistic level, hence the objective of this report. Various computational tools were employed for this purpose. From our findings, it was revealed that van der Waals (vdW) interactions modulate the binding mechanisms of these inhibitors and play the most important role in the differential inhibitory activities of 11d , 11h, and 11e . The strong hydrogen bond formation between the aliphatic chain of 11d and key residue ARG841 was recognized as the reason for its higher activity and inhibitory potency relative to 11h and 11e . Moreover, the extension of the N‐terminal loop into the active site for vdW interaction with the phenyl group of 11e and carbon–hydrogen bond formed between the aliphatic chain of 11e and LEU718 engendered a higher activity of 11e than 11h .     

Altered body weight associated with substance abuse: a look beyond food intake

Background: Substance abuse can cause a range of harmful secondary health consequences, including body weight changes. These remain poorly understood but can lead to metabolic disorders including obesity and diabetes. Energy balance is a function of the equation: energy balance?=?energy intake – energy expenditure; an imbalance to this equation results in body weight changes. Currently, in the clinical setting, changes to food intake (energy intake) are considered as the primary mediator of body weight changes related to substance abuse, reflected in the current treatment focus on nutritional intervention. The influence of substance abuse on energy expenditure receives less attention. The aim of this think-piece is to consider potential causes of body weight changes during active substance abuse and abstinence, by focussing on the components of the energy balance equation.

Methods: We discuss both human and animal studies on the effects of substance abuse on energy balance, with particular focus on animal models utilising pair-feeding, which enable investigation of energy balance whilst controlling for the effects of altered food intake.

Results: We demonstrate that whilst some drugs of abuse affect food intake, this effect is inconsistent. Furthermore, body weight changes do not match food intake changes.

Conclusion: We provide evidence that drugs of abuse can affect both energy intake and energy expenditure; contributing to the observed body weight changes. This think-piece highlights that treatment strategies for body weight changes related to substance abuse cannot focus solely on nutritional interventions, but should consider the impact of broader disruptions to energy balance.