J. Pers. Med., Volume 11, Issue 11 (November 2021) – 193 articles

Precision medicine is a term used to describe medical care, which is specifically tailored to an individual patient or disease with the aim of ensuring the best clinical outcome whilst reducing the risk of adverse effects. Phaeochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours with uncertain malignant potential. Over recent years, the molecular profiling of PPGLs has increased our understanding of the mechanisms that drive tumorigenesis. A high proportion of PPGLs are hereditary, with non-hereditary tumours commonly harbouring somatic mutations in known susceptibility genes. Through detailed interrogation of genotype-phenotype, correlations PPGLs can be classified into three different subgroups or clusters. Thus, PPGLs serve as an ideal paradigm for developing, testing and implementing precision medicine concepts in the clinic. In this review, we provide an overview of PPGLs and highlight how detailed molecular characterisation of these tumours provides current and future opportunities for precision oncology. Full article

(1) Background: COVID-19 may lead to refractory hypoxemia requiring venovenous extracorporeal membrane oxygenation (ECMO). Survival rate if ECMO is implemented as rescue therapy after corticosteroid failure is unknown. We aimed to investigate if ECMO implemented after failure of the full-recommended 10-day corticosteroid course can improve outcome. (2) Methods: We conducted a three-center cohort study including consecutive dexamethasone-treated COVID-19 patients requiring ECMO between 03/2020 and 05/2021. We compared survival at hospital discharge between patients implemented after (ECMO-after group) and before the end of the 10-day dexamethasone course (ECMO-before group). (3) Results: Forty patients (28M/12F; age, 57 years (51–62) (median (25th–75th percentiles)) were included, 28 (70%) in the ECMO-before and 12 (30%) in the ECMO-after group. In the ECMO-before group, 9/28 patients (32%) received the 6 mg/day dexamethasone regimen versus 12/12 (100%) in the ECMO-after group (p < 0.0001). The rest of the patients received an alternative dexamethasone regimen consisting of 20 mg/day during 5 days followed by 10 mg/day during 5 days. Patients in the ECMO-before group tended to be younger (57 years (51–59) versus 62 years (57–67), p = 0.053). In the ECMO-after group, no patient (0%) survived while 12 patients (43%) survived in the ECMO-before group (p = 0.007). (4) Conclusions: Survival is poor in COVID-19 patients requiring ECMO implemented after the full-recommended 10-day dexamethasone course. Since these patients may have developed a particularly severe presentation, new therapeutic strategies are urgently required. Full article

In orthognathic surgery, patient-specific osteosynthesis implants (PSIs) represent a novel approach for the reproduction of the virtual surgical planning on the patient. The aim of this study is to analyse the quality of maxillo-mandibular positioning using a hybrid mandible-first mandibular-PSI-guided procedure on twenty-two patients while the upper maxilla was fixed using manually bent stock titanium miniplates. The virtual surgical plan was used to design PSIs and positioning guides, which were then 3D printed using biocompatible materials. A Cone Beam Computed Tomography (CBCT) scan was performed one month after surgery and postoperative facial skeletal models were segmented for comparison against the surgical plan. A three-dimensional cephalometric analysis was carried out on both planned and obtained anatomies. A Spearman correlation matrix was computed on the calculated discrepancies in order to achieve a more comprehensive description of maxillo-mandibular displacement. Intraoperatively, all PSIs were successfully applied. The procedure was found to be accurate in planned maxillo-mandibular positioning reproduction, while maintaining a degree of flexibility to allow for aesthetics-based verticality correction in a pitch range between −5.31 and +1.79 mm. Such a correction did not significantly affect the achievement of planned frontal symmetry. Full article

A deeper understanding of how health-related quality of life relates to the clinical and individual characteristics of patients is essential for the delivery of patient-centered dermatological care. The current study aimed to examine the role of individual differences in emotion dysregulation and social anxiety in modulating quality of life in psoriatic patients. A total of 130 patients affected by psoriasis were consecutively enrolled in the study as they approached the Dermatology Unit of Sant’Orsola-Malpighi Hospital of Bologna. Clinical information gathered included illness severity, assessed with the Psoriasis Area and Severity Index (PASI) and the Body Surface Area (BSA); illness onset; familiarity; and prescribed treatment. The patient-reported outcome measures were the Dermatology Life Quality Index (DLQI), measuring the patient’s quality of life; the Psoriasis Skin Appearance Bothersomeness scale (PSAB), measuring patient’s perception of illness severity; the Difficulties in Emotion Regulation Scale (DERS), assessing emotion dysregulation traits; and the Social Interaction Anxiety Scale (SIAS), measuring anxiety about social interactions. Patients with moderate-to-severe psoriasis reported significantly lower quality of life compared to mildly affected patients. In addition, of the patients affected by mild psoriasis, those characterized by emotion dysregulation and social anxiety traits showed significantly lower levels of quality of life. Our findings suggest that individual differences in emotion dysregulation and social anxiety contribute to health-related quality of life in addition to illness severity. Therapeutic approaches that combine dermatological care with psychological support, especially focused on emotional regulation skills, may be useful to improve clinical outcomes in patients with psoriasis. Full article

