Volatility, Uncertainty, Complexity, and Ambiguity (VUCA) in Healthcare.

Our professional activity is constantly under pressure from a multitude of elements and factors that can be classified into the four components of the VUCA phenomenon-volatility, uncertainty, complexity, and ambiguity-components that define the turbulence and challenges of the external environment. Considering the general elements of this phenomenon, we designed a new VUCA dimension specific to the healthcare field within which we have identified and analyzed all the factors that can influence the main actors of the doctor-patient relationship and the effects that can occur within the healthcare system in which this relationship is born. In this context, we generated the VUCA treatment in healthcare capable of mitigating the impact of this phenomenon; this treatment involves essential elements in overcoming possible crises and vulnerabilities of the medical profession. The VUCA treatment in healthcare requires combating volatility, uncertainty, complexity, and ambiguity through vision, understanding, clarity, and agility, which are grounded in the doctor's need to acquire cross-functional competencies (soft skills). These competencies are applicable by using functional mechanisms and techniques that support the doctor in developing adaptability and anticipation skills, understanding the patient's needs and addressing them, and ensuring the functionality and efficiency of the healthcare system by transferring these elements from micro-management to macro-management levels.

The Phenomenon of Antiretroviral Drug Resistance in the Context of Human Immunodeficiency Virus Treatment: Dynamic and Ever Evolving Subject Matter.

Human immunodeficiency virus (HIV) is a significant global health issue that affects a substantial number of individuals across the globe, with a total of 39 million individuals living with HIV/AIDS. ART has resulted in a reduction in HIV-related mortality. Nevertheless, the issue of medication resistance is a significant obstacle in the management of HIV/AIDS. The unique genetic composition of HIV enables it to undergo rapid mutations and adapt, leading to the emergence of drug-resistant forms. The development of drug resistance can be attributed to various circumstances, including noncompliance with treatment regimens, insufficient dosage, interactions between drugs, viral mutations, preexposure prophylactics, and transmission from mother to child. It is therefore essential to comprehend the molecular components of HIV and the mechanisms of antiretroviral medications to devise efficacious treatment options for HIV/AIDS.

Evaluation of Neuro-Hormonal Dynamics after the Administration of Probiotic Microbial Strains in a Murine Model of Hyperthyroidism.

The microbiota-gut-brain axis has received increasing attention in recent years through its bidirectional communication system, governed by the ability of gut microorganisms to generate and regulate a wide range of neurotransmitters in the host body. In this research, we delve into the intricate area of microbial endocrinology by exploring the dynamic oscillations in neurotransmitter levels within plasma and brain samples. Our experimental model involved inducing hyperthyroidism in mice after a "probiotic load" timeframe using two strains of probiotics (Lactobacillus acidophilus, Saccharomyces boulardii, and their combination). These probiotic interventions continued throughout the experiment and were intended to uncover potential modulatory effects on neurotransmitter levels and discern if certain probiotic strains exhibit any protection from hyperthyroidism. Moreover, we aimed to outline the eventual connections between the gut microbiota and the hypothalamus-pituitary-thyroid axis. As our study reveals, there are significant fluctuations in crucial neurotransmitters within the hyperthyroidism model, related to the specific probiotic strain or combination. These findings could support future therapeutic approaches, help healthcare professionals choose between different probiotic therapies, and also allow us proceed with caution when administering such treatments, depending on the health status of hyperthyroid patients.

Dietary Influence on Drug Efficacy: A Comprehensive Review of Ketogenic Diet-Pharmacotherapy Interactions.

