The reporting completeness and transparency of systematic reviews of prognostic prediction models for COVID-19 was poor: a methodological overview of systematic reviews.

OBJECTIVES: To conduct a methodological overview of reviews to evaluate the reporting completeness and transparency of systematic reviews (SRs) of prognostic prediction models (PPMs) for COVID-19. STUDY DESIGN AND SETTING: MEDLINE, Scopus, Cochrane Database of Systematic Reviews, and Epistemonikos (epistemonikos.org) were searched for SRs of PPMs for COVID-19 until December 31, 2022. The risk of bias in systematic reviews tool was used to assess the risk of bias. The protocol for this overview was uploaded in the Open Science Framework (https://osf.io/7y94c). RESULTS: Ten SRs were retrieved; none of them synthesized the results in a meta-analysis. For most of the studies, there was absence of a predefined protocol and missing information on study selection, data collection process, and reporting of primary studies and models included, while only one SR had its data publicly available. In addition, for the majority of the SRs, the overall risk of bias was judged as being high. The overall corrected covered area was 6.3% showing a small amount of overlapping among the SRs. CONCLUSION: The reporting completeness and transparency of SRs of PPMs for COVID-19 was poor. Guidance is urgently required, with increased awareness and education of minimum reporting standards and quality criteria. Specific focus is needed in predefined protocol, information on study selection and data collection process, and in the reporting of findings to improve the quality of SRs of PPMs for COVID-19.

Exploring the association between sleep insufficiency and self-reported cardiovascular disease among northeastern Greeks.

Objective: To explore the association of sleep characteristics with cardiovascular disease (CVD) using self-reported questionnaires. Material and Methods: 957 adults between 19 and 86 years old were enrolled in this cross-sectional study. The participants were classified into three groups [short (<6h), normal (6-8h), and long (>8h) sleepers] by using multistage stratified cluster sampling. CVD was defined by a positive response to the questions: "Have you been told by a doctor that you have had a heart attack or angina or stroke or have you undergone bypass surgery?". Sleep quality, utilizing Epworth sleepiness scale, Athens insomnia scale, Pittsburgh sleep quality index and Berlin questionnaire, was also examined. Results: Prevalence of CVD was 9.5%. Individuals with CVD exhibited reduced sleep duration by 33 min (p<0.001) and sleep efficiency by 10% (p<0.001). In multivariable logistic regression analysis, adjusting for subjects' sociodemographic, lifestyle habits and health related characteristics, short sleep duration was almost three times more frequent in patients with CVD (aOR=2.86, p<0.001 in the entire sample; aOR=2.68, p=0.019 in women and aOR=2.57, p=0.009 in men). Furthermore, CVD was significantly associated with excessive daytime sleepiness (aOR=2.02, p=0.026), insomnia (aOR=1.93, p=0.010), poor sleep quality (aOR=1.90, p=0.006) and increased risk of obstructive sleep apnea (aOR=2.08, p=0.003). Conclusion: Our study highlights a strong correlation of sleep insufficiency with CVD and promotes early pharmacological or cognitive behavioral interventions in order to protect cardiovascular health.

Pharma 4.0-Artificially Intelligent Digital Twins for Solidified Nanosuspensions.

Digital twins capacitate the industry 4.0 paradigm by predicting and optimizing the performance of physical assets of interest, mirroring a realistic in-silico representation of their functional behaviour. Although advanced digital twins set forth disrupting opportunities by delineating the in-service product and the related process dynamic performance, they have yet to be adopted by the pharma sector. The latter, currently struggles more than ever before to improve solubility of BCS II i.e., hard-to-dissolve active pharmaceutical ingredients by micronization and subsequent stabilization. Herein we construct and functionally validate the first artificially intelligent digital twin thread, capable of describing the course of manufacturing of such solidified nanosuspensions given a defined lifecycle starting point and predict and optimize the relevant process outcomes. To this end, we referenced experimental data as the sampling source, which we then augmented via pattern recognition utilizing neural network propagations. The zeta-dynamic potential metrics of the nanosuspensions were correlated to the interfacial Gibbs energy, while the density and heat capacity of the material system was calculated via the Saft-γ-Mie statistical fluid theory. The curated data was then fused to physical and empirical laws to choose the appropriate theory and numeric description, respectively, before being polished by tuning the critical parameters to achieve the best fit with reality.