The substantia nigra (SN) pars compacta (SNpc) and pars reticulata (SNpr) are differentially affected in Parkinson’s disease (PD). Separating the SNpc and SNpr is challenging with standard magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) allows for the characterization of SN microstructure in a non-invasive manner. In this study, 29 PD patients and 28 healthy controls (HCs) were imaged with 1.5T MRI for DTI. Images were nonlinearly registered to standard space and SNpc and SNpr DTI parameters were measured. ANCOVA and receiver operator characteristic (ROC) analyses were performed. Clinical associations were assessed with Spearman correlations. Multiple corrections were controlled for false discovery rate. PD patients presented with significantly increased SNpc axial diffusivity (AD) (1.207 ± 0.068 versus 1.156 ± 0.045, p = 0.024), with ROC analysis yielding an under the curve of 0.736. Trends with Unified Parkinson’s Disease Rating Scale (UPDRS) III scores were identified for SNpc MD (rs = 0.449), AD (rs = 0.388), and radial diffusivity (rs = 0.391) (all p < 0.1). A trend between baseline SNpr MD and H&Y change (rs = 0.563, p = 0.081) over 2.9 years of follow-up was identified (n = 14). In conclusion, SN microstructure shows robust, clinically meaningful associations in PD. Full article

Introduction: An infection by COVID-19 triggers a dangerous cytokine storm, so tocilizumab has been introduced in Italy as an agent blocking the cytokine storm. This paper aims to describe the one-year survival of ICU patients treated with tocilizumab. Methods: This observational study enrolled all patients confirmed to be infected by COVID-19 who were admitted to the ICU in our center. We offered tocilizumab to all non-septic patients if they did not present any contraindications. Results: We enrolled 68 ICU patients in our center on 72 occasions during the enrollment period; we excluded four patients due to study criteria. The one-year mortality hazard ratio of treated patients was 0.64, with a confidence interval of 0.31 to 1.19, with p = 0.169. Among the survivors, 32 of 35 patients answered the phone interview (14 patients in the treated group and 18 in the untreated group); overall, the effect of COVID-19 on quality of life was 58.14%. These effects were lower in the tocilizumab group, with p = 0.016 *. Conclusions: Our observational data follow the most relevant largest trial. Patients treated with tocilizumab had lower rates of new-onset symptoms later COVID-19 ICU hospitalizations. As reported by recent medical literature, the presence of these symptoms suggests that a follow-up program for these types of patients could be useful. Full article

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10⁻⁸) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10⁻⁷) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies. Full article

The aim of this work was to identify genetic variants potentially involved in familial hypercholesterolemia in 43 genes associated with lipid metabolism disorders. Targeted high-throughput sequencing of lipid metabolism genes was performed (80 subjects with a familial-hypercholesterolemia phenotype). For patients without functionally significant substitutions in the above genes, multiplex ligation-dependent probe amplification was conducted to determine bigger mutations (deletions and/or duplications) in the LDLR promoter and exons. A clinically significant variant in some gene associated with familial hypercholesterolemia was identified in 47.5% of the subjects. Clinically significant variants in the LDLR gene were identified in 19 probands (73.1% of all variants identified in probands); in three probands (11.5%), pathogenic variants were found in the APOB gene; and in four probands (15.4%), rare, clinically significant variants were identified in genes LPL, SREBF1, APOC3, and ABCG5. In 12 (85.7%) of 14 children of the probands, clinically significant variants were detectable in genes associated with familial hypercholesterolemia. The use of clinical criteria, targeted sequencing, and multiplex ligation-dependent probe amplification makes it possible to identify carriers of rare clinically significant variants in a wide range of lipid metabolism genes and to investigate their influence on phenotypic manifestations of familial hypercholesterolemia. Full article

