Impact of Systemic Comorbidities on Ocular Hypertension and Open-Angle Glaucoma, in a Population from Spain and Portugal.

Open-angle glaucoma (OAG), the most prevalent clinical type of glaucoma, is still the main cause of irreversible blindness worldwide. OAG is a neurodegenerative illness for which the most important risk factor is elevated intraocular pressure (IOP). Many questions remain unanswered about OAG, such as whether nutritional or toxic habits, other personal characteristics, and/or systemic diseases influence the course of glaucoma. As such, in this study, we performed a multicenter analytical, observational, case-control study of 412 participants of both sexes, aged 40-80 years, that were classified as having ocular hypertension (OHT) or OAG. Our primary endpoint was to investigate the relationship between specific lifestyle habits; anthropometric and endocrine-metabolic, cardiovascular, and respiratory events; and commonly used psychochemicals, with the presence of OHT or OAG in an ophthalmologic population from Spain and Portugal. Demographic, epidemiological, and ocular/systemic clinical data were recorded from all participants. Data were analyzed using the R Statistics v4.1.2 and RStudio v2021.09.1 programs. The mean age was 62 ± 15 years, with 67-80 years old comprising the largest subgroup sample of participants in both study groups. The central corneal thickness (ultrasound pachymetry)-adjusted IOP (Goldman tonometry) in each eye was 20.46 ± 2.35 and 20.1 ± 2.73 mmHg for the OHT individuals, and 15.8 ± 3.83 and 16.94 ± 3.86 mmHg for the OAG patients, with significant differences between groups (both p = 0.001). The highest prevalence of the surveyed characteristics in both groups was for overweight/obesity and daily coffee consumption, followed by psychochemical drug intake, migraine, and peripheral vasospasm. Our data show that overweight/obesity, migraine, asthma, and smoking are major risk factors for conversion from OHT to OAG in this Spanish and Portuguese population.

The Relation of CFTR-Genotype and Associated Comorbidities to Development of Pulmonary Atelectasis in Cystic Fibrosis Patients

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Targeted Isolation of Anti-inflammatory Lignans from Justicia aequilabris by Molecular Networking Approach.

Herein, the isolation of secondary metabolites from the aerial parts of Justicia aequilabris guided by HPLC-MSn and molecular networking analyses is reported. Twenty-two known compounds were dereplicated. Three new lignans (aequilabrines A-C (1-3)) and three known compounds (lariciresinol-4'-O-ß-glucose (4), roseoside (5), and allantoin (6)) were obtained. The anti-inflammatory activity of compounds 1-3 was evaluated in vitro by inhibiting the nitric oxide production (NO) and pro-inflammatory activity on the cytokine IL-1ß. Compounds 2 and 3 showed significant inhibitory activity against NO production, with IC50 values of 9.1 and 7.3 µM, respectively. The maximum inhibition of IL-1ß production was 23.5% (1), 27.3% (2), and 32.5% (3).

Health-related quality of life of X-linked hypophosphatemia in Spain.

BACKGROUND: Health-related quality of life (HRQoL) of patients with X-linked hypophosphatemia (XLH) is lower than that of both the general population and the patients with other chronic diseases, mainly due to diagnostic delay, treatment difficulties, poor psychosocial support, and problems with social integration. Early diagnosis and optimal treatment are paramount to control the disease in patients with XLH, avoid complications, and maintain or improve their HRQoL. We, therefore, analyzed the HRQoL of pediatric and adult patients with XLH treated with conventional therapy in Spain. RESULTS: We used several versions of the EuroQol-5 dimensions (EQ-5D) instrument according to the age of patients with XLH. Then we compared the HRQoL of patients to that of the general Spanish population. Children with XLH (n = 21) had moderate problems in walking about (61.9%), washing or dressing themselves (9.52%), and performing their usual activities (33.33%). They also felt moderate pain or discomfort (61.9%) and were moderately anxious or depressed (23.81%). Adults with XLH (n = 29) had lower HRQoL, with problems in walking (93%, with 3.45% unable to walk independently), some level of pain (86%, with 3.45% experiencing extreme pain), problems with their usual activities (80%) and self-care (> 50%), and reported symptoms of anxiety and/or depression (65%). There were important differences with the general Spanish population. CONCLUSIONS: XLH impacts negatively on physical functioning and HRQoL of patients. In Spanish patients with XLH, the HRQoL was reduced despite conventional treatment, clearly indicating the need to improve the therapeutic approach to this disorder.