Association between sleep insufficiency and dyslipidemia: a cross-sectional study among Greek adults in the primary care setting.

Objective: To investigate the potential association between sleep insufficiency and dyslipidemia (DL) in the primary care setting using self-reported questionnaires. Material and Methods: 957 adults aged between 19 and 86 years old from the rural area of Thrace, Greece were enrolled in this cross-sectional study. Multistage stratifed cluster sampling was used and the subjects were classifed into three groups according to sleep duration [short (<6h), normal (6-8h), and long (>8h) sleep duration]. DL was defined by a positive response to the question "Have you ever been told by a doctor or health professional that your blood cholesterol or triglyceride levels were high?", or if they were currently taking antilipidemic agents. Sleep quality, utilizing Epworth sleepiness scale, Athens insomnia scale, Pittsburgh sleep quality index and Berlin questionnaire, was also examined. Results: DL prevalence was significantly associated with short sleep duration (aOR=2.18, p<0.001) and insomnia (aOR=1.43, p=0.050), while its relation with poor sleep quality (aOR=1.31, p=0.094) and risk for obstructive sleep apnea (aOR=1.32, p=0.097) were of marginal statistical significance. Concerning insomnia subtypes, DL was significantly associated with difficulties maintaining sleep (aOR=2.99, p<0.001) and early morning awakenings (aOR=1.38, p=0.050), but not difficulties initiating sleep (aOR=1.18, p=0.328). Conclusion: This study reveals an association between sleep pathology and DL. Thus, early pharmacological and cognitive or behavioral interventions that improve sleep are deemed necessary in order to decrease DL burden.

Integrating Elastic Tensor and PC-SAFT Modeling with Systems-Based Pharma 4.0 Simulation, to Predict Process Operations and Product Specifications of Ternary Nanocrystalline Suspensions.

Comminution of BCS II APIs below the 1 µm threshold followed by solidification of the obtained nanosuspensions improves their dissolution properties. The breakage process reveals new crystal faces, thus creating altered crystal habits of improved wettability, facilitated by the adsorption of stabilizing polymers. However, process-induced transformations remain unpredictable, mirroring the current limitations of our atomistic level of understanding. Moreover, conventional equations of estimating dissolution, such as Noyes-Whitney and Nernst-Brunner, are not suitable to quantify the solubility enhancement due to the nanoparticle formation; hence, neither the complex stabilizer contribution nor the adsorption influence on the interfacial tension occurring between the water and APIs is accounted for. For such ternary mixtures, no numeric method exists to correlate the mechanical properties with the interfacial energy, capable of informing the key process parameters and the thermodynamic stability assessment of nanosuspensions. In this work, an elastic tensor analysis was performed to quantify the API stability during process implementation. Moreover, a novel thermodynamic model, described by the stabilizer-coated nanoparticle Gibbs energy anisotropic minimization, was structured to predict the material's system solubility quantified by the application of PC-SAFT modeling. Comprehensively merging elastic tensor and PC-SAFT analysis into the systems-based Pharma 4.0 algorithm provided a validated, multi-level, built-in method capable of predicting the critical material quality attributes and corresponding key process parameters.

Pharma 4.0 Continuous mRNA Drug Products Manufacturing.

