Co-Administration of High-Dose Nebulized Colistin for Acinetobacter baumannii Bacteremic Ventilator-Associated Pneumonia: Impact on Outcomes.

Acinetobacter baumannii (A. baumannii) is a difficult-to-treat (DTR) pathogen that causes ventilator-associated pneumonia (VAP) associated with high mortality. To improve the outcome of DTR A. Baumannii VAP, nebulized colistin (NC) was introduced with promising but conflicting results on mortality in earlier studies. Currently, NC is used at a much higher daily dose compared to the past. Nevertheless, there is little evidence on the effect of high-dose NC on the outcomes of A. baumannii VAPs, especially in the current era where the percentage of colistin-resistant A. baumannii strains is rising. We conducted a retrospective study comparing bacteremic A. baumannii VAP patients who were treated with and without NC co-administration and were admitted in the Intensive Care Unit of University Hospital of Ioannina from March 2020 to August 2023. Overall, 59 patients (21 and 38 with and without NC coadministration, respectively) were included. Both 28-day and 7-day mortalities were significantly lower in the patient group treated with NC (52.4% vs. 78.9%, p 0.034 and 9.5% vs. 47.4%, p 0.003, respectively). Patients treated with NC had a higher percentage of sepsis resolution by day 7 (38.1% vs. 13.5%, p 0.023) and were more likely to be off vasopressors by day 7 (28.6% vs. 8.1%, p 0.039). The addition of NC in the treatment regime of A. baumannii VAP decreased mortality.

Simulation of Electrowetting-Induced Droplet Detachment: A Study of Droplet Oscillations on Solid Surfaces.

The electrowetting-induced detachment of droplets from solid surfaces is important for numerous applications in the fields of heat transfer and fluid mechanics. The forced oscillations of droplets on solid surfaces and their ability to detach are studied. In this study, the process is efficiently simulated by implementing a powerful methodology developed by our team. Our results agree with experiments showing that optimal detachment, in terms of actuation energy, is achieved when the application of voltage is synchronized with the spreading time of the droplet. Under these conditions, the droplet oscillates with a period close to that of a mirrored Rayleigh droplet. The relationship between the droplet's oscillation period and its physical properties is examined. During voltage-droplet synchronization, the droplet's ability to detach depends mostly on its contact angle, its viscosity, and the applied voltage. An energy analysis is also conducted, revealing how energy is supplied to the droplet by electrowetting-induced detachment.

Only 32.3% of Breast Cancer Families with Pathogenic Variants in Cancer Genes Utilized Cascade Genetic Testing.

BACKGROUND: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. METHODS: Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. RESULTS: In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. CONCLUSIONS: Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results.

Clinical Sepsis Phenotypes in Critically Ill Patients.

Sepsis, defined as the life-threatening dysregulated host response to an infection leading to organ dysfunction, is considered as one of the leading causes of mortality worldwide, especially in intensive care units (ICU). Moreover, sepsis remains an enigmatic clinical syndrome, with complex pathophysiology incompletely understood and a great heterogeneity both in terms of clinical expression, patient response to currently available therapeutic interventions and outcomes. This heterogeneity proves to be a major obstacle in our quest to deliver improved treatment in septic critical care patients; thus, identification of clinical phenotypes is absolutely necessary. Although this might be seen as an extremely difficult task, nowadays, artificial intelligence and machine learning techniques can be recruited to quantify similarities between individuals within sepsis population and differentiate them into distinct phenotypes regarding not only temperature, hemodynamics or type of organ dysfunction, but also fluid status/responsiveness, trajectories in ICU and outcome. Hopefully, we will eventually manage to determine both the subgroup of septic patients that will benefit from a therapeutic intervention and the correct timing of applying the intervention during the disease process.

Susac syndrome: neurological update (clinical features, long-term observational follow-up and management of sixteen patients).

Susac syndrome is a likely autoimmune microangiopathy affecting the brain, retina and inner ear. Due to the rarity of this condition, diagnosis and treatment can be challenging. Diagnosis is based on the presence of the clinical triad of central nervous system dysfunction, branch retinal artery occlusions and sensorineural hearing loss. Typical MRI findings of callosal and peri-callosal lesions may assist in diagnosis. Clinical course can be monophasic, polycyclic or chronic continuous. It is important to look out for red flags to attain an accurate diagnosis and follow a therapeutic algorithm based on severity of the disease and response to treatment. Patients are treated with steroids and immunosuppressive agents with a variable response. Early aggressive treatment especially in severe cases, may help in preventing relapses and morbidity/disability. This study highlights important diagnostic features and proposes a treatment algorithm based on clinical experience from management of 16 patients from 2 neuroscience centres in the UK since 2007, who were followed up over a long period of 3-15 years.

