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Abstract Taurine, although not a coding amino acid, is the most common free amino acid in the body. Taurine has multiple and complex functions in protecting mitochondria against oxidative-nitrosative stress. In this comprehensive review paper, we introduce a novel potential role for taurine in protecting from deuterium (heavy hydrogen) toxicity. This can be of crucial impact to either normal or cancer cells that have highly different mitochondrial redox status. Deuterium is an isotope of hydrogen with a neutron as well as a proton, making it about twice as heavy as hydrogen. We first explain the important role that the gut microbiome and the gut sulfomucin barrier play in deuterium management. We describe the synergistic effects of taurine in the gut to protect against the deleterious accumulation of deuterium in the mitochondria, which disrupts ATP synthesis by ATPase pumps. Moreover, taurine’s derivatives, N-chlorotaurine (NCT) and N-bromotaurine (NBrT), produced through spontaneous reaction of taurine with hypochlorite and hypobromite, have fascinating regulatory roles to protect from oxidative stress and beyond. We describe how taurine could potentially alleviate deuterium stress, primarily through metabolic collaboration among various gut microflora to produce deuterium depleted nutrients and deuterium depleted water, and in this way protect against leaky gut barrier, inflammatory bowel disease, and colon cancer.

Background: Osteoporotic fractures are a common clinical sign of Cushing syndrome (CS). However, Cushing diagnosis can occur years after this clinical manifestation. Methods: Herein, we present the case of a 45-year-old woman who was referred to our department for further diagnosis and treatment. Results: The patient was already under treatment for arterial hypertension and osteoporosis and was recently diagnosed with dyslipidemia and type 2 diabetes. She reported several previous fractures starting already 8 years before presentation. An adrenal CS was diagnosed, and the patient was treated with laparoscopic adrenalectomy, with a subsequent complete remission of her hypercortisolism. This case report presenting a particularly long time gap between initial osteoporosis signs and the final diagnosis underlines the need for an investigation into secondary osteoporosis in low-energy fractures also in the peripheral skeleton. In this context, we performed a literature review, including case reports with fragility fractures that were attributed to endogenous CS. Conclusions: In summary, a delayed diagnosis of CS in patients with a previous accumulation of such fractures is a worrisome observation and should be considered in everyday clinical practice in order to improve the timely diagnosis and treatment of CS.

Objectives Should a young person receive psychotherapy or medication for their depression and on what evidence do we base this decision? In this paper, we test the factors across modalities that may influence comparability between medication and psychotherapy trials.Methods We included 92 randomised controlled trials (RCTs) of psychotherapy and medication for child and adolescent depression (mean age 4–18 years). Using meta-analyses, we compared (a) participant characteristics and (b) trial characteristics in medication and psychotherapy trials. Lastly, we examined whether psychotherapy controls are well-matched to active conditions.Results Participants in medication RCTs had higher depression severity and were more frequently male compared with psychotherapy RCTs. There was a dramatic difference in the within-subject improvement due to placebo (SMD=−1.9 (95% CI: −2.1 to −1.7)) vs. psychotherapy controls (SMD=−0.6 (95% CI: −0.9 to −0.3)). Within psychotherapy RCTs, control conditions were less intensive on average than active conditions.Conclusions Medication and psychotherapy RCTs differ on fundamental participant and methodological characteristics, thereby raising questions about their comparability. Psychotherapy controls often involve little therapist contact and are easy-to-beat comparators. These findings cast doubt on the confidence with which psychotherapy is recommended for youth depression and highlight the pressing need to improve the evidence base.

Alzheimer's disease (AD) affects more women than men. Although women live longer than men, it is not longevity alone, but other factors, including metabolic changes, that contribute to the higher risk of AD in women. Metabolic pathways have been implicated in AD progression, but studies to date examined targeted pathways, leaving many metabolites unmeasured. Sex is often a neglected biological variable, and most metabolomic studies were not designed to investigate sex differences in metabolomic profiles. Here, we performed untargeted metabolomic profiling of sera from male and female patients with mild cognitive impairment (MCI), a common precursor to AD, and matched controls. We discovered significant metabolic changes in individuals with MCI, and found several pathways that were strongly associated with sex. Peptide energy metabolism demonstrated sexual dimorphism. Lipid pathways exhibited the strongest differences between female and male MCI patients, including specific phosphatidylcholine lipids, lysophospholipids, long-chain fatty acids, and monoacylglycerols. 1-palmitoleoyl glycerol and 1-arachidonoyl glycerol were higher in female MCI subjects than in male MCI subjects with no differences between control males and females. Conversely, specific dicarboxylic fatty acids were lower in female MCI subjects than male MCI subjects. In cultured astrocytes, 1-arachidonoyl glycerol promoted phosphorylation of the transcriptional regulator sphingosine kinase 2, which was inhibited by the transient receptor potential vanilloid 1 receptor antagonists, as well as chromatin remodelling. Overall, we identified novel sex-specific metabolites in MCI patients that could serve as biomarkers of MCI in both sexes, help further define AD etiology, and reveal new potential prevention strategies for AD.