Continuous mRNA drugs manufacturing is perceived to nurture flow processes featuring quality by design, controlled automation, real time validation, robustness, and reproducibility, pertaining to regulatory harmonization. However, the actual adaptation of the latter remains elusive, hence batch-to-continuous transition would a priori necessitate holistic process understanding. In addition, the cost related to experimental, pilot manufacturing lines development and operations thereof renders such venture prohibitive. Systems-based Pharmaceutics 4.0 digital design enabling tools, i.e., converging mass and energy balance simulations, Monte-Carlo machine learning iterations, and spatial arrangement analysis were recruited herein to overcome the aforementioned barriers. The primary objective of this work is to hierarchically design the related bioprocesses, embedded in scalable devices, compatible with continuous operation. Our secondary objective is to harvest the obtained technological data and conduct resource commitment analysis. We herein demonstrate for first time the feasibility of the continuous, end-to-end production of sterile mRNA formulated into lipid nanocarriers, defining the equipment specifications and the desired operational space. Moreover, we find that the cell lysis modules and the linearization enzymes ascend as the principal resource-intensive model factors, accounting for 40% and 42% of the equipment and raw material, respectively. We calculate MSPD 1.30-1.45 €, demonstrating low margin lifecycle fluctuation.

Polyelectrolyte Matrices in the Modulation of Intermolecular Electrostatic Interactions for Amorphous Solid Dispersions: A Comprehensive Review.

Polyelectrolyte polymers have been widely used in the pharmaceutical field as excipients to facilitate various drug delivery systems. Polyelectrolytes have been used to modulate the electrostatic environment and enhance favorable interactions between the drug and the polymer in amorphous solid dispersions (ASDs) prepared mainly by hot-melt extrusion. Polyelectrolytes have been used alone, or in combination with nonionic polymers as interpolyelectrolyte complexes, or after the addition of small molecular additives. They were found to enhance physical stability by favoring stabilizing intermolecular interactions, as well as to exert an antiplasticizing effect. Moreover, they not only enhance drug dissolution, but they have also been used for maintaining supersaturation, especially in the case of weakly basic drugs that tend to precipitate in the intestine. Additional uses include controlled and/or targeted drug release with enhanced physical stability and ease of preparation via novel continuous processes. Polyelectrolyte matrices, used along with scalable manufacturing methods in accordance with green chemistry principles, emerge as an attractive viable alternative for the preparation of ASDs with improved physical stability and biopharmaceutic performance.

The Effect of Phosphodiesterase-type 5 Inhibitors on Erectile Function: An Overview of Systematic Reviews.

Background: Multiple systematic reviews explore the effect of phosphodiesterase type 5 (PDE5) inhibitors on erectile dysfunction (ED), with each study addressing specific outcomes. However, physicians and policymakers require a holistic approach of this topic. Objective: To summarize the current evidence regarding the efficacy and safety of PDE5 inhibitors for the management of ED through an overview of systematic reviews. Methods: Studies were identified by searching PubMed, Web of Science, Cochrane Library and Scopus databases, as well as sources of grey literature until June 12, 2021 (PROSPERO: CRD42020216754). We considered systematic reviews, meta-analyses or network meta-analyses of randomized trials that provided outcomes about the efficacy and safety of any approved PDE5 inhibitor (avanafil, sildenafil, tadalafil and vardenafil). We constructed forest plots for meta-analytic effects regarding the change in erectile function, adverse events and dropouts after administration of PDE5 inhibitors in the general population and in specific patient groups. Results: We included 23 studies with 154,796 participants and a total of 258 meta-analytic effects. Sildenafil 25 mg [Weighted Mean Difference (WMD): 13.08, 95% Confidence Interval (CI): 10.1-16.06] seemed to be statistically superior to all interventions in improving erectile function compared to placebo, but studies with low-dose sildenafil are lacking. Moreover, comparing among different PDE5 inhibitors, sildenafil 50 mg or sildenafil 100 mg were considered the most effective compounds in the general population. The latter derived, however, predominantly from indirect comparisons among different PDE5 inhibitors. Still, sildenafil 100 mg was associated with more treatment-related adverse events and dropouts. Interestingly, low-dose daily tadalafil may be more effective than high-dose on-demand tadalafil (WMD: 1.24, 95% CI: 0.03-2.44). Furthermore, testosterone and PDE5 inhibitors in patients with ED and hypogonadism seem to further improve symptoms, while the addition of a-blockers in patients with urinary symptoms treated with PDE5 inhibitors does not provide additional benefits (WMD: -0.8, 95% CI: -1.65-0.06). Conclusion: Although the efficacy and safety of PDE5 inhibitors, compared to placebo, is well-documented, the existing evidence comparing different PDE5 inhibitors is low. Therefore, high-quality, head-to-head, trials comparing different PDE5 inhibitors are necessary to determine their ideal dosage and formulation based on their safety and efficacy profile. Systematic Review Registration: PROSPERO, identifier [CRD42020216754].

