Journal of Personalized Medicine — Open Access Journal

Omega-3 fatty acids (ω-3FAs), carotenoids, and vitamin E are important constituents of a healthy diet. While they are present in brain tissue, studies have shown that these key nutrients are depleted in individuals with mild cognitive impairment (MCI) in comparison to cognitively healthy individuals. Therefore, it is likely that these individuals will benefit from targeted nutritional intervention, given that poor nutrition is one of the many modifiable risk factors for MCI. Evidence to date suggests that these nutritional compounds can work independently to optimize the neurocognitive environment, primarily due to their antioxidant and anti-inflammatory properties. To date, however, no interventional studies have examined the potential synergistic effects of a combination of ω-3FAs, carotenoids and vitamin E on the cognitive function of patients with MCI. Individuals with clinically confirmed MCI consumed an ω-3FA plus carotenoid plus vitamin E formulation or placebo for 12 months. Cognitive performance was determined from tasks that assessed global cognition and episodic memory. Ω-3FAs, carotenoids, and vitamin E were measured in blood. Carotenoid concentrations were also measured in tissue (skin and retina). Individuals consuming the active intervention (n = 6; median [IQR] age 73.5 [69.5–80.5] years; 50% female) exhibited statistically significant improvements (p < 0.05, for all) in tissue carotenoid concentrations, and carotenoid and ω-3FA concentrations in blood. Trends in improvements in episodic memory and global cognition were also observed in this group. In contrast, the placebo group (n = 7; median [IQR] 72 (69.5–75.5) years; 89% female) remained unchanged or worsened for all measurements (p > 0.05). Despite a small sample size, this exploratory study is the first of its kind to identify trends in improved cognitive performance in individuals with MCI following supplementation with ω-3FAs, carotenoids, and vitamin E. Full article

Alzheimer’s disease (AD) is the sixth leading cause of death and is correlated with obesity, which is the second leading cause of preventable diseases in the United States. Obesity, diabetes, and AD share several common features, and inflammation emerges as the central link. High-calorie intake, elevated free fatty acids, and impaired endocrine function leads to insulin resistance and systemic inflammation. Systemic inflammation triggers neuro-inflammation, which eventually hinders the metabolic and regulatory function of the brain mitochondria leading to neuronal damage and subsequent AD-related cognitive decline. As an early event in the pathogenesis of AD, chronic inflammation could be considered as a potential biomarker in the treatment strategies for AD. Full article

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20–40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations. Full article

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene variant, c.3453G > C (D1152H), is associated with mild Cystic Fibrosis (CF) disease, though there is considerable clinical variability ranging from no detectable symptoms to lung disease with early acquisition of Pseudomonas aeruginosa. The approval extension of ivacaftor, the first CFTR modulator drug approved, to include D1152H was based on a positive drug response of defective CFTR-D1152H chloride channel function when expressed in FRT cells. Functional analyses of primary human nasal epithelial cells (HNE) from an individual homozygous for D1152H now revealed that while CFTR-D1152H demonstrated normal, wild-type level chloride conductance, its bicarbonate-selective conductance was impaired. Treatment with ivacaftor increased this bicarbonate-selective conductance. Extensive genetic, protein and functional analysis of the nasal cells of this D1152H/D1152H patient revealed a 90% reduction of CFTR transcripts due to the homozygous presence of the 5T polymorphism in the poly-T tract forming a complex allele with D1152H. Thus, we confirm previous observation in patient-derived tissue that 10% normal CFTR transcripts confer normal, wild-type level chloride channel activity. Together, this study highlights the benefit of patient-derived tissues to study the functional expression and pharmacological modulation of CF-causing mutations, in order to understand pathogenesis and therapeutic responses. Full article

Infection is an important factor leading to the exacerbation of heart failure (HF), resulting in hospitalization. Demodex species are obligatory parasites in human skin, and increased density was reported in immunocompromised patients. In this study, we aimed to investigate the Demodex density in hospitalized HF patients compared to that of healthy controls. Methods: This study included 36 HF patients and 36 age and sex-matched healthy controls. Five standardized biopsies were taken from the face of participants and assessed for Demodex by a light microscope. Results: At least one Demodex mite was detected in 20 HF patients and nine of the control group. The number of Demodex mites was significantly higher in the HF group (median 1; min. 0 and max. 10) compared to the control group (median 0; minimum. 0 and maximum. 3). Demodicidosis was positive in 14 of the HF patients. Demodicidosis was not detected in the control group. Conclusions: This study showed that Demodex positivity is more common in HF patients hospitalized for HF exacerbation. Demodicidosis should be considered in hospitalized HF patients. Full article