Acinetobacter baumannii Bloodstream Infections in the COVID-19 Era: A Comparative Analysis between COVID-19 and Non-COVID-19 Critically Ill Patients.

The coronavirus disease (COVID-19) pandemic increased the incidence of severe infections caused by multidrug-resistant (MDR) pathogens among critically ill patients, such as Acinetobacter baumannii (AB), whose bloodstream infections (BSIs) have been associated with significant mortality. Whether there is any difference in outcome between COVID-19 and non-COVID-19 patients with AB BSI still remains unknown. We conducted a retrospective study comparing clinical characteristics and outcomes of COVID-19 versus non-COVID-19 critically ill patients with AB BSI. Overall, 133 patients with AB BSI (102 COVID-19, 31 non-COVID-19) were studied. The 28-day mortality rate was high and did not differ significantly (69.6% COVID-19 vs. 61.3% non-COVID-19, p = 0.275). Patients with septic shock had a higher mortality rate irrespective of their status with the majority of deaths occurring during the first 7 days. COVID-19 patients were more likely to have ventilator-associated pneumonia (VAP) as the source of BSI (55.8% vs. 22.3%, respectively, p = 0.0001) and were more likely to develop acute respiratory distress syndrome (ARDS) (78.4% vs. 48.4%, respectively, p = 0.001), sepsis (86.3% vs. 67.7%, respectively, p = 0.03), and septic shock (88.3% vs. 58.1%, respectively, p = 0.007) compared to the non-COVID-19 patient group. In conclusion, COVID-19 patients with A. baumannii BSI have a high rate of mortality and more often develop septic shock, while VAP is the main origin of their BSI.

Application of next generation sequencing in cardiology: current and future precision medicine implications.

Inherited cardiovascular diseases are highly heterogeneous conditions with multiple genetic loci involved. The application of advanced molecular tools, such as Next Generation Sequencing, has facilitated the genetic analysis of these disorders. Accurate analysis and variant identification are required to maximize the quality of the sequencing data. Therefore, the application of NGS for clinical purposes should be limited to laboratories with a high level of technological expertise and resources. In addition, appropriate gene selection and variant interpretation can result in the highest possible diagnostic yield. Implementation of genetics in cardiology is imperative for the accurate diagnosis, prognosis and management of several inherited disorders and could eventually lead to the realization of precision medicine in this field. However, genetic testing should also be accompanied by an appropriate genetic counseling procedure that clarifies the significance of the genetic analysis results for the proband and his family. In this regard, a multidisciplinary collaboration among physicians, geneticists, and bioinformaticians is imperative. In the present review, we address the current state of knowledge regarding genetic analysis strategies employed in the field of cardiogenetics. Variant interpretation and reporting guidelines are explored. Additionally, gene selection procedures are accessed, with a particular emphasis on information concerning gene-disease associations collected from international alliances such as the Gene Curation Coalition (GenCC). In this context, a novel approach to gene categorization is proposed. Moreover, a sub-analysis is conducted on the 1,502,769 variation records with submitted interpretations in the Clinical Variation (ClinVar) database, focusing on cardiology-related genes. Finally, the most recent information on genetic analysis's clinical utility is reviewed.

Real-world annualized relapse rates from contemporary multiple sclerosis clinics in the UK: a retrospective multicentre cohort study.

BACKGROUND: Annualized relapse rate (ARR) is used as an outcome measure in multiple sclerosis (MS) clinical trials. Previous studies demonstrated that ARR has reduced in placebo groups between 1990 and 2012. This study aimed to estimate real-world ARRs from contemporary MS clinics in the UK, in order to improve the feasibility estimations for clinical trials and facilitate MS service planning. METHODS: A multicentre observational, retrospective study of patients with MS from 5 tertiary neuroscience centres in the UK. We included all adult patients with a diagnosis of MS that had a relapse between 01/04/2020 and 30/06/2020. RESULTS: One hundred thirteen out of 8783 patients had a relapse during the 3-month study period. Seventy-nine percent of the patients with a relapse were female, the mean age was 39 years, and the median disease duration was 4.5 years; 36% of the patients that had a relapse were on disease-modifying treatment. The ARR from all study sites was estimated at 0.05. The ARR for relapsing remitting MS (RRMS) was estimated at 0.08, while the ARR for secondary progressive MS (SPMS) was 0.01. CONCLUSIONS: We report a lower ARR compared to previously reported rates in MS.