Biopharmaceutics 4.0, Advanced Pre-Clinical Development of mRNA-Encoded Monoclonal Antibodies to Immunosuppressed Murine Models.

Administration of mRNA against SARS-CoV-2 has demonstrated sufficient efficacy, tolerability and clinical potential to disrupt the vaccination field. A multiple-arm, cohort randomized, mixed blind, placebo-controlled study was designed to investigate the in vivo expression of mRNA antibodies to immunosuppressed murine models to conduct efficacy, safety and bioavailability evaluation. Enabling 4.0 tools we reduced animal sacrifice, while interventions were designed compliant to HARRP and SPIRIT engagement: (a) Randomization, blinding; (b) pharmaceutical grade formulation, monitoring; (c) biochemical and histological analysis; and (d) theoretic, statistical analysis. Risk assessment molded the study orientations, according to the ARRIVE guidelines. The primary target of this protocol is the validation of the research hypothesis that autologous translation of Trastuzumab by in vitro transcribed mRNA-encoded antibodies to immunosuppressed animal models, is non-inferior to classical treatments. The secondary target is the comparative pharmacokinetic assessment of the novel scheme, between immunodeficient and healthy subjects. Herein, the debut clinical protocol, investigating the pharmacokinetic/pharmacodynamic impact of mRNA vaccination to immunodeficient organisms. Our design, contributes novel methodology to guide the preclinical development of RNA antibody modalities by resolving efficacy, tolerability and dose regime adjustment for special populations that are incapable of humoral defense.

Effect of phosphodiesterase-type 5 inhibitors on erectile function: an overview of systematic reviews and meta-analyses.

INTRODUCTION: Phosphodiesterase-type 5 inhibitors (PDE5i) are the recommended first-line treatment for erectile dysfunction. Previous systematic reviews and meta-analyses suggest that they are a safe and effective option in many patient groups. Similarly, PDE5i may be effective as part of combination therapy in non-responders to PDE5i. We will generate an overview of systematic reviews, meta-analyses and network meta-analyses aiming to summarise the available knowledge regarding the efficacy and safety of PDE5i in the general population and in multiple subgroups of patients. METHODS AND ANALYSIS: This overview was designed in accordance with the PRIO-harms and Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines and its protocol was registered at PROSPERO. We will systematically search PubMed, Web of Science, Cochrane Library and Scopus databases from inception to November 2020 without any language restrictions. We will include systematic reviews or meta-analyses: (1) comparing the efficacy and safety of any dose of PDE5i with each other, with placebo or with other effective treatments for the management of erectile function; (2) exploring the use of any PDE5i alone or in combination with other treatment modalities in the general male population or in specific subgroups and (3) conducted with systematic procedures. Our overview will employ the AMSTAR 2 tool to evaluate the quality of the included studies and the Grading of Recommendations Assessment, Development and Evaluation approach to assess the strength of evidence for all outcomes. We will construct forest plots of risk estimates with the corresponding CI for all outcomes. ETHICS AND DISSEMINATION: In this overview, we will undertake an extensive literature search in an attempt to evaluate the potential benefits and risks of treatment with one PDE5i versus another or versus placebo and provide recommendations for clinicians and policy-makers. No ethical approval is required. PROSPERO REGISTRATION NUMBER: CRD42020216754.