The aim of this study was to assess the predictive value of pre-biopsy blood-based markers in patients undergoing a fusion biopsy for suspicious prostate magnetic resonance imaging (MRI). We identified 365 consecutive patients who underwent MRI-targeted and systematic prostate biopsy for an MRI scored Prostate Imaging–Reporting and Data System Version (PI-RADS) ≥ 3. We evaluated the neutrophil/lymphocyte ratio (NLR), derived neutrophil/lymphocyte ratio (dNLR), platelet/lymphocyte ratio (PLR), systemic immune inflammation index (SII), lymphocyte/monocyte ratio (LMR,) de Ritis ratio, modified Glasgow Prognostic Score (mGPS), and prognostic nutrition index (PNI). Uni- and multivariable logistic models were used to analyze the association of the biomarkers with biopsy findings. The clinical benefits of biomarkers implemented in clinical decision-making were assessed using decision curve analysis (DCA). In total, 69% and 58% of patients were diagnosed with any prostate cancer and Gleason Grade (GG) ≥ 2, respectively. On multivariable analysis, only high dNLR (odds ratio (OR) 2.61, 95% confidence interval (CI) 1.23–5.56, p = 0.02) and low PNI (OR 0.48, 95% CI 0.26–0.88, p = 0.02) remained independent predictors for GG ≥ 2. The logistic regression models with biomarkers reached AUCs of 0.824–0.849 for GG ≥ 2. The addition of dNLR and PNI did not enhance the net benefit of a standard clinical model. Finally, we created the nomogram that may help guide biopsy avoidance in patients with suspicious MRI. In patients with PI-RADS ≥ 3 lesions undergoing MRI-targeted and systematic biopsy, a high dNLR and low PNI were associated with unfavorable biopsy outcomes. Pre-biopsy blood-based biomarkers did not, however, significantly improve the discriminatory power and failed to add a clinical benefit beyond standard clinical factors. Full article

The increasing availability of next generation sequencing (NGS) for personal genomics could promote pharmacogenomics (PGx) discovery and application. However, current tools for analysis and interpretation of pharmacogenomic variants from NGS data are inadequate, as none offer comprehensive analytic functions in a simple, web-based platform. In addition, no tools exist to analyze human leukocyte antigen (HLA) genes for determining potential risks of immune-mediated adverse drug reaction (IM-ADR). We describe PharmVIP, a web-based PGx tool, for one-stop comprehensive analysis and interpretation of genome-wide variants obtained from NGS platforms. PharmVIP comprises three main interpretation modules covering analyses of pharmacogenes involved in pharmacokinetics, pharmacodynamics and IM-ADR. The Guideline module provides Clinical Pharmacogenetics Implementation Consortium (CPIC) drug guideline recommendations based on the translation of genotypic data in genes having guidelines. The HLA module reports HLA genotypes, potential adverse drug reactions, and the relevant drug guidelines. The Pharmacogenes module is employed for prioritizing variants according to variant effect on gene function. Detailed, customizable reports are provided as exportable files and as an interactive web version. PharmVIP is a new integrated NGS workflow for the PGx community to facilitate discovery and clinical application. Full article

Airway wall remodeling is a pathology occurring in chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, and fibrosis. In 2017, the American Thoracic Society released a research statement highlighting the gaps in knowledge and understanding of airway wall remodeling. The four major challenges addressed in this statement were: (i) the lack of consensus to define “airway wall remodeling” in different diseases, (ii) methodologic limitations and inappropriate models, (iii) the lack of anti-remodeling therapies, and (iv) the difficulty to define endpoints and outcomes in relevant studies. This review focuses on the importance of cell-cell interaction, especially the bronchial epithelium, in asthma-associated airway wall remodeling. The pathology of “airway wall remodeling” summarizes all structural changes of the airway wall without differentiating between different pheno- or endo-types of asthma. Indicators of airway wall remodeling have been reported in childhood asthma in the absence of any sign of inflammation; thus, the initiation event remains unknown. Recent studies have implied that the interaction between the epithelium with immune cells and sub-epithelial mesenchymal cells is modified in asthma by a yet unknown epigenetic mechanism during early childhood. Full article

Many patients with adenoid-cystic carcinoma (ACC) experience an indolent course of disease over many years but face late recurrence, and long-term survivors are rare. Due to its infrequent occurrence, it is hard to predict outcome in these patients. The fibrinogen-to-lymphocyte ratio (FLR) was recently proposed as an outcome prognosticator in different cancer entities. We aimed to investigate its prognostic relevance in patients with head and neck ACC. This retrospective analysis was performed including all patients treated for ACC between 1998 and 2020. The FLR ratio was calculated based on pretreatment values (0–7 days). The study cohort was dichotomized based on optimized threshold value and compared for differences in outcome (overall survival (OS) and disease-free survival (DFS)). In the cohort of 39 included patients, the OS was significantly longer in the low (n = 28) compared to the high pretreatment FLR group (n = 11) (median OS 150.5 months, 95% confidence intervals (CI) 85.3–215.7 months vs. 29.4 months, 95% CI not reached; p = 0.0093). Similarly, the DFS was significantly longer in the low FLR group (median DFS 74.5 months, 95% CI 30.6–118.4 months vs. 11.0 months, 95% CI 5.1–16.9 months; p = 0.019). The FLR is an easily obtainable and simple marker and may be a valuable outcome prognosticator in patients with ACC. Further studies are needed for validation of our results. Full article