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging. Full article

Aerosol therapy is a key modality for drug delivery to the lungs of respiratory disease patients. Aerosol therapy improves therapeutic effects by directly targeting diseased lung regions for rapid onset of action, requiring smaller doses than oral or intravenous delivery and minimizing systemic side effects. In order to optimize treatment of critically ill patients, the efficacy of aerosol therapy depends on lung morphology, breathing patterns, aerosol droplet characteristics, disease, mechanical ventilation, pharmacokinetics, and the pharmacodynamics of cell-drug interactions. While aerosol characteristics are influenced by drug formulations and device mechanisms, most other factors are reliant on individual patient variables. This has led to increased efforts towards more personalized therapeutic approaches to optimize pulmonary drug delivery and improve selection of effective drug types for individual patients. Vibrating mesh nebulizers (VMN) are the dominant device in clinical trials involving mechanical ventilation and emerging drugs. In this review, we consider the use of VMN during mechanical ventilation in intensive care units. We aim to link VMN fundamentals to applications in mechanically ventilated patients and look to the future use of VMN in emerging personalized therapeutic drugs. Full article

Currently, 1% of the population of the Western world suffers from venous leg ulcers as a result of chronic venous insufficiency. Current treatment involves the use of moist wound healing, compression bandages, and intermittent pneumatic compression. Neuromuscular electrical stimulation is a novel potential new therapeutic method for the promotion of increased lower limb hemodynamics. The aim of this study was to measure the hemodynamic changes in the lower limb with the use of two neuromuscular electrical stimulation devices. Twelve healthy volunteers received two neuromuscular stimulation device interventions. The Geko^TM and National University of Ireland (NUI) Galway neuromuscular electrical stimulation devices were randomized between dominant and non-dominant legs. Hemodynamic measurements of peak venous velocity (cm/s), the time average mean velocity (TAMEAN) (cm/s), and ejected volume (mL) of blood were recorded. Peak venous velocity was significantly increased by the Geko^TM and the NUI Galway device compared to baseline blood flow (p < 0.0001), while only the voluntary contraction produced significant increases in TAMEAN and ejected volume (both p < 0.05). Neuromuscular muscular electrical stimulation can produce adequate increases in lower limb hemodynamics sufficient to prevent venous stasis. Greater use of neuromuscular stimulation devices could be considered in the treatment of conditions related to chronic venous insufficiency but requires further research. Full article

For years, it has been thought that the field of dentistry was referring exclusively to some diseases that strictly affect the oral cavity. Dental caries, periodontal disease, and pathologies associated with their worsening were considered almost the only interest in scientific research in dentistry. Recent studies have begun to shed light on the effect of the oral microbiota on general health and on the crucial role of dentistry in its maintenance. In this way, we came to understand that the bacterial populations that make up the oral microbiota can vary profoundly between individuals and that contribute in a fundamental way to outlining the so-called "oral signature". This characteristic is called into question to evaluate the susceptibility, or lack thereof, of the subject to the contraction of a wide range of pathologies, apparently not connected with oral health. From this evidence, it will also be possible to study therapeutic approaches aimed at the eradication of species considered at risk or colonization with species considered protective; thus, giving life to so-called "personalized dentistry". Therefore, this Special Issue is aimed at spreading the scientific knowledge over the current limits in terms of new molecular and culturomic approaches towards the diagnosis of oral microbiota and the treatment techniques of eventually associated systemic diseases. In vivo studies and systematic literature reviews with quantitative analysis of results, when possible, will be given a high priority. Full article

Neurodegenerative processes of various types of dementia start years before symptoms, but the presence of a “neural reserve”, which continuously feeds and supports neuroplastic mechanisms, helps the aging brain to preserve most of its functions within the “normality” frame. Mild cognitive impairment (MCI) is an intermediate stage between dementia and normal brain aging. About 50% of MCI subjects are already in a stage that is prodromal-to-dementia and during the following 3 to 5 years will develop clinically evident symptoms, while the other 50% remains at MCI or returns to normal. If the risk factors favoring degenerative mechanisms are modified during early stages (i.e., in the prodromal), the degenerative process and the loss of abilities in daily living activities will be delayed. It is therefore extremely important to have biomarkers able to identify—in association with neuropsychological tests—prodromal-to-dementia MCI subjects as early as possible. MCI is a large (i.e., several million in EU) and substantially healthy population; therefore, biomarkers should be financially affordable, largely available and non-invasive, but still accurate in their diagnostic prediction. Neurodegeneration initially affects synaptic transmission and brain connectivity; methods exploring them would represent a 1st line screening. Neurophysiological techniques able to evaluate mechanisms of synaptic function and brain connectivity are attracting general interest and are described here. Results are quite encouraging and suggest that by the application of artificial intelligence (i.e., learning-machine), neurophysiological techniques represent valid biomarkers for screening campaigns of the MCI population. Full article