Simultaneous Proximal Median and Ulnar Neuropathy: A Rare Complication of 24-hour Ambulatory Blood Pressure Monitoring with Unexpected Neurophysiological Findings.

Introduction:Ambulatory blood pressure monitoring (ABPM) is a non-invasive method of obtaining brachial artery pressure assessment over 24 hours while patients undergo normal daily activities. Side effects, such as peripheral petechiae, limb edema, and sleep disturbance, are usually mild and reversible. Case report:A 67-year-old male presented with excruciating left hand pain and weakness on waking up from night sleep, having worn a cuff on his left arm for a whole day in the context of 24-hour ABPM. Clinical extremeexamination confirmed hypoesthesia in the left median and ulnar nerve distribution and weakness solely affecting ulnar and sparing median innervated hand muscles. Neurophysiological testing was performed. Interestingly, although median and ulnar motor responses were abnormal the respective sensory responses were unremarkable. Conclusion:To our knowledge, this is the first reported case of simultaneous proximal median and ulnar neuropathy complicating 24-hour ABPM. From a neurophysiological standpoint, it is also intriguing as this is a rare case of peripheral neuropathy with prominent motor fibre involvement, but normal sensory responses.

Association of antipsychotic use with raised eosinophil count.

The current study aimed to assess the possibility of an association between first and second generation antipsychotic medication and raised eosinophil count. A total of 22 in-patients at the psychiatric unit of the University General Hospital 'Attikon', a tertiary hospital, were included in the present study. Patients had received antipsychotic monotherapy and did not have any co-morbidities or require additional treatments. Patients were monitored weekly and their eosinophil count was assessed. One-way ANOVA and summary measures analysis were applied to study the effect of time and medication type on the absolute eosinophil concentration (or relative percentage) for each patient. The differences in mean eosinophil concentrations or relative percentage by patient and time were also assessed. An increase in the absolute concentration and the relative percentage of eosinophils over time was observed in patients receiving Olanzapine, Haloperidol and Aripiprazole. However, there was no difference between individual medications. In conclusion, antipsychotics may be associated with increased eosinophil count over time; however, larger studies involving more patients and a longer follow-up are required to reach a definitive conclusion.

Sildenafil 4.0-Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era.

Sildenafil is a potent selective, reversible inhibitor of phosphodiesterase type 5 (PDE5) approved for the treatment of erectile dysfunction and pulmonary arterial hypertension. Whilst twenty years have passed since its original approval by the US Food and Drug Administration (USFDA), sildenafil enters the fourth industrial era catalyzing the treatment advances against erectile dysfunction and pulmonary hypertension. The plethora of detailed clinical data accumulated and the two sildenafil analogues marketed, namely tadalafil and vardenafil, signify the relevant therapeutic and commercial achievements. The pharmacokinetic and pharmacodynamic behavior of the drug appears complex, interdependent and of critical importance whereas the treatment of special population cohorts is considered. The diversity of the available formulation strategies and their compatible administration routes, extend from tablets to bolus suspensions and from per os to intravenous, respectively, inheriting the associated strengths and weaknesses. In this comprehensive review, we attempt to elucidate the multi-disciplinary elements spanning the knowledge fields of chemical synthesis, physicochemical properties, pharmacology, clinical applications, biopharmaceutical profile, formulation approaches for different routes of administration and analytical strategies, currently employed to guide the development of sildenafil-based compositions.

Age and gender effects on the association of sleep insufficiency with hypertension among adults in Greece.