A formal assessment of pharmacogenomics clinical decision support (PGx-CDS) by providers is lacking in the literature. The objective of this study was to evaluate the usability of PGx-CDS tools that have been implemented in a healthcare setting. We enrolled ten prescribing healthcare providers and had them complete a 60-min usability session, which included interacting with two PGx-CDS scenarios using the “Think Aloud” technique, as well as completing the Computer System Usability Questionnaire (CSUQ). Providers reported positive comments, negative comments, and suggestions for the two PGx-CDS during the usability testing. Most provider comments were in favor of the current PGx-CDS design, with the exception of how the genotype and phenotype information is displayed. The mean CSUQ score for the PGx-CDS overall satisfaction was 6.3 ± 0.95, with seven strongly agreeing and one strongly disagreeing for overall satisfaction. The implemented PGx-CDS at our institution was well received by prescribing healthcare providers. The feedback collected from the session will guide future PGx-CDS designs for our healthcare system and provide a framework for other institutions implementing PGx-CDS. Full article

The Clinical Pharmacogenetics Implementation Consortium (CPIC^®) establishes evidence-based guidelines for utilizing pharmacogenetic information for certain priority drugs. Warfarin, clopidogrel and simvastatin are cardiovascular drugs that carry strong prescribing guidance by CPIC. The respective pharmacogenes for each of these drugs exhibit considerable variability amongst different ethnic/ancestral/racial populations. Race and ethnicity are commonly employed as surrogate biomarkers in clinical practice and can be found in many prescribing guidelines. This is controversial due to the large variability that exists amongst different racial/ethnic groups, lack of detailed ethnic information and the broad geographic categorization of racial groups. Using a retrospective analysis of electronic health records (EHR), we sought to determine the degree to which self-reported race/ethnicity contributed to the probability of adverse drug reactions for these drugs. All models used individuals self-reporting as White as the comparison group. The majority of apparent associations between different racial groups and drug toxicity observed in the “race only” model failed to remain significant when we corrected for covariates. We did observe self-identified Asian race as a significant predictor (p = 0.016) for warfarin hemorrhagic events in all models. In addition, patients identifying as either Black/African-American (p = 0.001) or Other/Multiple race (p = 0.019) had a lower probability of reporting an adverse reaction than White individuals while on simvastatin even after correcting for other covariates. In both instances where race/ethnicity was predictive of drug toxicity (i.e., warfarin, simvastatin), the findings are consistent with the known global variability in the pharmacogenes described in the CPIC guidelines for these medications. These results confirm that the reliability of using self-identified race/ethnic information extracted from EHRs as a predictor of adverse drug reactions is likely limited to situations where the genes influencing drug toxicity display large, distinct ethnogeographic variability. Full article

Despite recent advances in the treatment of non-small cell lung cancer (NSCLC), less than 10% of patients survive the first five years when the disease has already spread at primary diagnosis. Methods: Blood samples were taken from 118 NSCLC patients at primary diagnosis or at progression of the disease before the start of a new treatment line and enriched for circulating tumor cells (CTCs) by microfluidic Parsortix™ (Angle plc, Guildford GU2 7AF, UK) technology. The gene expression of epithelial cancer stem cell (CSC), epithelial to mesenchymal (EMT), and lung-related markers was assessed by qPCR, and the association of each marker with overall survival (OS) was evaluated using log-rank tests. Results: EpCAM was the most prevalent transcript, with 53.7% positive samples at primary diagnosis and 25.6% at recurrence. EpCAM and CK19, as well as NANOG, PROM1, TERT, CDH5, FAM83A, and PTHLH transcripts, were associated with worse OS. However, only the CSC-specific NANOG and PROM1 were related to the outcome both at primary diagnosis (NANOG: HR 3.21, 95%CI 1.02–10.14, p = 0.016; PROM1: HR 4.23, 95% CI 0.65–27.56, p = 0.007) and disease progression (NANOG: HR 4.17, 95%CI 0.72–24.14, p = 0.025; PROM1: HR 4.77, 95% CI 0.29–78.94, p = 0.032). Conclusions: The present study further underlines the relevance of the molecular characterization of CTCs. Our multi-marker analysis highlighted the prognostic value of cancer stem cell-related transcripts at primary diagnosis and disease progression. Full article