(1) Background and purpose: SPIDER (Strengthening Program for Intensive Developmental Exercises and activities for Reaching health capability) is dedicated for patients suffering from Cerebral Palsy, Sclerosis Multiplex, Spinal Bifida, Spinal Muscular Atrophy and strokes. Authors proposed a computer model for the evaluation patient’s condition and the rehabilitation progress. (2) Methods: The 2-year-old and 76-year-old patients with neurological problems, who underwent individual therapy included balancing and coordination practising with SPIDER device. The model comparing the forces, which act during the therapy process, such as the expander and gravity forces, was worked out using Matlab software. (3) Results: The model allowed controlling the changes into the patients centre of gravity forces continuous adjustment and postural stability during any patient’s movement. After rehabilitation sessions, lasted for 28 days during which patients received the progress information and the therapist got the numeric data, regarding the period of the therapy. (4) Conclusions: The first patient was able to move, dramatically improved the ability to balance and coordination. The second one presented change in gait, improvement in mobility, motor function and decreased fall risk. The proposed computer model gives information about the forces acting to the patient body. The physiotherapist can evaluate the progress of patient verticalization and receive information, in the form of numbers and charts. Full article

Alzheimer’s disease (AD) is diagnosed using neuropsychological testing, supported by amyloid and tau biomarkers and neuroimaging abnormalities. The cause of neuropsychological changes is not clear since they do not correlate with biomarkers. This study investigated if changes in cellular metabolism in AD correlate with neuropsychological changes. Fibroblasts were taken from 10 AD patients and 10 controls. Metabolic assessment included measuring total cellular ATP, extracellular lactate, mitochondrial membrane potential (MMP), mitochondrial respiration and glycolytic function. All participants were assessed with neuropsychological testing and brain structural MRI. AD patients had significantly lower scores in delayed and immediate recall, semantic memory, phonemic fluency and Mini Mental State Examination (MMSE). AD patients also had significantly smaller left hippocampal, left parietal, right parietal and anterior medial prefrontal cortical grey matter volumes. Fibroblast MMP, mitochondrial spare respiratory capacity (MSRC), glycolytic reserve, and extracellular lactate were found to be lower in AD patients. MSRC/MMP correlated significantly with semantic memory, immediate and delayed episodic recall. Correlations between MSRC and delayed episodic recall remained significant after controlling for age, education and brain reserve. Grey matter volumes did not correlate with MRSC/MMP. AD fibroblast metabolic assessment may represent an emergent disease biomarker of AD. Full article

In order to develop a predictive model that can distinguish Parkinson's disease dementia (PDD) from other dementia types, such as Alzheimer's dementia (AD), it is necessary to evaluate and identify the predictive accuracy of the cognitive profile while considering the non-motor symptoms, such as depression and rapid eye movement (REM) sleep behavior disorders. This study compared Parkinson's disease (PD)’s non-motor symptoms and the diagnostic predictive power of cognitive profiles that distinguish AD and PD using machine learning. This study analyzed 118 patients with AD and 110 patients with PDD, and all subjects were 60 years or older. In order to develop the PDD prediction model, the dataset was divided into training data (70%) and test data (30%). The prediction accuracy of the model was calculated by the recognition rate. The results of this study show that Parkinson-related non-motor symptoms, such as REM sleep behavior disorders, and cognitive screening tests, such as Korean version of Montreal Cognitive Assessment, were highly accurate factors for predicting PDD. It is required to develop customized screening tests that can detect PDD in the early stage based on these results. Furthermore, it is believed that including biomarkers such as brain images or cerebrospinal fluid as input variables will be more useful for developing PDD prediction models in the future. Full article

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the “real world” of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments. Full article

As pharmacogenomic (PGx) use in healthcare increases, a better understanding of patient needs will be necessary to guide PGx result delivery. The Coriell Personalized Medicine Collaborative (CPMC) is a prospective study investigating the utility of personalized medicine. Participants received online genetic risk reports for 27 potentially actionable complex diseases and 7 drug–gene pairs and could request free, telephone-based genetic counseling (GC). To explore the needs of individuals receiving PGx results, we conducted a retrospective qualitative review of inquiries from CPMC participants who requested counseling from March 2009 to February 2017. Eighty out of 690 (12%) total GC inquiries were focused on the discussion of PGx results, and six salient themes emerged: “general help”, “issues with drugs”, “relevant disease experience”, “what do I do now?”, “sharing results”, and “other drugs”. The number of reported medications with a corresponding PGx result and participant engagement were significantly associated with PGx GC requests (p < 0.01 and p < 0.02, respectively). Our work illustrates a range of questions raised by study participants receiving PGx test results, most of which were addressed by a genetic counselor with few requiring referrals to prescribing providers or pharmacists. These results further support a role for genetic counselors in the team-based approach to optimal PGx result delivery. Full article