X-linked hypophosphatemia (XLH) is a severe inherited disease. It is caused by loss of phosphorus by kidneys. As a result, blood level of phosphorus is low, affectingX-linked hypophosphatemia (XLH) is a severe inherited disease. It is caused by loss of phosphorus by kidneys. As a result, blood level of phosphorus is low, affecting bones and muscles. Patients can have growth retardation, short stature, rickets, limb deformities, pain and other health problems despite traditional treatment. Consequently, their quality of life can be very bad. However, a recently available new treatment (burosumab) can improve this quality of life. We studied the quality of life of children and adults with XLH treated with traditional treatment in Spain. Results showed that children had moderate problems, but adults reported moderate-to-severe problems in walking and performing their usual activities and self-care. Pain and anxiety and/or depression were very frequent. There were important differences with the general Spanish population. Moreover, we also found that XLH is associated to high healthcare cost and even higher socioeconomic cost. Our results highlight the need of improving the treatment of XLH.bones and muscles. Patients can have growth retardation, short stature, rickets, limb deformities, pain and other health problems despite traditional treatment. Consequently, their quality of life can be very bad. However, a recently available new treatment (burosumab) can improve this quality of life. We studied the quality of life of children and adults with XLH treated with traditional treatment in Spain. Results showed that children had moderate problems, but adults reported moderate-to-severe problems in walking and performing their usual activities and self-care. Pain and anxiety and/or depression were very frequent. There were important differences with the general Spanish population. Moreover, we also found that XLH is associated to high healthcare cost and even higher socioeconomic cost. Our results highlight the need of improving the treatment of XLH.

Cost-effectiveness analysis of the first-line EGFR-TKIs in patients with advanced EGFR-mutated non-small-cell lung cancer.

AIM: To evaluate the cost-effectiveness of first-line treatments, such as erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib, for patients diagnosed with stage IIIB/IV NSCLC harboring EGFR mutations. MATERIALS & METHODS: A partitioned survival model was developed to estimate quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio (ICER) from the perspective of the Spanish National Health System. Two Bayesian NMAs were performed independently, by using the polynomial fraction method to fit Kaplan-Meier curves for overall survival and progression-free survival. Deterministic and probabilistic sensitivity analyses were performed to evaluate the uncertainty. RESULTS: The ICER was calculated for the four first-line treatments by comparing them with gefitinib, and the ratios obtained were as follows: €166,416/QALY for osimertinib, €183,682/QALY for dacomitinib, €167,554/QALY for afatinib, €36,196/QALY for erlotinib. It was seen that patients who received osimertinib presented higher QALYs (0.49), followed by dacomitinib (0.33), afatinib (0.32), erlotinib (0.31), and gefitinib (0.28). CONCLUSIONS: Gefitinib is the most cost-effective treatment. In terms of QALYs gained, Osimertinib was more effective than all other TKIs. Nevertheless, with a Spanish threshold of €24,000/QALY, the reduction in the acquisition cost of osimertinib will have to be greater than 70%, to obtain a cost-effectiveness alternative.

Antidiarrheal Effect of Zornia brasiliensis Vogel (Leguminosae) on Mice Involves Adrenergic Pathway Activation.

Several secondary metabolites have been isolated from Zornia brasiliensis (Leguminosae), mainly flavonoids. These compounds are known for many pharmacological actions, such as antispasmodic and antidiarrheal. Therefore, we evaluated the antidiarrheal effect of the ethanolic extract obtained from Zornia brasiliensis aerial parts (ZB-EtOHAP), as well as its underlying mechanisms. Castor-oil-induced diarrhea, fluid accumulation, and intestinal transit (normal and castor oil induced) were performed to assess the antidiarrheal, antisecretory, and antipropulsive activities of the extract. The involvement of opioid and adrenergic pathways was also investigated. ZB-EtOHAP inhibited, in a dose-dependent manner, both total defecation frequency and the number of watery stools. The extract showed no effect on fluid accumulation or normal intestinal transit. On the other hand, when the animals were pretreated with castor oil, the extract decreased the distance traveled by the marker in the small intestine. Investigation of the involvement of opioid and adrenergic systems showed that the pharmacological potency of the extract did not change in the presence of naloxone, but it was reduced in the presence of yohimbine. The data indicate that Zornia brasiliensis has an antidiarrheal effect due to inhibition of the intestinal motility through adrenergic pathway activation.