It is widely acknowledged that the ketogenic diet (KD) has positive physiological effects as well as therapeutic benefits, particularly in the treatment of chronic diseases. Maintaining nutritional ketosis is of utmost importance in the KD, as it provides numerous health advantages such as an enhanced lipid profile, heightened insulin sensitivity, decreased blood glucose levels, and the modulation of diverse neurotransmitters. Nevertheless, the integration of the KD with pharmacotherapeutic regimens necessitates careful consideration. Due to changes in their absorption, distribution, metabolism, or elimination, the KD can impact the pharmacokinetics of various medications, including anti-diabetic, anti-epileptic, and cardiovascular drugs. Furthermore, the KD, which is characterised by the intake of meals rich in fats, has the potential to impact the pharmacokinetics of specific medications with high lipophilicity, hence enhancing their absorption and bioavailability. However, the pharmacodynamic aspects of the KD, in conjunction with various pharmaceutical interventions, can provide either advantageous or detrimental synergistic outcomes. Therefore, it is important to consider the pharmacokinetic and pharmacodynamic interactions that may arise between the KD and various drugs. This assessment is essential not only for ensuring patients' compliance with treatment but also for optimising the overall therapeutic outcome, particularly by mitigating adverse reactions. This highlights the significance and necessity of tailoring pharmacological and dietetic therapies in order to enhance the effectiveness and safety of this comprehensive approach to managing chronic diseases.

Association Between Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) With Diabetic Retinopathy in Type 2 Diabetic Patients.

Diabetic retinopathy (DR) is one of the main causes of blindness worldwide, but an effective screening is challenging due to limited available retina specialists. Finding novel biomarkers could help clinical decision in prioritizing ophthalmological consultation in patients at risk of developing severe DR. This study aims to investigate the association between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the presence and severity of DR in patients with T2DM. A retrospective study was performed on 90 patients with T2DM admitted in the Ophthalmology Clinic, Emergency University Hospital Bucharest in Bucharest, Romania, between March 2022 and March 2023, for routine cataract surgery. The cases were divided into three groups according to the severity of DR: no DR (noDR), non-proliferative diabetic retinopathy (NPDR), and proliferative DR (PDR) groups. NLR values raised significantly in the PDR group, no DR group (p = 0.003), and NPDR group (p = 0.026), while PLR values did not differ statistically significant among the groups (p = 0.059). No difference in terms of age, sex, HbA1C, and comorbidities were observed. In the multivariate analysis, the NLR (OR = 2.01, [1.29; 3.14], p = 0.0019) and diabetic nephropathy (OR = 3.84, [1.23; 11.98], p = 0.0203) were associated with higher rates of PDR. NLR may be a promising tool in the risk stratification of T2DM patients with DR.

[Corrigendum] Effect of the combination of Lactobacillus acidophilus (probiotic) with vitamin K3 and vitamin E on Escherichia coli and Staphylococcus aureus: An in vitro pathogen model and metastasis in vivo.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, in Fig. 3B on p. 7 showing the results of immunohistochemistry staining experiments, the data panels shown for the 'L+K' and 'EC+E+K' groups were strikingly similar, such that they appeared to be derived from the same original source, where these panels were intended to show the results from differently performed experiments. The authors have re­examined their original data, and realize that Fig. 3B was inadvertently assembled incorrectly; specifically, the data shown for the 'L+K' group in Fig. 3B were featured incorrectly. The revised version of Fig. 3, now containing the correct data for the 'L+K' experimental group in Fig. 3B is shown on the next page. Note that this error did not adversely affect either the results or the overall conclusions reported in this study. All the authors agree with the publication of this corrigendum. They also wish to apologize to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 27: 119, 2023; DOI: 10.3892/mmr.2023.13006].

Effect of the combination of Lactobacillus acidophilus (probiotic) with vitamin K3 and vitamin E on Escherichia coli and Staphylococcus aureus: An in vitro pathogen model.