Background There is limited data on the reasons for escalation or de-escalation of COPD inhaled therapies in routine clinical practice, especially after the follow-up pharmacological treatment guidance on the 2019 GOLD report and the 2020 ERS guideline on ICS withdrawal.Methods The STEPINCOPD study was a 12-week, two-visit, prospective observational study that aimed to describe the reasons for change of inhaled therapies, in accordance with GOLD recommendations 2021. Only patients that had a recent change in their inhaled medication were enrolled. Moreover, we investigated associations between physicians’ and patients’ characteristics and adherence to GOLD recommendations.Results 1429 patients were enrolled from 146 centers (138 private practice and 8 hospitals) throughout Greece. At enrollment, the most frequent reasons for treatment change were lack of clinical (78.9%) or spirometric (49.5%) response to previous treatment, change in CAT score (45.1%), and mMRC score (28.2%). At the follow-up visit, most common reasons were lack of clinical response to previous treatment (71.4%), COPD exacerbations (59.5%), changes in CAT score (52.4%), lack of spirometric response (42.9%) and lower respiratory tract infections (31%). We observed high adherence to the GOLD 2021 recommendations (81.6% at enrollment and 92.9% at follow-up). Physicians’ age and consideration of GOLD recommendations for prescription choice, as well as patients’ CAT score were significant predictors of adherence to GOLD.Conclusion The STEPINCOPD study highlights the reasons for inhaled treatment change in Greek physicians with high adherence to GOLD recommendations and provides insights for future research that may inform the development of decision support tools.

Deuterium is a natural isotope of hydrogen, containing a neutron as well as a proton, which makes it twice as heavy as hydrogen. In this paper, we develop a theoretical argument that human metabolism strives to minimize the amount of deuterium in mitochondrial water, because it causes a stutter in ATPase pumps, introducing excess reactive oxygen species and reduced ATP production. Gut microbes produce hydrogen gas that is 80 % depleted in deuterium (deupleted). This gas is recycled into organic matter that supplies deupleted nutrients to the host, such as acetate, butyrate, and choline. Mitochondrial dysfunction is associated with many chronic diseases, most notably, cancer. Dehydrogenases, through proton tunneling, typically have a high deuterium kinetic isotope effect (KIE), and they supply deupleted protons to the ATPase pumps via NADH (nicotinamide adenine dinucleotide) synthesis. We propose that a tumor may arise as a consequence of mitochondrial stress in immune cells due to excess deuterium, and that the tumor microenvironment can support immune cell recovery from mitochondrial dysfunction. Cancer cells alter protein expression to support deuterium sequestration through membrane-bound vesicular ATPase, and they release deupleted nutrients, mainly lactate, into the extracellular milieu and the circulation. Deuterium depleted water (DDW) has been shown to prolong life in cancer patients. An organic high fat diet rich in B vitamins, especially niacin, riboflavin, and folate, augmented with natural prebiotics and probiotics, supports deuterium homeostasis and likely protects from cancer.

Lutein, a plant-derived xanthophyl-carotenoid, is an exceptional antioxidant and anti-inflammatory constituent found in food. High dietary intake of lutein is beneficial against eye disease, improves cardiometabolic health, protects from neurodegenerative diseases, and is beneficial for liver, kidney, and respiratory health. Lutein protects against oxidative and nitrosative stress, both of which play a major role in long COVID and mRNA vaccination injury syndromes. Lutein is an important natural agent for therapeutic use against oxidative and nitrosative stress in chronic illnesses such as cardiovascular and neurodegenerative diseases and cancer. It can also potentially inhibit spike protein-induced inflammation. Rich dietary supplementation of lutein, naturally derived in non-biodegradable Extra Virgin Olive Oil (EVOO), can most optimally be used against oxidative and nitrosative stress during post-COVID and mRNA vaccination injury syndromes. Due to its high oleic acid (OA) content, EVOO supports optimal absorption of dietary lutein. The main molecular pathways by which the SARS-CoV-2 spike protein induces pathology, nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) and activated protein (AP)-1, can be suppressed by lutein. Synergy with other natural compounds for spike protein detoxification is likely.

Lutein, a plant-derived xanthophyl-carotenoid, is an exceptional antioxidant and anti-inflammatory constituent found in food. High dietary intake of lutein is beneficial against eye disease, improves cardiometabolic health, protects from neurodegenerative diseases, and is beneficial for liver, kidney, and respiratory health. Lutein protects against oxidative and nitrosative stress, both of which play a major role in post-COVID and mRNA vaccination injury syndromes. Lutein is an important natural agent for therapeutic use against oxidative and nitrosative stress in chronic illnesses such as cardiovascular and neurodegenerative diseases and cancer. It can also potentially inhibit spike protein-induced inflammation. Rich dietary supplementation of lutein, naturally derived in non-biodegradable Extra Virgin Olive Oil (EVOO), can most optimally be used against oxidative and nitrosative stress during post-COVID and mRNA vaccination injury syndromes. Due to its high oleic acid (OA) content, EVOO supports optimal absorption of dietary lutein. The main molecular pathways by which the SARS-CoV-2 spike protein induces pathology, nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) and activated protein (AP)-1, can be suppressed by lutein. Synergy with other natural compounds for spike protein detoxification is likely.