Titanium dioxide nanotubes with triazine-methacrylate monomer to improve physicochemical and biological properties of adhesives.

OBJECTIVE: Formulate experimental adhesives containing titanium dioxide nanotubes (nt-TiO2) or titanium dioxide nanotubes with a triazine-methacrylate monomer (nt-TiO2:TAT) and evaluate the effect of these fillers on the physical, chemical, and biological properties of the adhesives. METHODS: First, nt-TiO2 were synthesized via a hydrothermal method. The nt-TiO2 were mixed with a triazine-methacrylate monomer (TAT) to formulate nt-TiO2:TAT, which were characterized by transmission electron microscopy (TEM). The nt-TiO2, TAT, and nt-TiO2:TAT were evaluated via Fourier Transform Infrared, Ultraviolet-visible, and micro-Raman spectroscopies. An experimental adhesive resin was formulated with bisphenol A glycerolate dimethacrylates, 2-hydroxyethyl methacrylate, and photoinitiator/co-initiator system. nt-TiO2 or nt-TiO2:TAT were incorporated at 2.5 wt.% and 5 wt.% in the adhesive. The base resin without nt-TiO2 or nt-TiO2:TAT was used as a control group. The adhesives were evaluated for antibacterial activity, cytotoxicity, polymerization kinetics, degree of conversion (DC), Knoop hardness, softening in solvent (ΔKHN%), ultimate tensile strength (UTS), 24 h- and 1 year- microtensile bond strength (µ-TBS). RESULTS: TEM confirmed the nanotubular morphology of TiO2. FTIR, UV-vis, and micro-Raman analyses showed the characteristic peaks of each material, indicating the impregnation of TAT in the nt-TiO2. Adhesives with nt-TiO2:TAT showed antimicrobial activity against biofilm formation compared to control (p < 0.05), without differences in the viability of planktonic bacteria (p > 0.05). All groups showed high percentages of pulp cell viability. The polymerization kinetics varied among groups, but all presented DC above 50%. The addition of 5 wt.% of nt-TiO2 and both groups containing nt-TiO2:TAT showed higher values ​​of Knoop hardness compared to the control (p < 0.05). The groups with nt-TiO2:TAT presented lower ΔKHN% (p < 0.05) and higher UTS (p < 0.05) than the control group. After one year, the group with 5 wt.% of nt-TiO2, as well as both groups containing nt-TiO2:TAT, showed higher µ-TBS than the control (p < 0.05). SIGNIFICANCE: The mixing of a triazine-methacrylate monomer with the nt-TiO2 generated a filler that improved the physicochemical properties of the adhesive resins and provided antibacterial activity, which could assist in preventing carious lesions around tooth-resin interfaces. The set of physical, chemical, and biological properties of the formulated polymer, together with the greater stability of the bond strength over time, make nt-TiO2:TAT a promising filler for dental adhesive resins.

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.

BACKGROUND: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. METHODS: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. FINDINGS: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. INTERPRETATION: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. FUNDING: COALITION COVID-19 Brazil and EMS.