An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. AREAS COVERED: Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. EXPERT OPINION: S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.

Molecular profile and clinical features of patients with gliomas using a broad targeted next generation-sequencing panel.

Gliomas are the most common malignant primary brain tumors characterized by poor prognosis. The genotyping of tumors using next generation sequencing (NGS) platforms enables the identification of genetic alterations that constitute diagnostic, prognostic and predictive biomarkers. The present study investigated the molecular profile of 32 tumor samples from 32 patients with high-grade gliomas by implementing a broad 80-gene targeted NGS panel while reporting their clinicopathological characteristics and outcomes. Subsequently, 14 of 32 tumor specimens were also genotyped using a 55-gene NGS panel to validate the diagnostic accuracy and clinical utility of the extended panel. The median follow-up was 19.2 months. In total, 129 genetic alterations including 33 structural variants were identified in 38 distinct genes. Among 96 variants (single nucleotide variants and insertions and deletions), 38 were pathogenic and 58 variants of unknown clinical significance. TP53 was the most frequently mutated gene, followed by PTEN and IDH1 genes. Glioma patients with IDH1 mutant tumors were younger and had significantly longer overall survival compared to patients with wild-type IDH1 tumors. Similarly, tumors with TP53 mutations were more likely observed in younger patients with glioma. Subsequently, a comparison of mutational profiles of samples analyzed by both panels was also performed. Implementation of the comprehensive pan-cancer and the MOL panels resulted in the identification of 37 and 15 variants, respectively. Of those, 13 were common. Comprehensive pan-cancer panel identified 24 additional variants, 22 of which were located in regions that were not targeted by the MOL panel. By contrast, the MOL panel identified two additional variants. Overall, the present study demonstrated that using an extended tumor profile assay instead of a glioma-specific tumor profile panel identified additional genetic changes that may be taken into consideration as potential therapeutic targets for glioma diagnosis and molecular classification.

MARGINAL: An Automatic Classification of Variants in BRCA1 and BRCA2 Genes Using a Machine Learning Model.

Implementation of next-generation sequencing (NGS) for the genetic analysis of hereditary diseases has resulted in a vast number of genetic variants identified daily, leading to inadequate variant interpretation and, consequently, a lack of useful clinical information for treatment decisions. Herein, we present MARGINAL 1.0.0, a machine learning (ML)-based software for the interpretation of rare BRCA1 and BRCA2 germline variants. MARGINAL software classifies variants into three categories, namely, (likely) pathogenic, of uncertain significance and (likely) benign, implementing the criteria established by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP). We first annotated BRCA1 and BRCA2 variants using various sources. Then, we automatically implemented the ACMG-AMP criteria, and we finally constructed the ML model for variant classification. To maximize accuracy, we compared the performance of eight different ML algorithms in a classification scheme based on a serial combination of two classifiers. The model showed high predictive abilities with maximum accuracy of 92% and 98%, recall of 92% and 98% and specificity of 90% and 98% for the first and second classifiers, respectively. Our results indicate that using a gene and disease-specific ML automated software for clinical variant evaluation can minimize conflicting interpretations.

Age at onset predicts outcome in aquaporin-4-IgG positive neuromyelitis optica spectrum disorder from a United Kingdom population.

BACKGROUND: There are few studies exploring the prognostic factors in patients with aquaporin-4 (AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: To assess the predictors of outcome in patients with AQP4-antibody positive NMOSD from a United Kingdom (UK) population. METHODS: A retrospective study of 52 patients from 2 neuroscience centres in the UK Midlands. RESULTS: The most common initial presentations were acute myelitis and optic neuritis, with 22/52 cases (42.3%) each. Relapsing course was seen in 32 patients (61.5%) with mean annualised relapse rate of 0.43 (standard deviation 0.45) and a mean interval time to first relapse of 31 months (range 2-108). The median Expanded Disability Status Scale (EDSS) score at the last follow up was 4 (range 1-9). Age at onset was an independent predictor of disability in the whole cohort of patients with NMOSD. For every 10-year increase in age at disease onset, the risk of developing an EDSS score of ≥4 increased by 34%. Patients who presented initially with a longitudinally extensive transverse myelitis (LETM) showed a higher risk to develop disability, compared to other clinical presentations (median time of 4 years versus 13 years). Late onset (LO-NMOSD) patients were likely to reach an EDSS score of 4 more quickly, compared to early onset (EO-NMOSD) (median time of 7 years versus 13 years). Higher median EDSS score at last follow up was observed in LO-NMOSD compared to EO-NMOSD (6 versus 2). CONCLUSION: Increasing age at onset and LETM predict disability in AQP-4-IgG positive NMOSD patients.