The gut microbiota plays a key role in maintaining health and regulating the host's immune response. The use of probiotics and concomitant vitamins can increase mucus secretion by improving the intestinal microbial population and prevent the breakdown of tight junction proteins by reducing lipopolysaccharide concentration. Changes in the intestinal microbiome mass affect multiple metabolic and physiological functions. Studies on how this microbiome mass and the regulation in the gastrointestinal tract are affected by probiotic supplements and vitamin combinations have attracted attention. The current study evaluated vitamins K and E and probiotic combinations effects on Escherichia coli and Staphylococcus aureus. Minimal inhibition concentrations of vitamins and probiotics were determined. In addition, inhibition zone diameters, antioxidant activities and immunohistochemical evaluation of the cell for DNA damage were performed to evaluate the effects of vitamins and probiotics. At the specified dose intervals, L. acidophilus and vitamin combinations inhibit the growth of Escherichia coli and Staphylococcus aureus. It could thus contribute positively to biological functions by exerting immune system­strengthening activities.

Gut Microbiota Dysbiosis in Diabetic Retinopathy-Current Knowledge and Future Therapeutic Targets.

Diabetic retinopathy is one of the major causes of blindness today, despite important achievements in diagnosis and therapy. The involvement of a gut-retina axis is thought to be a possible risk factor for several chronic eye disease, such as glaucoma, age-related macular degeneration, uveitis, and, recently, diabetic retinopathy. Dysbiosis may cause endothelial disfunction and alter retinal metabolism. This review analyzes the evidence regarding changes in gut microbiota in patients with DR compared with diabetics and healthy controls (HCs). A systematic review was performed on PubMed, Web of Science, and Google Scholar for the following terms: "gut microbiota" OR "gut microbiome" AND "diabetic retinopathy". Ultimately, 9 articles published between 2020 and 2022 presenting comparative data on a total of 228 T2DM patients with DR, 220 patients with T2DM, and 118 HCs were analyzed. All of the studies found a distinctive microbial beta diversity in DR vs. T2DM and HC, characterized by an altered Firmicutes/Bacteroidetes ratio, a decrease in butyrate producers, and an increase in LPS-expressing and pro-inflammatory species in the Bacteroidetes and Proteobacteria phyla. The probiotic species Bifidobacterium and Lactobacillus were decreased when compared with T2DM. Gut microbiota influence retinal health in multiple ways and may represent a future therapeutic target in DR.

Collateral Victims of Defensive Medical Practice.

This paper analyzes the phenomenon of defensive medical practice, starting from the doctor-patient relationship, and the behavioral and professional factors that can influence the proper functioning of this relationship and the healthcare system. We analyze medical malpractice, given the increase in the number of accusations, as an essential factor in triggering the defensive behavior of doctors, together with other complementary factors that emphasize the need for protection and safety of doctors. The possible consequences for the doctor-patient relationship that defensive practice can generate are presented and identified by analyzing the determining role of the type of health system (fault and no-fault). At the same time, we investigate the context in which overspecialization of medical personnel can generate a form of defensive practice as a result of the limiting effect on the performance of a certain category of operations and procedures. The increase in the number of malpractice accusations impacts the medical community-"the stress syndrome induced by medical malpractice"-turning doctors into collateral victims who, under the pressure of diminishing their reputational safety, practice defensively to protect themselves from future accusations. This type of defensive behavior puts pressure on the entire healthcare system by continuously increasing costs and unresolved cases, which impact patients by limiting access to medical services in the public and private sectors.

New method for risk assessment in environmental health: The paradigm of heavy metals in honey.