Lesión pulmonar de etiología micobacteriana / Pulmonary injury of mycobacterial etiology

Mycobacterium lentiflavum infrecuentemente provoca patogenicidad en el ser humano, aunque se ha descrito como causante de linfadenitis cervical y afectación pulmonar. Generalmente presenta un curso clínico poco agresivo y se asocia un patrón radiológico nódulo-bronquiectásico. En nuestro caso relatamos un paciente con clínica respiratoria inespecífica y presencia de bronquiectasias y lesiones de morfología pseudonodular en la tomografía computarizada (TC) torácica. En la TC torácica de control y tomografía por emisión de positrones (PET) se evidenció aumento de tamaño y del metabolismo de dichas lesiones. Se realiza biopsia para descartar malignidad creciendo en cultivo de la muestra Mycobacterium lentiflavum

Mycobacterium lentiflavum infrequently causes pathogenicity in humans, although it has been identified as causing cervical lymphadenitis and lung involvement. It usually has a poorly aggressive clinical course and a nodule-bronchiectatic radiological pattern is associated. In our case, we report a patient with a nonspecific respiratory clinic and presence of bronchiectasis and pseudonodular morphology lesions in thoracic computed tomography. In the thoracic CT scan of positron emission tomography (PET) there was evidence of an increase in the size and metabolism of these lesions. Biopsy is performed to rule out malignancy, with Mycobacterium lentiflavum growing in sample culture

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.

BACKGROUND: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. METHODS: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. RESULTS: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. CONCLUSIONS: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).

Mixing and matching methylotrophic enzymes to design a novel methanol utilization pathway in E. coli.

One-carbon (C1) compounds, such as methanol, have recently gained attention as alternative low-cost and non-food feedstocks for microbial bioprocesses. Considerable research efforts are thus currently focused on the generation of synthetic methylotrophs by transferring methanol assimilation pathways into established bacterial production hosts. In this study, we used an iterative combination of dry and wet approaches to design, implement and optimize this metabolic trait in the most common chassis, E. coli. Through in silico modelling, we designed a new route that "mixed and matched" two methylotrophic enzymes: a bacterial methanol dehydrogenase (Mdh) and a dihydroxyacetone synthase (Das) from yeast. To identify the best combination of enzymes to introduce into E. coli, we built a library of 266 pathway variants containing different combinations of Mdh and Das homologues and screened it using high-throughput 13C-labeling experiments. The highest level of incorporation of methanol into central metabolism intermediates (e.g. 22% into the PEP), was obtained using a variant composed of a Mdh from A. gerneri and a codon-optimized version of P. angusta Das. Finally, the activity of this new synthetic pathway was further improved by engineering strategic metabolic targets identified using omics and modelling approaches. The final synthetic strain had 1.5 to 5.9 times higher methanol assimilation in intracellular metabolites and proteinogenic amino acids than the starting strain did. Broadening the repertoire of methanol assimilation pathways is one step further toward synthetic methylotrophy in E. coli.

Bioactive Compounds from the Aerial Parts of Evolvulus linarioides.

Three new caryophyllane-type sesquiterpenoids, linariophyllenes A-C (1-3), two new hamamelitol derivatives, linaritols A (4) and B (5), two new chromones, linariosides A (6) and B (7), and three known chromones, cnidimol C (8), monnieriside A (9), and undulatoside A (10), were identified from the aerial parts of Evolvulus linarioides. The structures of these compounds were elucidated by NMR, MS, and IR data. The absolute configurations of compounds 1-5 and 7 were established via electronic circular dichroism data. The anti-inflammatory potential of compounds 1-5 and 7-10 was evaluated by determining their ability to inhibit the production of nitric oxide (NO) and proinflammatory cytokine IL-1ß by stimulated J774 macrophages. Compounds tested at noncytotoxic concentrations inhibited NO production by macrophages, exhibiting IC50 values between 17.8 and 66.2 µM, and inhibited IL-1ß production by stimulated macrophages by 72.7-96.2%.

Citrulline and muscle protein homeostasis in three different models of hypercatabolism.

