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.

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.

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.

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.

COVID-19 screening during fertility treatment: how do guidelines compare against each other?

Various fertility scientific societies have published pathways and recommendations for COVID-19 screening during fertility treatments. As there is currently very limited research evidence on how to best deliver this screening, it is not surprising that there are noticeable differences between their recommendations. This paper compares the screening pathways recommended by these guidelines, in the light of the emerging evidence. It proposes the more liberal use of viral testing for improving detection of asymptomatic or mildly symptomatic fertility patients. It also argues that a negative test result on symptomatic individuals should not be over-relied upon for allowing the treatment to proceed. In these cases, a low threshold for cancellation may still need to be maintained.

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.

Adapting in the COVID-19 Era.

How to cite this article: Papathanakos G, Andrianopoulos I, Papathanasiou A, Lepida D, Koulouras V. Adapting in the COVID-19 Era. Indian J Crit Care Med 2020;24(12):1286-1287.

How to Achieve Reversible Electrowetting on Superhydrophobic Surfaces.

Collapse (Cassie to Wenzel) wetting transitions impede the electrostatically induced reversible modification of wettability on superhydrophobic surfaces, unless a strong external actuation (e.g., substrate heating) is applied. Here we show that collapse transitions can be prevented (the droplet remains suspended on the solid roughness protrusions) when the electrostatic force, responsible for the wetting modification, is smoothly distributed along the droplet surface. The above argument is initially established theoretically and then verified experimentally.

Combination of solifenacin with tamsulosin reduces prostate volume and vascularity as opposed to tamsulosin monotherapy in patients with benign prostate enlargement and overactive bladder symptoms: Results from a randomized pilot study.

OBJECTIVES: To identify the potential influence of antimuscarinics on morphometric parameters of the prostate in patients with benign prostatic enlargement and overactive bladder. METHODS: Non-neurological patients with prostate volume >30 mL, predominately storage lower urinary tract symptoms, three or more urgency episodes per 24 h, maximum flow rate ≥10 mL/s and post-void residual ≤100 mL were recruited for this study. They were randomized to receive either tamsulosin or tamsulosin + solifenacin. Patients were submitted to transrectal and transvesical ultrasonography, pressure-flow study and prostate-specific antigen test, and completed the International Prostate Symptom Score, bladder diary and overactive bladder questionnaire at induction and at 6 months. End-study changes in morphometric prostate parameters (total prostate and adenoma volumes, prostate vascularity), as measured by transrectal ultrasound, were the principal outcomes. RESULTS: A reduction in total prostate volume (mean -9.5%) was noted in the combination group, as opposed to an increase in the monotherapy group (+9.2%; P < 0.001). Similar changes were reflected in adenoma volume (monotherapy +17.4% vs combination -12.5%, P = 0.001) and in prostate vascularity (monotherapy +149.3% vs combination -19.8%, P = 0.001). Both treatment regimens improved the International Prostate Symptom Score (P = 0.001); monotherapy improved the voiding subscale (P = 0.01) more, whereas combination therapy improved the storage subscale (P = 0.024). Cystometric capacity improved in the combination group (P < 0.001). Post-void residual was increased in the combination group (+34.79%), as opposed to a decrease in the monotherapy group (-17.05%; P = 0.001). CONCLUSIONS: The results of this pilot study suggest that solifenacin might affect morphometric properties of the prostate, decreasing total prostate and adenoma volume, as well as vascularity. A molecular effect of antimuscarinics on the prostate, in parallel with their expected bladder effect, warrants further investigation.

Thermocapillary Droplet Actuation: Effect of Solid Structure and Wettability.

We examine the thermocapillary-driven flow of a droplet on a nonuniformly heated patterned surface. Using a sharp-interface scheme, capable of efficiently modeling the flow over complex surfaces, we perform 2D and 3D finite element simulations for a wide range of substrate wettabilities, i.e., from hydrophilic to superhydrophobic surfaces. Our results demonstrate that the contact angle hysteresis, due to the presence of the solid structures, is responsible for the appearance of a critical thermal gradient beyond which droplet migration is possible; the latter has been reported by experimental observations. The migration velocity as well as the direction of motion strongly depend on the combined action of the net mechanical force along the contact line and the thermocapillary induced flow at the liquid-air interface. We also show that through proper control and design of the substrate wettability, contact angle hysteresis, and induced flow field it is possible to manipulate the droplet dynamics: in particular, controlling its motion along a predefined track or entrapping by a wetting defect a droplet based on its size, as well as providing appropriate conditions for enhanced mixing inside the droplet.

Reversible cerebral vasoconstriction syndrome as a cause of thunderclap headache: a retrospective case series study.

