Parameters for delivering ethnically and gender-sensitive primary care in cardiovascular health through telehealth. Systematic review.

OBJECTIVE: To determine the parameters for providing primary care in cardiovascular health, with an ethnic and gender focus through telemedicine. STUDY DESIGN: Systematic Literature Review. METHODS: A systematic review was conducted using databases including PUBMED, Cochrane Library, CINAHL, EMBASE VHL, and other relevant sources. We included articles published in the last 15 years on parameters of telemedicine care with a differential approach focusing on ethnicity and gender. Screening, full-text reading, and information extraction were performed in duplicate and independently, though methodological quality assessment was not conducted. RESULTS: Twenty-eight studies were included, with 46.43% originating from Australia and 50.00% employing a qualitative approach. Thirty-five point seventy-one percent provided operational recommendations, and 32.14% related to the ethnic approach. Seven operational categories were identified: holistic approach to health, flexible approach to health, accessible health services, continuous improvement in service quality, culturally appropriate and qualified workforce, self-determination and empowerment, and community participation. Additionally, five categories were identified pertaining to the ethnic approach: public policy in favor of ancestral knowledge in primary health care, training of community agents and health personnel from an intercultural perspective, complementarity between traditional and western health practices, and the recognition of telehealth's value in intercultural approaches. CONCLUSIONS: There is a need to adjust operational aspects related to the implementation of indigenous public policy, and to increase the number of qualified community human resources to provide holistic, comprehensive, and culturally appropriate care. Regarding gender, there is a necessity to implement public policy based on health determinants that will dismantle barriers to accessing gender-specific services and comprehensively assess cardiovascular risk.

Intramolecular Thiol- and Selenol-Assisted Delivery of Hydrogen Sulfide.

Arylthioamides have been frequently employed to assess the chemical biology and pharmacology of hydrogen sulfide (H2 S). From this class of donors, however, extremely low H2 S releasing efficiencies have been reported and proper mechanistic studies have been omitted. Consequently, millimolar concentrations of arylthioamides are required to liberate just trace amounts of H2 S, and via an unidentified mechanistic pathway, which obfuscates the interpretation of any biological activity that stems from their use. Herein, we report that H2 S release from this valuable class of donors can be markedly enhanced through intramolecular nucleophilic assistance. Specifically, we demonstrate that both disulfide- and diselenide-linked thioamides are responsive to biologically relevant concentrations of glutathione and release two molar equivalents of H2 S via an intramolecular cyclization that significantly augments their rate and efficiency of sulfide delivery in both buffer and live human cells.

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain.

A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain.

Highly selective staining and quantification of intracellular lipid droplets with a compact push-pull fluorophore based on benzothiadiazole.

A robust lipophilic dye, based on the structures of the benzothiadiazole heterocycle, was shown to be a potent fluorescent stain for the selective imaging of lipid droplets (LDs) within both live and fixed human cells. Its small molecular framework, large Stokes shift, and vastly improved photostability over that of the current status quo, Nile Red, highlight its tremendous potential as a versatile chemical tool for facilitating LD imaging and research.

An Innovative Hydrogen Peroxide-Sensing Scaffold and Insight Towards its Potential as an ROS-Activated Persulfide Donor.

Reactive sulfur species, such as hydrogen sulfide, persulfides, and polysulfides, have recently emerged as key signaling molecules and important physiological mediators within mammalian systems. To better assess the therapeutic potential of their exogenous administration, we report on the development of a unique hydrogen peroxide (H2 O2 )-sensing motif and its capacity for providing cellular protection against oxidative stress while serving as a reactive oxygen species (ROS)-activated persulfide donor. With the strategic implementation of a gem-dimethyl group to promote both stability and cyclization, we found the initial rate of payload release from this newly derived scaffold to be directly proportional to the concentration of H2 O2 and to proceed via an unprecedented pathway that avoids the production of electrophilic byproducts, a severe limitation that has plagued the physiological application of previous designs.

Selenosulfides Tethered to gem-Dimethyl Esters: A Robust and Highly Versatile Framework for H2 S Probe Development.

Selenosulfides coupled to gem-dimethyl esters provide an exceptional platform for H2 S probe development. With the sulfur half being nonessential to its high reactivity and selectivity towards H2 S, we highlight the unique flexibility of our design by improving its biocompatibility and tissue specificity through structural modifications of its sulfide moiety.

Infections in newly diagnosed Spanish patients with systemic lupus erythematosus: data from the RELES cohort.