Background: We aimed to investigate the relationship between sleep characteristics with hypertension using self-reported questionnaires. Material & methods: A total of 957 adults were classified into three groups (short [<6 h], normal [6-8 h] and long [>8 h] sleepers). Hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or use of antihypertensive medication at the time of interview. Results: Overall prevalence of hypertension was 34.3%. Association between short sleep duration and hypertension that was age-specific, present only among younger and middle aged individuals and sparing the elderly, but not gender-specific, as no discrepancies existed between males and females in all age groups, was evident. Conclusion: This study promotes early pharmacological or cognitive behavioral interventions on sleep disturbances in order to reduce hypertension burden.

Lay abstract Hypertension, or high blood pressure, is considered the leading cause of cardiovascular death and disability and is usually treated with medication to lower blood pressure and by making changes to the dietary habits of the patient. Lack of sleep is also a potential risk factor for high blood pressure. However, results on this matter have been contradictory so far. We investigated the relationship between sleep characteristics with high blood pressure in a representative Greek population using self-reported questionnaires. Our study revealed that short sleep duration, excessive daytime sleepiness, insomnia, poor sleep quality and high risk of obstructive sleep apnea are associated with increased prevalence of hypertension among younger and middle-aged adults, affecting everyone equally, regardless of sex. Thus, early medical or cognitive behavioral interventions that improve sleep might be necessary in order to reduce high blood pressure and consequently risk of other diseases of the heart and blood vessels.

Assessment of Combination Therapies vs Monotherapy for Erectile Dysfunction: A Systematic Review and Meta-analysis.

Importance: Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes. Objective: To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED. Data Sources: Studies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020. Study Selection: Randomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included. Data Extraction and Synthesis: Data extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: A meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients. Results: A total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24; I2 = 77%; 95% PI, -0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of α-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, -0.06 to 1.65; I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23; I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40; I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83; I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85; I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high. Conclusions and Relevance: This study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED.

COVID-19 and its consequences on mental health (Review).

As one year is approaching since the beginning of the Coronavirus disease 2019 (COVID-19) pandemic, it is important to acknowledge the detrimental effect that it is having on mental health at the individual, societal and public health levels. The current review presents the direct and indirect psychological impact of COVID-19 on the general public, as well as on vulnerable groups, including the elderly, the young, healthcare professionals, people with pre-existing mental health issues, those infected by COVID-19, homeless people and refugees. Important findings are discussed in the present review, including the social stigma in older people associated with portraying COVID-19 as the disease of the elderly, and the limited psychological impact of COVID-19 in the severely mentally ill, alongside the response of the mental healthcare systems globally to this unparalleled public health crisis. The important lessons to be learnt so far can help formulate individual mental health recommendations, as well as improved intervention and prevention public health strategies.

Sleep insufficiency and incident diabetes mellitus among indigenous and minority populations in Greece.

OBJECTIVE: To investigate the potential association between sleep pathology and diabetes mellitus (DM) using self-reported questionnaires. MATERIAL AND METHODS: 957 adults aged between 19 and 86 years old were enrolled in this cross-sectional study. Multistage stratified cluster sampling was used and subjects were classified into three groups [short (<6h), normal (6-8h) and long (>8h) sleep duration]. Individuals were classified as diabetics if they responded positively to the questions: "Have you ever been told that you are diabetic or have high blood sugar by a health professional?" or "Are you on antidiabetic medication?". Sleep quality, utilizing Epworth sleepiness scale, Athens insomnia scale, Pittsburgh sleep quality index and Berlin questionnaire, was also examined. RESULTS: DM prevalence was higher among expatriated and Muslim Greeks (23.1% and 18.7%, respectively) compared to indigenous Greek Christians (4.4%). DM prevalence was significantly associated with short sleep duration (aOR=2.82, p<0.001), excessive daytime sleepiness (aOR=2.09, p=0.019) and poor sleep quality (aOR=2.56, p<0.001), while its relation with insomnia (aOR=1.63, p=0.065) and risk for obstructive sleep apnea (aOR=1.53, p=0.080) were of marginal statistical significance. CONCLUSION: This study indicates an association between sleep quantity, quality and DM and supports early pharmacological and cognitive behavioral interventions on sleep disturbances in order to reduce the burden of DM with increased focus on minority population needs.