Thunderclap headache is a common emergency department presentation. Although subarachnoid hemorrhage (SAH) should be the first diagnosis to exclude, reversible cerebral vasoconstriction syndrome (RCVS) is an important alternative cause, which may be commoner than appreciated. Reversible cerebral vasoconstriction syndrome is characterized by multifocal narrowing of cerebral arteries, typically manifested by acute, severe headache with or without neurologic deficits. To compare and discuss the clinical and radiologic characteristics of patients with RCVS. We report 4 cases of RCVS, presenting at a single unit in 1 year. All presented with thunderclap headache, whereas half of them had additional neurologic symptoms such as right homonymous hemianopia, right-sided weakness, and slurred speech. Brain computed tomography was normal in 2 of our patients, but subsequent cerebrospinal fluid analysis revealed xanthochromia consistent with SAH. The remaining 2 patients demonstrated intracerebral hemorrhage on computed tomography. All of our patients underwent digital subtraction angiography that showed segmental narrowing and dilatation of one or more cerebral arteries without any signs of aneurysm. Repeat digital subtraction angiography after 3 months was entirely normal prompting the diagnosis of RCVS. Thunderclap headache requires urgent workup to identify the underlying cause. Although SAH is the most important diagnosis to exclude in the first instance, emergency physicians should be aware of other causes and how they present, such as RCVS. Early recognition of this condition is important in order to remove precipitants, avoid unnecessary investigations, and inform patients about their prognosis.

NMR-based lipidomic analysis of blood lipoproteins differentiates the progression of coronary heart disease.

Abnormal lipid composition and metabolism of plasma lipoproteins play a crucial role in the pathogenesis of coronary heart disease (CHD). A (1)H NMR-based lipidomic approach was used to investigate the correlation of coronary artery stenosis with the atherogenic (non-HDL) and atheroprotective (HDL) lipid profiles in 99 patients with CHD of various stages of disease and compared with 60 patients with normal coronary arteries (NCA), all documented in coronary angiography. The pattern recognition models created from lipid profiles predicted the presence of CHD with a sensitivity of 87% and a specificity of 88% in the HDL model and with 90% and 89% in the non-HDL model, respectively. Patients with mild, moderate, and severe coronary artery stenosis were progressively differentiated from those with NCA in the non-HDL model with a statistically significant separation of severe stage from both mild and moderate. In the HDL model, the progressive differentiation of the disease stages was statistically significant only between patients with mild and severe coronary artery stenosis. The lipid constituents of lipoproteins that mainly characterized the initial stages and then the progression of the disease were the high levels of saturated fatty acids in lipids in both HDL and non-HDL particles, the low levels of HDL-phosphatidylcholine, HDL-sphingomyelin, and omega-3 fatty acids and linoleic acid in lipids in non-HDL particles. The conventional lipid marker, total cholesterol, found in low levels in HDL and in high levels in non-HDL, also contributed to the onset of the disease but with a much lower coefficient of significance. (1)H NMR-based lipidomic analysis of atherogenic and atheroprotective lipoproteins could contribute to the early evaluation of the onset of coronary artery disease and possibly to the establishment of an appropriate therapeutic option.

Implementing the ESHRE 'poor responder' criteria in research studies: methodological implications.

The Bologna criteria for defining poor ovarian response (POR) during IVF provide a useful template for new research in this field of assisted conception. However, designing studies around the European Society for Human Reproduction and Embryology POR criteria can be methodologically challenging, as the new definition includes various POR subpopulations with diverse baseline characteristics and unknown clinical prognosis. When designing RCTs, potential result bias may be introduced if women from each subpopulation are not evenly allocated between intervention groups. In the case of small or moderate-size RCTs, a single-sequence randomization method may not ensure balanced allocation between groups. Stratified randomization methods provide an alternative methodological approach. Depending on the chosen methodology, patient characteristics and outcomes within each intervention group may be better reported according to relevant subpopulations.

Neither Lippmann nor Young: enabling electrowetting modeling on structured dielectric surfaces.

Aiming to illuminate mechanisms of wetting transitions on geometrically patterned surfaces induced by the electrowetting phenomenon, we present a novel modeling approach that goes beyond the limitations of the Lippmann equation and is even relieved from the implementation of the Young contact angle boundary condition. We employ the equations of the capillary electrohydrostatics augmented by a disjoining pressure term derived from an effective interface potential accounting for solid/liquid interactions. Proper parametrization of the liquid surface profile enables efficient simulation of multiple and reconfigurable three-phase contact lines (TPL) appearing when entire droplets undergo wetting transitions on patterned surfaces. The liquid/ambient and the liquid/solid interfaces are treated in a unified context tackling the assumption that the liquid profile is wedge-shaped at any three-phase contact line. In this way, electric field singularities are bypassed, allowing for accurate electric field and liquid surface profile computation, especially in the vicinity of TPLs. We found that the invariance of the microscopic contact angle in electrowetting systems is valid only for thick dielectrics, supporting published experiments. By applying our methodology to patterned dielectrics, we computed all admissible droplet equilibrium profiles, including Cassie-Baxter, Wenzel, and mixed wetting states. Mixed wetting states are computed for the first time in electrowetting systems, and their relative stability is presented in a clear and instructive way.