CanVaS: Documenting the genetic variation spectrum of Greek cancer patients.

National genetic variation registries vastly increase the level of detail for the relevant population, while directly affecting patient management. Herein, we report CanVaS, a Cancer Variation reSource aiming to document the genetic variation of cancer patients in Greece. CanVaS comprises germline genetic data from 7,363 Greek individuals with a personal and/or family history of malignancy. The data set incorporates approximately 24,000 functionally annotated rare variants in 97 established or suspected cancer susceptibility genes. For each variant, allele frequency for the Greek population, interpretation for clinical significance, anonymized family and segregation information, as well as phenotypic traits of the carriers, are included. Moreover, information on the geographic distribution of the variants across the country is provided, enabling the study of Greek population isolates. Direct comparisons between Greek (sub)populations with relevant genetic resources are supported, allowing fine-grain localized adjustment of guidelines and clinical decision-making. Most importantly, anonymized data are available for download, while the Leiden Open Variation Database schema is adopted, enabling integration/interconnection with central resources. CanVaS could become a stepping-stone for a countrywide effort to characterize the cancer genetic variation landscape, concurrently supporting national and international cancer research. The database can be accessed at: http://ithaka.rrp.demokritos.gr/CanVaS.

Modelling of Electrowetting-Induced Droplet Detachment and Jumping over Topographically Micro-Structured Surfaces.

Detachment and jumping of liquid droplets over solid surfaces under electrowetting actuation are of fundamental interest in many microfluidic and heat transfer applications. In this study we demonstrate the potential capabilities of our continuum-level, sharp-interface modelling approach, which overcomes some important limitations of convectional hydrodynamic models, when simulating droplet detachment and jumping dynamics over flat and micro-structured surfaces. Preliminary calculations reveal a considerable connection between substrate micro-topography and energy efficiency of the process. The latter results could be extended to the optimal design of micro-structured solid surfaces for electrowetting-induced droplet removal in ambient conditions.

Impact of substrate elasticity on contact angle saturation in electrowetting.

The electrostatically assisted wettability enhancement of dielectric solid surfaces, commonly termed as electrowetting-on-dielectric (EWOD), facilitates many microfluidic applications due to simplicity and energy efficiency. The application of a voltage difference between a conductive droplet and an insulated electrode substrate, where the droplet sits, is enough for realizing a considerable contact angle change. The contact angle modification is fast and almost reversible; however it is limited by the well-known saturation phenomenon which sets in at sufficiently high voltages. In this work, we experimentally show and computationally support the effect of elasticity and thickness of the dielectric on the onset of contact angle saturation. We found that the effect of elasticity is important especially for dielectric thickness smaller than 10 µm and becomes negligible for thickness above 20 µm. We attribute our findings on the effect of the dielectric thickness on the electric field, as well as on the induced electric stresses distribution, in the vicinity of the three phase contact line. Electric field and electric stresses distribution are numerically computed and support our findings which are of significant importance for the design of soft materials based microfluidic devices.

The risk of poor ovarian response during repeat IVF.