The release of heavy metals into the natural environment creates problems due to their persistence. They can accumulate in the food chain presenting a dangerous sign for ecosystems and human health. The metals in honey could be of agrochemical or industrial origin. Regular consumption of honey and bee products contaminated with various pollutants in high concentrations can cause serious health problems due accumulation of toxic substances in the body. In the current study, we aimed to determine the concentrations of chromium, cadmium, zinc, copper, lead and nickel in four types of honey (linden, acacia, rapeseed and polyfloral honey) and soil collected from three regions with different degrees of pollution. For the risk characterization, we used a new methodology that calculated the corrected estimated daily intake and the source hazard quotient for each metal and the adversity-specific hazard index. There was a strong influence of the degree of environmental pollution on the level of contaminants in the honey samples. In the case of a single chemical assessment, an HQ above 10 was obtained for Cd in linden, rapeseed and polyfloral honey from area 1 and an HQ above 1 was obtained for Cd in the other honey samples from the 3 areas, for Cu in all honey samples from all the 3 areas, for Pb in linden, rapeseed and polyfloral honey from area 1 and for Cr in linden honey for area 2. HIA calculated as a sum of all HQS of heavy metals in food reveals an increase and moderate risk for nephrotoxicity, bone demineralisation, cardiotoxicity, developmental toxicity, small decrease in body weight or body weight gain after consumption of honey impurified with heavy metals. A strict monitorization of heavy metals in honey samples from farmers should be done in order to protect the consumers.

Effects of Achieving Sustained Virologic Response after Direct-Acting Antiviral Agents on Long-Term Liver Fibrosis in Diabetics vs. in Non-Diabetic Patients with Chronic Hepatitis C Infection.

Because of the prevalence of HCV worldwide as well as its undiagnosed population due to a lack of screening, HCV can be considered a modern pandemic disease. In 2016, the World Health Organization (WHO) set goals for HCV's elimination that included a 65 percent reduction in mortality and an 80 percent reduction in newly infected cases by 2030. This study is a follow-up evaluation of 80 patients who received interferon-free treatment with direct-acting agents (DAA) for chronic HCV infection between the second half of 2017 and the end of 2018. They were assessed using a FibroMax test prior to DAA administration. Two pills/day of Ombitasvir 12.5 mg/Paritaprevir 75 mg/Ritonavir 50 mg and two pills/day of Dasabuvir 250 mg were given to the patients for 8 weeks. After treatment, all 80 patients in this study achieved an SVR (sustained virologic response), and the FibroMax test was performed three years later. Our study found that successfully treating HCV infection can play a significant role in reducing fibrosis in T2DM patients. In comparison to those of ActiTest and SteatoTest, FibroMax scores showed a significantly greater reduction in T2DM patients than in treatment-naive patients.

An Overview Regarding Microbial Aspects of Production and Applications of Bacterial Cellulose.

Cellulose is the most widely used biopolymer, accounting for about 1.5 trillion tons of annual production on Earth. Bacterial cellulose (BC) is a form produced by different species of bacteria, representing a purified form of cellulose. The structure of bacterial cellulose consists of glucose monomers that give it excellent properties for different medical applications (unique nanostructure, high water holding capacity, high degree of polymerization, high mechanical strength, and high crystallinity). These properties differ depending on the cellulose-producing bacteria. The most discussed topic is related to the use of bacterial cellulose as a versatile biopolymer for wound dressing applications. The aim of this review is to present the microbial aspects of BC production and potential applications in development of value-added products, especially for biomedical applications.

Thrombosis and Haemostasis challenges in COVID-19 - Therapeutic perspectives of heparin and tissue-type plasminogen activator and potential toxicological reactions-a mini review.

The coronavirus disease (COVID)-19 pandemic is a major challenge for the health systems worldwide. Acute respiratory distress syndrome (ARDS), is one of the most common complications of the COVID-19 infection. The activation of the coagulation system plays an important role in the pathogenesis of ARDS. The development of lung coagulopathy involves thrombin generation and fibrinolysis inhibition. Unfractionated heparin and its recently introduced counterpart low molecular weight heparin (LMWH), are widely used anticoagulants with a variety of clinical indications allowing for limited and manageable physio-toxicologic side effects while the use of protamine sulfate, heparin's effective antidote, has made their use even safer. Tissue-type plasminogen activator (tPA) is approved as intravenous thrombolytic treatment. The present narrative review discusses the use of heparin and tPA in the treatment of COVID-19-induced ARDS and their related potential physio-toxicologic side effects. The article is a quick review of articles on anticoagulation in COVID infection and the potential toxicologic reactions associated with these drugs.