An ascending thoracic aortic aneurysm (ATAA) is a heterogeneous disease showing different patterns of aortic dilatation and valve morphologies, each with distinct clinical course. This study aimed to explore the aortic morphology and the associations between shape and function in a population of ATAA, while further assessing novel risk models of aortic surgery not based on aortic size. Shape variability of n = 106 patients with ATAA and different valve morphologies (i.e., bicuspid versus tricuspid aortic valve) was estimated by statistical shape analysis (SSA) to compute a mean aortic shape and its deformation. Once the computational atlas was built, principal component analysis (PCA) allowed to reduce the complex ATAA anatomy to a few shape modes, which were correlated to shear stress and aortic strain, as determined by computational analysis. Findings demonstrated that shape modes are associated to specific morphological features of aneurysmal aorta as the vessel tortuosity and local bulging of the ATAA. A predictive model, built with principal shape modes of the ATAA wall, achieved better performance in stratifying surgically operated ATAAs versus monitored ATAAs, with respect to a baseline model using the maximum aortic diameter. Using current imaging resources, this study demonstrated the potential of SSA to investigate the association between shape and function in ATAAs, with the goal of developing a personalized approach for the treatment of the severity of aneurysmal aorta. Full article

Background: Very little is known regarding the prevalence of opioid induced hyperalgesia (OIH) in day to day medical practice. The aim of this study was to evaluate the physician’s perception of the prevalence of OIH within their practice, and to assess the level of physician’s knowledge with respect to the identification and treatment of this problem. Methods: An electronic questionnaire was distributed to physicians who work in anesthesiology, chronic pain, and/or palliative care in Canada. Results: Of the 462 responses received, most were from male (69%) anesthesiologists (89.6%), in the age range of 36 to 64 years old (79.8%). In this study, the suspected prevalence of OIH using the average number of patients treated per year with opioids was 0.002% per patient per physician practice year for acute pain, and 0.01% per patient per physician practice year for chronic pain. Most physicians (70.2%) did not use clinical tests to help make a diagnosis of OIH. The treatment modalities most frequently used were the addition of an NMDA antagonist, combined with lowering the opioid doses and using opioid rotation. Conclusions: The perceived prevalence of OIH in clinical practice is a relatively rare phenomenon. Furthermore, more than half of physicians did not use a clinical test to confirm the diagnosis of OIH. The two main treatment modalities used were NMDA antagonists and opioid rotation. The criteria for the diagnosis of OIH still need to be accurately defined. Full article

Like several neurodegenerative disorders, such as Prion and Parkinson diseases, Alzheimer’s disease (AD) is characterized by spreading mechanism of aggregated proteins in the brain in a typical “prion-like” manner. Recent genetic studies have identified in four genes associated with inherited AD (amyloid precursor protein-APP, Presenilin-1, Presenilin-2 and Apolipoprotein E), rare mutations which cause dysregulation of APP processing and alterations of folding of the derived amyloid beta peptide (Aβ). Accumulation and aggregation of Aβ in the brain can trigger a series of intracellular events, including hyperphosphorylation of tau protein, leading to the pathological features of AD. However, mutations in these four genes account for a small of the total genetic risk for familial AD (FAD). Genome-wide association studies have recently led to the identification of additional AD candidate genes. Here, we review an update of well-established, highly penetrant FAD-causing genes with correlation to the protein misfolding pathway, and novel emerging candidate FAD genes, as well as inherited risk factors. Knowledge of these genes and of their correlated biochemical cascade will provide several potential targets for treatment of AD and aging-related disorders. Full article

Background: The study aimed to investigate the relationships between F-18 fluorodeoxyglucose (18F)FDG uptake and neuropsychological assessment in Alzheimer’s disease (AD). Methods: We evaluated 116 subjects with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a brain PET/CT with (18F)FDG, cerebrospinal fluid (CSF) assay, mini-mental state examination (MMSE) and further neuropsychological tests: Rey auditory verbal learning test, immediate recall (RAVLT immediate); Rey auditory verbal learning test, delayed recall (RAVLT, delayed); Rey complex figure test, copy (RCFT, copy); Rey complex figure test, delayed recall (RCFT, delayed); Raven’s colored progressive matrices (RCPM); phonological word fluency test (PWF) and Stroop test. We performed the statistical analysis by using statistical parametric mapping (SPM12; Wellcome Department of Cognitive Neurology, London, UK). Results: A significant relationship has been reported between (18F)FDG uptake and RAVLT immediate test in Brodmann area (BA)37 and BA22 and with RCFT, copy in BA40, and BA7. We did not find any significant relationships with other tests. Conclusion: In the AD population, brain (18F)FDG uptake is moderately related to the neuropsychological assessment, suggesting a limited impact on statistical data analysis of glucose brain metabolism. Full article