RESEARCH QUESTION: What are the incidence and risk factors for poor ovarian response (POR) during repeat IVF? DESIGN: A retrospective analysis of 1224 consecutive patients who underwent at least two IVF stimulations in a single centre over a 6-year period. Risk factors from the initial treatment were assessed for association with POR during repeat IVF using logistic regression analysis. A simple, practical predictive model was constructed and evaluated for accuracy and calibration, based on the factors that demonstrated significant association with subsequent POR. POR during repeat IVF was defined as ≤3 retrieved oocytes or cancellation before retrieval following recruitment of ≤3 mature follicles. RESULTS: The risk of POR during repeat IVF was approximately 11.5%. A higher POR risk during repeat IVF is associated with a reduced oocyte yield during the initial treatment (≤3 oocytes: odds ratio [OR] 14, 95% confidence interval [CI] 6.42-30.24; 4-9 oocytes: OR 4.13, 95% CI 2.00-8.54; 10-15 oocytes: OR 1) and low ovarian reserve (anti-Müllerian hormone [AMH] <5.4 pmol/l: OR 3.54, 95% CI 2.24-5.59; AMH 5.4-25 pmol/l: OR 1). Women with low ovarian reserve who experience POR during the initial IVF have the highest risk of suffering POR again during repeat IVF (57% within 1 year). Other groups, such as women with unexpected POR or expected poor responders with suboptimal ovarian response during the initial IVF, are also at risk of exhibiting POR during a subsequent treatment (28% within 1 year). CONCLUSIONS: As there is a clear association between POR and lower live birth rates, this practical model may help manage patients' expectations during repeat IVF treatment.

Detrusor Overactivity May Be a Prognostic Factor for Better Response to Combination Therapy Over Monotherapy in Male Patients With Benign Prostatic Enlargement and Storage Lower Urinary Tract Symptoms.

PURPOSE: Several trials have shown that in men with overactive bladder (OAB) and benign prostate enlargement (BPE), the combination of an α-blocker with an anticholinergic is superior to α-blocker monotherapy. The purpose of this study is to explore whether urodynamic detrusor overactivity (DO) affects clinical outcomes in men with BPE and OAB. METHODS: This is a post hoc analysis of a prospective, randomized trial, designed to evaluate the changes of morphometric parameters of the prostate following monotherapy or combination therapy in men with BPE-OAB. The initial study recruited men aged ≥50 years, with BPE and predominantly storage lower urinary tract symptoms (LUTS). Patients were randomized to receive tamsulosin monotherapy or a combination of tamsulosin and solifenacin for 26 weeks. All participants completed a 3-day bladder diary and the International Prostate Symptom Score (IPSS), and then underwent pressure-flow and ultrasonographic studies. Data were stratified and analysed based on the urodynamic observation of DO at baseline (DO vs. non-DO). The primary endpoint was the mean change in urgency episodes from baseline. Secondary outcomes were the changes in nocturia, total IPSS, and urodynamic parameters. RESULTS: Sixty-nine men were initially randomized, but only 60 men were included in this analysis. Urgency episodes significantly improved in men with DO who received combination therapy compared to the DO monotherapy subgroup (P=0.04) or to the non-DO combination treatment subgroup (P=0.038). Nocturia also improved in the DO combination treatment subgroup as compared to the non-DO combination subgroup (P=0.037). The 24-hour frequency and total IPSS significantly improved from baseline without significant differences among the subgroups. CONCLUSION: The present study suggests that baseline DO could be a prognostic factor for a better response to combination therapy over monotherapy in men with BPE and storage LUTS.

Early Signs of Atherogenic Features in the HDL Lipidomes of Normolipidemic Patients Newly Diagnosed with Type 2 Diabetes.

Cardiovascular disease (CVD) is the major cause of death in patients with type-2 diabetes mellitus (T2DM), although the factors that accelerate atherosclerosis in these patients are poorly understood. The identification of the altered quantity and quality of lipoproteins, closely related to atherogenesis, is limited in routine to a pattern of high triglycerides and low HDL-cholesterol (HDL-C) and in research as dysfunctional HDLs. We used the emerging NMR-based lipidomic technology to investigate compositional features of the HDLs of healthy individuals with normal coronary arteries, drug-naïve; recently diagnosed T2DM patients with normal coronary arteries; and patients with recent acute coronary syndrome. Patients with T2DM and normal serum lipid profiles even at diagnosis presented significant lipid alterations in HDL, characterized by higher triglycerides, lysophosphatidylcholine and saturated fatty acids; and lower cholesterol, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, plasmalogens and polyunsaturated fatty acids, an atherogenic pattern that may be involved in the pathogenesis of atherosclerosis. These changes are qualitatively similar to those found, more profoundly, in normolipidemic patients with established Coronary Heart Disease (CHD). We also conclude that NMR-based lipidomics offer a novel holistic exploratory approach for identifying and quantifying lipid species in biological matrixes in physiological processes and disease states or in disease biomarker discovery.