Death by SARS-CoV 2: a Romanian COVID-19 multi-centre comorbidity study.

Evidence regarding the relation between SARS-CoV-2 mortality and the underlying medical condition is scarce. We conducted an observational, retrospective study based on Romanian official data about location, age, gender and comorbidities for COVID-19 fatalities. Our findings indicate that males, hypertension, diabetes, obesity and chronic kidney disease were most frequent in the COVID-19 fatalities, that the burden of disease was low, and that the prognosis for 1-year survival probability was high in the sample. Evidence shows that age-dependent pairs of comorbidities could be a negative prognosis factor for the severity of disease for the SARS-CoV 2 infection.

Heavy metal and pesticide levels in dairy products: Evaluation of human health risk.

Cattle milk's health benefits can be compromised by the presence of contaminants. The levels of cadmium, copper, lead and zinc, and residues of dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyldichloroethane (DDD), dichlorodiphenyltrichloroethane (DDT) were determined in soil, milk and cheese samples collected from cow farms from 3 Romanian areas with industrial and agriculture tradition. A new methodology was applied for the determination of the corrected estimated daily intake (cEDI) corresponding to the aggregate dietary exposure. For the risk assessment, we calculated the source hazard quotient (HQs) for each contaminant and the adversity specific hazard index (HIA). Cadmium, copper, lead and zinc, and the sum of DDT levels in soil samples were below maximum residue levels (MRLs). The MRLs of lead and DDD were exceeded in milk and cheese samples from all the 3 areas. The MRLs of copper and zinc were exceeded in cheese samples from area 2 and 3. HQs >10 for lead indicates increased risk, while HQ > 1 for copper and sum of DDT indicates moderate risk for both milk and cheese. By calculating the HIA, we identified a moderate and increase risk for nephrotoxicity, hepatotoxicity, hematotoxicity, cardiotoxicity and reproduction toxicity after consumption of the dairy products from the 3 areas.

Recent advances, approaches and challenges in targeting pathways for potential COVID-19 vaccines development.

During the COVID-19 pandemic in a modern era, there is a global consensus on the need for the rapid development of a vaccine against SARS-CoV-2 for effective and sustainable control. Developing these vaccines is fundamental to public health. This urgent need is supported by the scientific explosion in structural and genomic biology that facilitates the urgent development of an ideal COVID-19 vaccine, using new pathways to facilitate its large-scale development, testing, and manufacture. Here, we summarize the types of COVID-19 candidate vaccines, their current stage in early testing in human clinical trials, and the challenges for their implementation.

Biochemical adaptation of wild and cultivated soybean against toxicity of lead salts.

Agricultural production is becoming increasingly dependent on the environmental factors that alter soil properties, plant productivity, and product quality. Environment pollution caused by heavy metals because of human activities are among the most dangerous pollutants on the biosphere. Here, we have studied the biochemical adaptation of wild and cultivated soybeans to the simulated effects of lead nitrate and lead acetate. Lead in the form of acetate had a relevant toxic effect, as evidenced by a significant increase in the concentration of malonic dialdehyde in the treated samples relative to control samples. Catalase and peroxidase, possibly performing a signaling function, are involved in the adaptation to the toxicity of Pb salts. The studied Pb salts showed a predominant stimulating effect on the specific activity of acid phosphatases in cultivated soybean, while the ribonuclease activity changed in both Glycine species. Moreover, in wild soybean, it was mostly suppressive, except for the first day. We found that the electrophoretic spectra of acid phosphatases of soybean seedlings was highly stabile, while that of ribonucleases varied depending on the salt. On the seventh day of exposure, lead nitrate caused a decrease in the specific activity of the studied hydrolases of seedlings of cultivated and wild soybeans. A change in the number or electrophoretic mobility of multiple forms of enzymes during treatment with Pb salts was revealed, which indicates the adaptation of the plants at the molecular genetic level. These results imply that the observed enzymes can be used as sensitive indicators for predicting the effects of heavy metals on soybean.