Given that radium-223 is a radiopharmaceutical that induces DNA damage, and olaparib is a PARP inhibitor that interferes with DNA repair mechanisms, we hypothesized their synergy in metastatic castration-resistant prostate cancer (mCRPC). We sought to demonstrate the safety and efficacy of olaparib + radium-223. We conducted a multicenter phase I 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases. The primary objective was to establish the RP2D of olaparib, with secondary objectives of safety, PSA response, alkaline phosphatase response, radiographic progression-free survival (rPFS), overall survival, and efficacy by homologous recombination repair (HRR) gene status. Twelve patients were enrolled; all patients received a prior androgen receptor signaling inhibitor (ARSI; 100%) and 3 patients (25%) prior docetaxel. Dose-limiting toxicities (DLT) included cytopenias, fatigue, and nausea. No DLTs were seen in the observation period however delayed toxicities guided the RP2D. The RP2D of olaparib was 200 mg orally twice daily with radium-223. The most common treatment-related adverse events were fatigue (92%) and anemia (58%). The rPFS at 6 months was 58% (95% confidence interval, 27%-80%). Nine patients were evaluable for HRR gene status; 1 had a BRCA2 alteration (rPFS 11.8 months) and 1 had a CDK12 alteration (rPFS 3.1 months). Olaparib can be safely combined with radium-223 at the RP2D 200 mg orally twice daily with fixed dose radium-223. Early clinical benefit was observed and will be investigated in a phase II study.

Lutein, a plant-derived xanthophyl-carotenoid, is an exceptional antioxidant and anti-inflammatory constituent found in food. High dietary intake of lutein is beneficial against eye disease, improves cardiometabolic health, protects from neurodegenerative diseases, and is beneficial for liver, kidney, and respiratory health. Lutein protects against oxidative and nitrosative stress, both of which play a major role in long COVID and mRNA vaccination injury syndromes. Lutein is an important natural agent for therapeutic use against oxidative and nitrosative stress in chronic illnesses such as cardiovascular and neurodegenerative diseases and cancer. It can also potentially inhibit spike protein-induced inflammation. Rich dietary supplementation of lutein, naturally derived in non-biodegradable Extra Virgin Olive Oil (EVOO), can most optimally be used against oxidative and nitrosative stress during post-COVID and mRNA vaccination injury syndromes. Due to its high oleic acid (OA) content, EVOO supports optimal absorption of dietary lutein. The main molecular pathways by which the SARS-CoV-2 spike protein induces pathology, nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) and activated protein (AP)-1, can be suppressed by lutein. Synergy with other natural compounds for spike protein detoxification is likely.

Background/Objectives: Small airway disease/dysfunction (SAD) is crucial in obstructive airway diseases but is less investigated in interstitial lung disease (ILD). There are only a few physiological studies investigating SAD in the context of pulmonary fibrosis. Oscillometry is a simple technique that assesses SAD with minimal patient effort. In this study, we investigated the role of oscillometry in patients with mild pulmonary fibrosis without evident obstructive disorder, focusing on small airways. Methods: Oscillometry and pulmonary function test (PFT) data of consecutive patients newly diagnosed with pulmonary fibrosis of unknown etiology in a university hospital ILD clinic were collected and analyzed. Results: Data from 34 patients with mild pulmonary fibrosis were collected in 6 months. Disease severity, as evaluated by FVC, presented strong correlations with the oscillometry parameters: resistance (R5: r = −0.588, p < 0.001), reactance (X5: r = 0.671, p < 0.001), resonant frequency (Fres: r = −0.562, p = 0.001), and the area of reactance (AX: r = −0.515, p = 0.002). The oscillometry parameter R5-19-expressing was abnormal in 27% of patients, correlated with FEF25-75% (r = −0.370, p = 0.021) and was a predictor of a FEF25-75% < 60% pred. with AUC 0.738 (95%Cl 0.519–0.956). R5-19 correlated with FVC (r = −0.481, p = 0.004) and was the only SAD parameter that correlated with the composite physiologic index (CPI, r = 0.338, p = 0.04), while FEF 25-75% and RV/TLC% did not. Conclusions: Oscillometry is an easy to perform technique that may reveal early mechanical alterations caused by pulmonary fibrosis. Peripheral resistance, as expressed by R5-19, which identifies small airway dysfunction as a marker of peripheral lung pathology, may be complementary to pulmonary function testing and may also have prognostic implications for ILD patients.