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles.

In the quest for a formidable weapon against the SARS-CoV-2 pandemic, mRNA therapeutics have stolen the spotlight. mRNA vaccines are a prime example of the benefits of mRNA approaches towards a broad array of clinical entities and druggable targets. Amongst these benefits is the rapid cycle "from design to production" of an mRNA product compared to their peptide counterparts, the mutability of the production line should another target be chosen, the side-stepping of safety issues posed by DNA therapeutics being permanently integrated into the transfected cell's genome and the controlled precision over the translated peptides. Furthermore, mRNA applications are versatile: apart from vaccines it can be used as a replacement therapy, even to create chimeric antigen receptor T-cells or reprogram somatic cells. Still, the sudden global demand for mRNA has highlighted the shortcomings in its industrial production as well as its formulation, efficacy and applicability. Continuous, smart mRNA manufacturing 4.0 technologies have been recently proposed to address such challenges. In this work, we examine the lab and upscaled production of mRNA therapeutics, the mRNA modifications proposed that increase its efficacy and lower its immunogenicity, the vectors available for delivery and the stability considerations concerning long-term storage.

Overcoming the Solubility Barrier of Ibuprofen by the Rational Process Design of a Nanocrystal Formulation.

Wet media milling, coupled with spay drying, is a commonly proposed formulation strategy for the production and solidification of nanosuspensions in order to overcome the solubility barrier of BCS Class II substances. However, the application of mechanically and thermally intensive processes is not straightforward in the cases of ductile and/or low melting point substances that may additionally be susceptible to eutectic formation. Using ibuprofen (IBU) as a model drug with non-favorable mechanical and melting properties, we attempt to rationalize nanocrystal formulation and manufacturing in an integrated approach by implementing Quality by Design (QbD) methodology, particle informatics techniques and computationally assisted process design. Wet media milling was performed in the presence of different stabilizers and co-milling agents, and the nanosuspensions were solidified by spray-drying. The effects of key process parameters (bead diameter, milling time and rotational speed) and formulation variables (stabilizer type and drug/stabilizer ratio) on the critical quality attributes (CQAs), i.e., Z-average size, polydispersity index (PDI), ζ-potential and redispersibility of spray-dried nanosuspensions were evaluated, while possible correlations between IBU free surface energy and stabilizer effectiveness were studied. The fracture mechanism and surface stabilization of IBU were investigated by computer simulation of the molecular interactions at the crystal lattice level. As a further step, process design accounting for mass-energy balances and predictive thermodynamic models were constructed to scale-up and optimize the design space. Contemplating several limitations, our multilevel approach offers insights on the mechanistic pathway applicable to the substances featuring thermosensitivity and eutectic tendency.

Graphene-Wrapped Copper Nanoparticles: An Antimicrobial and Biocompatible Nanomaterial with Valuable Properties for Medical Uses.

The great demand for antibacterial, biocompatible, and easily manufactured nanostructures has led to the design and development of graphene-wrapped copper nanoparticles (CuNPs) supported on Si wafers. In this study, we investigated the antibacterial properties of graphene/CuNPs nanostructures against Gram-positive and Gram-negative bacteria. Additional experiments regarding graphene/CuNPs nanostructures behavior against mouse fibroblast cell line L929 indicated their biocompatibility and consequently render them as model biomaterials for medical uses. Biofunctionalization of graphene/CuNPs nanostructures with a high-molecular-weight protein (green fluorescent protein), which retains its functionality after a "tight binding" on the nanostructure's surface, opens the way for attaching and other proteins, or biomolecules of great biological interest, to prepare novel biomaterials.