Mycophenolate mofetil is a key immunosuppressant that is metabolized into mycophenolic acid (MPA). The prognostic impact of MPA-focused therapeutic drug monitoring on allograft prognosis has not been determined in kidney transplant recipients with diabetes. In this study, we assessed the pharmacokinetics of MPA and allograft prognosis in recipients with diabetes. This study retrospectively analyzed 64 adult kidney transplant recipients. MPA blood concentration data (e.g., the time to the maximum concentration (Tmax), and the area under the concentration–time curve from 0 to 12 h (AUC_0–12)) were collected at 3 weeks and 3 months after kidney transplantation. Of the 64 recipients, 15 had pre-existing diabetes. At 3 months after kidney transplantation, the Tmax of MPA was significantly longer in recipients with diabetes (mean (standard deviation): 2.8 (2.1) h) than in recipients without diabetes (1.9 (1.1) h, p = 0.02). However, the allograft estimated glomerular filtration rate and acute rejection rate, including borderline change, did not differ according to the diabetes status in patients with adjusted AUC_0–12 of MPA within the target range. In conclusion, a longer Tmax of MPA was observed in recipients with diabetes; however, acceptable allograft prognosis was observed in kidney transplant recipients with diabetes and a sufficient AUC_0–12 of MPA. Full article

Background: The primary aim of this study was to identify modifiable patient-related predictors of blood transfusions and perioperative complications in total hip and knee arthroplasty. Individual predictor-adjusted risks can be used to define preoperative treatment thresholds. Methods: We performed this retrospective monocentric study in orthopaedic patients who underwent primary total knee or hip arthroplasty. Multivariate logistic regression models were used to assess the predictive value of patient-related characteristics. Predictor-adjusted individual risks of blood transfusions and the occurrence of any perioperative adverse event were calculated for potentially modifiable risk factors. Results: 3754 patients were included in this study. The overall blood transfusion and complication rates were 4.8% and 6.4%, respectively. Haemoglobin concentration (Hb, p < 0.001), low body mass index (BMI, p < 0.001) and estimated glomerular filtration rate (eGFR, p = 0.004) were the strongest potentially modifiable predictors of a blood transfusion. EGFR (p = 0.001) was the strongest potentially modifiable predictor of a complication. Predictor-adjusted risks of blood transfusions and acute postoperative complications were calculated for Hb and eGFR. Hb = 12.5 g/dL, BMI = 17.6 kg/m², and eGFR = 54 min/mL were associated, respectively, with a 10% risk of a blood transfusion, eGFR = 59 mL/min was associated with a 10% risk of a complication. Conclusion: The individual risks for blood transfusions and acute postoperative complications are strongly increased in patients with a low preoperative Hb, low BMI or low eGFR. We recommend aiming at a preoperative Hb ≥ 13g/dL, an eGFR ≥ 60 mL/min and to avoid a low BMI. Future studies must show if a preoperative increase of eGFR and BMI is feasible and truly beneficial. Full article

Postoperative gastrointestinal bleeding (PGIB) is a serious complication with expensive medical costs and a high mortality rate. This study aims to analyze the incidence of PGIB and its associated factors, including its relationship with postoperative analgesic use. Patients aged ≥20 years who received various kinds of surgery from 2013 to 2017 were included (n = 1,319,807). PGIB was defined by admission with ICD-10 codes of gastrointestinal bleeding plus transfusion within 2 months after surgery. A total of 3505 (0.27%) subjects had PGIB, and the incidence was much higher for those who underwent major gastrointestinal and major cardiovascular surgery (1.9% for both), followed by major head and neck (0.7%), major genitourinary (0.5%), and orthopedic surgery (0.45%). On multivariate analysis, older age, male sex, lower income, comorbidities, peptic ulcer disease, and congestive heart failure were associated with a higher risk of gastrointestinal bleeding. Among analgesics, steroid use was associated with increased postoperative bleeding risk (adjusted OR: 1.36, 95% CI: 1.25–1.48). Acetaminophen/nonsteroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors, anticonvulsants, antidepressants, and opioids were not associated with increased risk. PGIB is considerable for major surgeries, and its risk should be considered, especially for patients with older age and comorbidities and use of steroids. Full article