Clinical significance of serum melatonin in predicting the severity of oral squamous cell carcinoma.

Melatonin, the primary hormone produced by the pineal gland, is intensely assessed for its anticancer properties. This study aimed to reveal the clinical significance of serum melatonin levels in predicting the severity of oral squamous cell carcinoma (OSCC). For this purpose, 40 male patients with OSCC and 30 healthy subjects were enrolled in this study. The serum levels of melatonin were determined by ELISA. The results revealed that the melatonin concentrations were significantly lower in the patients with OSCC compared with the controls (18.2 vs. 47.6 pg/ml, P<0.001). In addition, the serum melatonin levels had a high predictive accuracy for discriminating patients with OSCC with T-depth of invasion (DOI) II from the healthy controls (89.1%), as well as in discriminating patients with OSCC with nodal metastasis from those without nodal metastasis (83.8%). On the whole, the findings of this study suggest that the serum melatonin concentrations are closely related to the severity of OSCC and may thus be used to assess the different stages of oral cancer objectively and accurately. The present study also supports the conclusion that melatonin may be a potential therapeutic agent for use in the treatment of patients with OSCC.

Adverse and hormetic effects in rats exposed for 12 months to low dose mixture of 13 chemicals: RLRS part III.

The aim of the current study was to evaluate the effects of a mixture of thirteen common chemicals on rats, after a one-year exposure to doses around the acceptable daily intake (ADIs), using blood and urinary tests. The influence of low doses of the mixture on weight gain, water consumption, feed consumption and feed efficiency, biochemistry parameters, haematological parameters, blood lymphocytes subsets, serum inflammation profile and urine parameters was evaluated. Our mixture caused a moderate monotonic increase of the males' appetite and a non-monotonic increase of anabolism and a monotonic increase of appetite for the females. Regarding biochemical parameters, the exposure to the test mixture caused non-monotonic increases of AST and ALT, a decrease of PChE in males and plausibly a monotonic biliary obstruction in both sexes. Monocytes significantly increased in low dose groups of both sexes. A significant decrease of all the lymphocytes subclasses and an increased expression of TNF-α protein associated with an increased expression of IFN-γ protein observed in various groups. It became apparent that after twelve months of exposure very low doses of the tested mixture had both non-monotonic and monotonic harmful effects on different levels on rats.

The use of structural alerts to avoid the toxicity of pharmaceuticals.

In order to identify compounds with potential toxicity problems, particular attention is paid to structural alerts, which are high chemical reactivity molecular fragments or fragments that can be transformed via bioactivation by human enzymes into fragments with high chemical reactivity. The concept has been introduced in order to reduce the likelihood that future candidate substances as pharmaceuticals will have undesirable toxic effects. A significant proportion (∼78-86%) of drugs characterized by residual toxicity contain structural alerts; there is also evidence indicating the formation of active metabolites as a causal factor for the toxicity of 62-69% of these molecules. On the other hand, the pharmacological action of certain drugs depends on the formation of reactive metabolites. Detailed assessment of the potential for the formation of active metabolites is recommended to characterize a biologically active compound. Although many prescribed drugs frequently contain structural alerts and form reactive metabolites, the vast majority of these drugs are administered in low daily doses. Avoiding structural alerts has become almost a norm in new drug design. An in-depth review of the biochemical reactivity of these structural alerts for new drug candidates is critical from a safety point of view and is currently being monitored in the discovery of drugs. The chemical strategies applied to structural alerts in molecules to limit the toxicity are: •partial replacement or full replacement of the structural alert;•reduction of electronic density;•introduction of a structural element of metabolic interest (metabolic switching);•multiple approaches. Therefore, chemical intervention strategies to eliminate bioactivation are often interactive processes; their success depends largely on a close working relationship between drug chemists, pharmacologists and researchers in metabolic science.