Supplementation of enteral nutrition (EN) by specific amino acids (AAs) has been proposed to prevent muscle protein loss in intensive care unit (ICU) patients. Citrulline (Cit), which has been shown to stimulate muscle protein synthesis in other situations, may be of interest in this setting. Our aim was to assess the effect of Cit in three catabolic models relevant to critical illness: endotoxemia (LPS), traumatic brain injury (TBI), and TBI with infectious complications (TBI-Ec), which are characterized by different alterations in protein homeostasis. Fifty-eight male Sprague-Dawley rats (200-220 g) were randomized to receive a standard diet ad libitum (CON, n = 9) or to undergo catabolic injuries on day 0 (D0, n = 49), and EN (Sondalis HP energy® 290 kcal/kg/d) from day 1 (D1) combined with Cit (2 g/kg/d) or isonitrogenous non-essential AAs (NEAAs) until day 3 (D3). Endotoxemia was induced by IP injection of LPS from E. coli (3 mg/kg), TBI by hydraulic percussion, and infectious complications (TBI-Ec) by administration of luminescent E. coli on D1. Nitrogen balance (ΔN) and 3-methylhistidine (3-MHis) were measured daily. Muscle protein synthesis (MPS, measured by the SUnSET method) and mTORC1 activation (S6K-1 and 4E-BP1 phosphorylation) were measured on D3 2 h after the arrest of enteral nutrition in soleus, extensor digitorum longus (EDL), gastrocnemius and tibialis muscles. ΔN was lower (p < 0.001) in all three models of injury compared with basal and CON from D1 to D3, and more negative in the LPS-CIT (p < 0.05) than in the LPS group. The 3-MHis/creatinine ratio was significantly increased on D1 in all groups compared with CON, and on D2 only in the LPS and TBI groups (p < 0.0001, LPS and TBI vs. CON). MPS was similar in all groups in soleus and tibialis but significantly higher in EDL in LPS-CIT [LPS-CIT: 4.5 ± 1.7 (mean ± SD) vs. CON: 2.3 ± 1.2; and vs. LPS-NEAA: 3.1 ± 2.3] and in gastrocnemius (LPS-CIT vs. CON; p = 0.05). S6K-1 phosphorylation in the EDL was also higher in LPS-CIT vs. CON (LPS-CIT: 0.94 ± 0.51 CON: 0.42 ± 0.28), but not in gastrocnemius. IL-6 plasma level was significantly higher in all the catabolic groups vs. CON (p < 0.005) with no difference between treatments (Cit or NEAAs). In conclusion, the TBI model showed only a rise in muscle proteolysis, whereas the LPS model displayed a rise in both protein synthesis and proteolysis. Secondly, our results show that the Cit effect varies according to the type of injury and to the muscle under study. The stimulation of MPS rate and the mTOR pathway in LPS-treated rats contrasts with degraded ΔN, suggesting that the Cit effect on protein metabolism in critically ill rats is limited at the whole-body level.

The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2016: a summary.

BACKGROUND: This article summarizes the ERA-EDTA Registry's 2016 Annual Report, by describing the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2016 within 36 countries. METHODS: In 2017 and 2018, the ERA-EDTA Registry received data on patients undergoing RRT for ESRD in 2016 from 52 national or regional renal registries. In all, 32 registries provided individual patient data and 20 provided aggregated data. The incidence and prevalence of RRT and the survival probabilities of these patients were determined. RESULTS: In 2016, the incidence of RRT for ESRD was 121 per million population (pmp), ranging from 29 pmp in Ukraine to 251 pmp in Greece. Almost two-thirds of patients were men, over half were aged ≥65 years and almost a quarter had diabetes mellitus as their primary renal diagnosis. Treatment modality at the start of RRT was haemodialysis for 84% of patients. On 31 December 2016, the prevalence of RRT was 823 pmp, ranging from 188 pmp in Ukraine to 1906 pmp in Portugal. In 2016, the transplant rate was 32 pmp, varying from 3 pmp in Ukraine to 94 pmp in the Spanish region of Catalonia. For patients commencing RRT during 2007-11, the 5-year unadjusted patient survival probability on all RRT modalities combined was 50.5%. For 2016, the incidence and prevalence of RRT were higher among men (187  and 1381 pmp) than women (101 and 827 pmp), and men had a higher rate of kidney transplantation (59 pmp) compared with women (33 pmp). For patients starting dialysis and for patients receiving a kidney transplant during 2007-11, the adjusted patient survival probabilities appeared to be higher for women than for men.

Afectación cardiaca en pacientes con enfermedad hepática avanzada, más allá del síndrome hepatopulmonar / Cardiac involvement in patients with end-stage liver disease, beyond the hepatopulmonary syndrome

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