Stress, anxiety, and post-surgical chest pain are common problems among patients with thoracic surgical pathology. The way in which psychological distress is managed—the coping style—can influence the postsurgical evolution and quality of life of patients. In our study, we monitored the influence of coping style on patients’ anxiety and the intensity of post-operative chest pain. We conducted a cross-sectional study on 90 subjects with thoracic surgical pathology. One month after their surgeries, patients completed the following scales and questionnaires, translated, adapted, and validated for the Romanian population: COPE scale inventory, Generalized Anxiety Disorder-7 Questionnaire, McGill Pain Questionnaire, and Numeric Pain Rating Scale. Anxiety (evaluated using the Generalized Anxiety Disorder-7 Questionnaire) and postoperative thoracic pain intensity (evaluated by means of the Numeric Pain Rating Scale, Number of Words Chosen, and McGill Pain Questionnaire) were significantly higher in patients exhibiting social-focused coping than in patients presenting emotion-focused or problem-focused coping as their main coping style (Kruskal–Wallis, p = 0.028, p = 0.022, p = 0.042, p = 0.007). In our study, there were no differences observed in pain intensity relative to level of anxiety. Coping style is an important concept in the management of anxiety and pain experienced by patients undergoing chest surgery. Therefore, a multidisciplinary approach should be considered in clinical practice. Full article

Purpose—Visual complaints are common in trauma cases. However, not every institution provides immediate ophthalmic consultations 24 h per day. Some patients may receive an ophthalmic consultation but without positive findings. We tried to evaluate risk factors for ocular emergencies in trauma patients. Then, the ophthalmologists could be selectively consulted. Methods—From January 2019 to December 2019, head injuries patients concurrent with suspected ocular injuries were retrospectively reviewed. All of the patients received comprehensive ophthalmic examinations by ophthalmologists. Patients with and without ocular injuries were compared. Specific ophthalmic evaluations that could be primarily performed by primary trauma surgeons were also analyzed in detail. Results—One hundred forty cases were studied. Eighty-nine (63.6%) patients had ocular lesions on computed tomography (CT) scans or needed ophthalmic medical/surgical intervention. Near 70% (69.7%, 62/89) of patients with ocular injuries were diagnosed by CT scans. There was a significantly higher proportion of penetrating injuries in patients with ocular injuries than in patients without ocular injuries (22.5% vs. 3.9%, p = 0.004). Among the patients with blunt injuries (N = 118), 69 (58.5%) patients had ocular injuries. These patients had significantly higher proportions of periorbital swelling (89.9% vs. 67.3%, p = 0.002) and diplopia (26.1% vs. 8.2%, p = 0.014) than patients without ocular injuries. Conclusions—In patients with head injuries, concomitant ocular injuries with indications for referral should always be considered. CT serves as a rapid and essential diagnostic tool for the evaluation of concomitant ocular injuries. Ophthalmologists could be selectively consulted for patients with penetrating injuries or specific ocular presentations, thus reducing the burden of ophthalmologists. Full article

MR imaging provides excellent spatial and contrast resolution to stage locally advanced vulvar cancer (LAVC) for tumor and nodal evaluation in order to facilitate the planning of treatment. Although there are no standard indications for how to estimate the clinical stage of International Federation of Gynecology and Obstetrics at diagnosis, MR imaging can depict the tumor and its extension to the vulvar region and adjacent organs, such as the vagina, urethra, and anus. Optimizing the MR imaging protocol and technique is fundamental for correct staging. The aim of this overview was to focus on the role of MR imaging in LAVC staging. We define vulvar anatomy and corresponding MR imaging findings, MR imaging protocol, and technique. Moreover, we describe the MR imaging findings of LAVC with example cases stage by stage. Key imaging findings based on signal intensity, diffusion restriction, and enhancement are portrayed to correctly identify and stage vulvar cancer. A structured report for LAVC staging is reported in order to give all necessary information to the clinicians and to facilitate MR imaging comprehension. Full article

Multiple sclerosis (MS), a neuroinflammatory disorder, occurs as non-progressive or progressive phenotypes; both forms present with diverse symptoms that may reduce quality of life (QoL). Adherence to healthy lifestyle behaviors has been associated with higher QoL in people with MS; whether these associations differ based on MS phenotype is unknown. Cross-sectional self-reported observational data from 1108 iConquerMS participants were analysed. Associations between lifestyle behaviors and QoL were assessed by linear regression, and phenotype differences via moderation analyses. Diet, wellness, and physical activity, but not vitamin D or omega-3 supplement use, were associated with QoL. Specifically, certain diet types were negatively associated with QoL in relapsing-remitting MS (RRMS), and positively associated in progressive MS (ProgMS). Participation in wellness activities had mixed associations with QoL in RRMS but was not associated in ProgMS. Physical activity was positively associated with QoL in RRMS and ProgMS. Phenotype differences were observed in diet and wellness with physical QoL, and physical activity with most QoL subdomains. Our findings show lifestyle behaviors are associated with QoL and appear to differ based on MS phenotype. Future studies assessing timing, duration, and adherence of adopting lifestyle behaviors may better inform their role in MS management. Full article