Pre-thymectomy disease severity predicts outcome in acetylcholine receptor antibody-positive generalised myasthenia gravis.

INTRODUCTION: There are only a few studies exploring post-thymectomy outcome in patients with acetylcholine receptor antibody (AChR-Ab)-positive generalised myasthenia gravis (MG). OBJECTIVE: To assess the predictors of outcome in patients with AChR-Ab-positive generalised MG who underwent thymectomy. METHODS: A retrospective study of 53 patients from a single neuroscience centre in the UK. RESULTS: The mean disease duration from diagnosis was 6.2 ± 4.3 years. Pre-thymectomy, 37 patients had mild weakness affecting muscles other than ocular muscles, 11 patients had moderate weakness and 5 patients had severe weakness. 27/53 patients had thymoma. Post-thymectomy (mean duration of 5.7 ± 4.2 years), 34 patients (64%) had a good outcome characterised by Myasthenia Gravis Foundation of America Post-Intervention Status of complete stable remission (no symptoms or signs of MG for at least 1 year without any therapy) or pharmacological remission (no symptoms or signs of MG with some form of therapy) or minimal manifestations (no symptoms of functional limitations from MG but weakness on examination of some muscles with or without some form of therapy) on last follow-up visit. Having thymomatous or non-thymomatous MG did not predict the outcome. The only variable that did predict outcome was pre-thymectomy disease severity; patients with mild weakness before thymectomy had a favourable outcome. We found an accuracy of 83% predicting outcome (95% confidence interval (CI) 60%, 100%) with a sensitivity of 84% (95% CI 68%, 94%) and specificity of 81% (95% CI 54%, 96%). CONCLUSION: Disease severity before thymectomy predicts outcome in patients with AChR-Ab-positive generalised MG.

Genetic Testing of Breast Cancer Patients with Very Early-Onset Breast Cancer (≤30 Years) Yields a High Rate of Germline Pathogenic Variants, Mainly in the BRCA1, TP53, and BRCA2 Genes.

Early-onset breast cancer constitutes a major criterion for genetic testing referral. Nevertheless, studies focusing on breast cancer patients (≤30 years) are limited. We investigated the contribution and spectrum of known breast-cancer-associated genes in 267 Greek women with breast cancer ≤30 years while monitoring their clinicopathological characteristics and outcomes. In this cohort, a significant proportion (39.7%) carried germline pathogenic variants (PVs) distributed in 8 genes. The majority, namely 36.7%, involved BRCA1, TP53, and BRCA2. PVs in BRCA1 were the most prevalent (28.1%), followed by TP53 (4.5%) and BRCA2 (4.1%) PVs. The contribution of PVs in CHEK2, ATM, PALB2, PTEN, and RAD51C was limited to 3%. In the patient group ≤26 years, TP53 PVs were significantly higher compared to the group 26-30 years (p = 0.0023). A total of 74.8% of TP53 carriers did not report a family history of cancer. Carriers of PVs receiving neoadjuvant chemotherapy showed an improved event-free survival (p < 0.0001) compared to non-carriers. Overall, many women with early-onset breast cancer carry clinically actionable variants, mainly in the BRCA1/2 and TP53 genes. The inclusion of timely testing of TP53 in these patients provides essential information for appropriate clinical management. This is important for countries where reimbursement involves the cost of genetic analysis of BRCA1/2 only.

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.

Intensive Care Unit Mortality Trends during the First Two Years of the COVID-19 Pandemic in Greece: A Multi-Center Retrospective Study.

Data on COVID-19 mortality among patients in intensive care units (ICUs) from Eastern and/or Southern European countries, including Greece, are limited. The purpose of this study was to evaluate the ICU mortality trends among critically ill COVID-19 patients during the first two years of the pandemic in Greece and to further investigate if certain patients' clinical characteristics contributed to this outcome. We conducted a multi-center retrospective observational study among five large university hospitals in Greece, between February 2020 and January 2022. All adult critically ill patients with confirmed COVID-19 disease who required ICU admission for at least 24 h were eligible. In total, 1462 patients (66.35% males) were included in this study. The mean age of this cohort was 64.9 (±13.27) years old. The 28-day mortality rate was 35.99% (n = 528), while the overall in-hospital mortality was 50.96% (n = 745). Cox regression analysis demonstrated that older age (≥65 years old), a body mass index within the normal range, and a delay in ICU admission from symptom onset, as well as worse baseline clinical severity scores upon ICU admission, were associated with a greater risk of death. Mortality of critically ill COVID-19 patients was high during the first two years of the pandemic in Greece but comparable to other countries. Risk factors for death presented in this study are not different from those that have already been described for COVID-19 in other studies.