Familial tooth agenesis (FTA), distinguished by developmental failure of selected teeth, is one of the most prevalent craniofacial anomalies in humans. Mutations in genes involved in WNT/β-catenin signaling, including AXIN2 WNT10A, WNT10B, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(Met168Arg), p.(Ala754Pro), and p.(Asn1075Ser). The three missense mutations were predicted to cause structural destabilization of the LRP6 protein. Two probands carrying both an LRP6 mutant allele and a WNT10A variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic LRP6 mutations in a patient with many missing teeth further supported the dose-dependence of LRP6-associated FTA. Analysis of 21 FTA cases with 15 different LRP6 loss-of-function mutations revealed high heterogeneity of disease severity and a distinctive pattern of missing teeth, with maxillary canines being frequently affected. We hypothesized that various combinations of sequence variants in WNT-related genes can modulate WNT signaling activities during tooth development and cause a wide spectrum of tooth agenesis severity, which highlights the importance of exome/genome analysis for the genetic diagnosis of FTA in this era of precision medicine. Full article

Rationale: The resting-state paradigm is frequently applied in electroencephalography (EEG) research; however, it is associated with the inability to control participants’ thoughts. To quantify subjects’ subjective experiences at rest, the Amsterdam Resting-State Questionnaire (ARSQ) was introduced covering ten dimensions of mind wandering. We aimed to estimate associations between subjective experiences and resting-state microstates of EEG. Methods: 5 min resting-state EEG data of 197 subjects was used to evaluate temporal properties of seven microstate classes. Bayesian correlation approach was implemented to assess associations between ARSQ domains assessed after resting and parameters of microstates. Results: Several associations between Comfort, Self and Somatic Awareness domains and temporal properties of neuroelectric microstates were revealed. The positive correlation between Comfort and duration of microstates E showed the strongest evidence (BF₁₀ > 10); remaining correlations showed substantial evidence (10 > BF₁₀ > 3). Conclusion: Our study indicates the relevance of assessments of spontaneous thought occurring during the resting-state for the understanding of the intrinsic brain activity reflected in microstates. Full article

The association between exposure to general anesthesia (GA) and the risk of dementia is still undetermined. To investigate a possible link to the development of dementia in older people who have undergone GA, we analyzed nationwide representative cohort sample data from the Korean National Health Insurance Service. The study cohort comprised patients over 55 years of age who had undergone GA between January 2003 and December 2004 and consisted of 3100 patients who had undergone GA and 12,400 comparison subjects who had not received anesthesia. After the nine-year follow-up period, we found the overall incidence of dementia was higher in the patients who had undergone GA than in the comparison group (10.5 vs. 8.8 per 1000 person-years), with the risk being greater for women (adjusted HR of 1.44; 95% CI, 1.19–1.75) and those with comorbidities (adjusted HR of 1.39; 95% CI, 1.18–1.64). Patients who underwent GA showed higher risks for Alzheimer’s disease and vascular dementia (adjusted HR of 1.52; 95% CI, 1.27–1.82 and 1.64; 95% CI, 1.15–2.33, respectively). This longitudinal study using a sample cohort based on a nationwide population sample demonstrated a significant positive association between GA and dementia, including Alzheimer’s disease and vascular dementia. Full article

Background: Bladder cancer is one of the most common malignancies. Its diagnosis is based on transurethral cystoscopy. Virtual reality (VR) is a three-dimensional world generated through the projection of images, the emission of sounds and other stimuli. VR has been proven to be a very effective “distractor” and, thus, a useful tool in managing pain. The aim of this study was to determine whether the use of VR sets is technically feasible during the cystoscopy and whether the use of VR devices would reduce the degree of ailments associated with the procedure; Methods: The study prospectively included both men and women who qualified for rigid cystoscopy due to both primary and follow-up diagnostics. The study group underwent rigid cystoscopy with the VR set and the control group underwent the procedure without the VR set. Patients enrolled in both groups were subjected to blood pressure, heart rate and saturation measurements before, during and after the procedure. Additionally, the patients were asked to describe the severity of fear, pain sensations and nausea associated with the procedure. Non-verbal pain manifestations were assessed using the adult adjusted Faces, Legs, Activity, Cry and Consolability (FLACC) scale; Results: The study population included 103 patients (74M/29F; mean age 64.4 years). Pain intensity differed significantly between the groups, reaching lower values in the VR group. In all analyzed subgroups the use of the VR set was associated with higher levels of nausea. The mean FLACC score reached higher values for patients without the VR set. Blood pressure as well as heart rate increased during the procedure and decreased afterwards. The increase in systolic blood pressure and pulse rate was statistically higher in the control group; Conclusions: This study confirmed that cystoscopy is associated with considerable preprocedural fear and severe pain. Blood pressure and heart rate rise significantly during the cystoscopy. VR sets can lower pain perception during cystoscopy, but they may cause moderate nausea. Full article

Primary malignancies in adult brains are globally fatal. Computer vision, especially recent developments in artificial intelligence (AI), have created opportunities to automatically characterize and diagnose tumor lesions in the brain. AI approaches have provided scores of unprecedented accuracy in different image analysis tasks, including differentiating tumor-containing brains from healthy brains. AI models, however, perform as a black box, concealing the rational interpretations that are an essential step towards translating AI imaging tools into clinical routine. An explainable AI approach aims to visualize the high-level features of trained models or integrate into the training process. This study aims to evaluate the performance of selected deep-learning algorithms on localizing tumor lesions and distinguishing the lesion from healthy regions in magnetic resonance imaging contrasts. Despite a significant correlation between classification and lesion localization accuracy (R = 0.46, p = 0.005), the known AI algorithms, examined in this study, classify some tumor brains based on other non-relevant features. The results suggest that explainable AI approaches can develop an intuition for model interpretability and may play an important role in the performance evaluation of deep learning models. Developing explainable AI approaches will be an essential tool to improve human–machine interactions and assist in the selection of optimal training methods. Full article

Studies showed that the gastrointestinal (GI) tract is one of the most important pathways for SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19). As SARS-CoV-2 cellular entry depends on the ACE2 receptor and TMPRSS2 priming of the spike protein, it is important to understand the molecular mechanisms through which these two proteins and their cognate transcripts interact and influence the pathogenesis of COVID-19. In this study, we quantified the expression, associations, genetic modulators, and molecular pathways for Tmprss2 and Ace2 mRNA expressions in GI tissues using a systems genetics approach and the expanded family of highly diverse BXD mouse strains. The results showed that both Tmprss2 and Ace2 are highly expressed in GI tissues with significant covariation. We identified a significant expression quantitative trait locus on chromosome 7 that controls the expression of both Tmprss2 and Ace2. Dhx32 was found to be the strongest candidate in this interval. Co-expression network analysis demonstrated that both Tmprss2 and Ace2 were located at the same module that is significantly associated with other GI-related traits. Protein–protein interaction analysis indicated that hub genes in this module are linked to circadian rhythms. Collectively, our data suggested that genes with circadian rhythms of expression may have an impact on COVID-19 disease, with implications related to the timing and treatment of COVID-19. Full article

Trop-2 is an ideal candidate for targeted therapeutics because it is a transmembrane protein with an extracellular domain overexpressed in a wide variety of tumors, and is upregulated in normal cells. Consequently, several Trop-2-targeted drugs have recently been developed for clinical use, such as anti-Trop-2 antibodies. Sacituzumab govitecan, a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, was recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer. In Italy, this treatment cannot be used in clinical practice because it has not yet been approved by the Agenzia Italiana del Farmaco (AIFA, Rome, Italy). In Italy, this is not a new problem, in fact, when a new compound is approved by the U.S. and Europe, there is often a delay in its approval for use. The adoption of universal guidelines and the standardization of Trop-2 evaluation is urgently needed. Full article

Numerous Virtual Reality (VR) systems address post-stroke functional recovery of the lower extremity (LE), most of them with low early applicability due to the gait autonomy they require. The aim of the present study was to evaluate the feasibility of a specific VR treatment and its clinical effect on LE functionality, gait, balance, and trunk control post-stroke. A controlled, prospective, clinical trial was carried out with 20 stroke patients, who were divided into two groups: the first group (VR + CP; n = 10) received combined therapy of 1 h VR and 1 h of conventional physiotherapy (CP) and the second group (CP; n = 10) received 2 h of CP (5 days/week, for 3 weeks). The following pre-post-intervention measuring scales were used: Functional Ambulatory Scale (FAC), Functional Independence Measure (FIM), Fugl-Meyer Assessment (FM), Berg Balance Scale (BBS), and Trunk Control Test (TCT). Only VR + CP showed a significant improvement in FAC. In FIM, CP presented a tendency to significance, whereas VR + CP showed significance. Both groups improved significantly in FM (especially in amplitude/pain in VR + CP and in sensitivity in CP) and in BBS. In TCT, there was a non-significant improvement in both groups. The results indicate that the intervention with VR is a feasible treatment in the post-stroke functional re-education of the LE, with the potential to be an optimal complement of CP. Full article