OBJECTIVES: Using data of patients from the inception cohort Registro Español de Lupus Eritematoso Sistémico (RELES), we aimed to analyse the incidence of severe infection in the first two years of follow-up and how predictors of infection change during the course of systemic lupus erythematosus (SLE). MATERIAL AND METHODS: The study included 282 patients. Markers of lupus activity, prednisone doses and immunosuppressive therapy were compared between patients with and without infections in the first and second year of the disease. Drug therapy administered during the first month of follow-up has been considered as a potential predictor of infections during the first year and medications administered during the first year have been considered potential predictors of infections during the second. RESULTS: Nineteen patients (6.4%) had a documented episode of major infection during the first year of follow-up and 16 patients (5.67%) during the second. The following variables were associated with infections during the first year: hypocomplementaemia at diagnosis ( p < 0.01), nephritis at diagnosis ( p = 0.03), SLEDAI score ( p < 0.01), prednisone >30 mg/day ( p = 0.01), methylprednisolone pulses ( p = 0.05) and mycophenolate use ( p = 0.02). The independent variables in the final model were hypocomplementaemia (odds ratio (OR) 4.41, 95% confidence interval (CI) 0.96-20.20, p = 0.05) and a dose of prednisone >30 mg/day (OR 6.60, 95% CI 1.34-32.42, p = 0.02). The following variables were associated with infections during the second year: dose of prednisone > 7.5 mg/day ( p = 0.05), methylprednisolone pulses ( p = 0.07), duration of therapy with antimalarials ( p = 0.09), therapy with mycophenolate ( p = 0.01), therapy with cyclophosphamide ( p = 0.05). The independent variables in the final model were a dose of prednisone >7.5 mg/day (OR 4.52, 95% CI 0.99-21, p = 0.054) and duration of therapy with antimalarials as a protective factor (OR 0.99, 95% CI 0.99-1.00, p = 0.053). CONCLUSIONS: The low incidence of early infections in the RELES cohort is partially explained by the extended use of antimalarials and by the general avoidance of prolonged high doses of prednisone. Patients with high baseline activity are at a higher risk of infection during the first months but therapy with medium-high doses of prednisone is the main predictor of infectious events. Thus, every effort should be made to limit oral glucocorticoid use from the very beginning of the SLE course.

Postoperative effects on lower third molars of using mouthwashes with super-oxidized solution versus 0.2% chlorhexidine gel: A randomized double-blind trial.

BACKGROUND: The main objective of the present study is to evaluate the effects and possible benefits with regard to the postoperative period of lower third molar extractions, comparing the intraalveolar application of a bioadhesive gel of 0.2% chlorhexidine (CHX) to the use of a mouthwash with a super-oxidized solution, (SOS) Dermacyn® Wound Care (Oculus Innovative Sciences lnc., California, USA). MATERIAL AND METHODS: A randomized double-blind study was carried out in 20 patients with a split-mouth design, with a total of 40 extractions of symmetrically impacted bilateral lower third molars. Patients were divided into two groups, a control group (C = 20) and an experimental group (D = 20). Any infectious complications, wound healing, plaque accumulation in the stitches, and presence of trismus and inflammation were evaluated using the distance between different facial points, at three, eight, and fifteen days after extraction. Pain, swelling, and amount of analgesics taken were evaluated using the VAS scale throughout the 15 days following extraction. Tolerance to treatment was evaluated using a verbal scale. Results were statistically compared using the Student's t- and chi-squared tests. RESULTS: No statistically significant differences were found between the two groups with regard to infectious complications, swelling, or wound healing. Use of analgesics and self-reported pain levels were slightly lower in the experimental group than in the control group during days 6 and 7 of the study (p < 0.05). The global treatment tolerance was satisfactory and similar in both groups. CONCLUSIONS: Both CHX and SOS are effective at improving the postoperative period after extraction of lower third molars.

Microfluidic devices for the study of sperm migration.

Microfluidics technology offers us an opportunity to model the biophysical and biochemical environments encountered by sperm moving through the female reproductive tract and, at the same time, to study sperm swimming dynamics at a quantitative level. In humans, coitus results in the deposition of sperm in the vagina at the entrance to the cervix. Consequently, sperm must swim or be drawn through the cervix, uterus, uterotubal junction and oviductal isthmus to reach the oocyte in the oviductal ampulla. Only a very small percentage of inseminated sperm reach the ampulla in the periovulatory period, indicating that strong selection pressures act on sperm during migration. A better understanding of how sperm interact with the female tract would inspire improvements in diagnosis of fertility problems and development of novel-assisted reproductive technologies that minimize damage to sperm and mimic natural selection pressures on sperm.

Assessing the feasibility of two hybrid MBR systems using PAC for removing macro and micropollutants.

The removal of 10 organic micropollutants (OMPs) was studied in two MBRs using different types of membrane (flat sheet microfiltration, MF, and hollow fiber ultrafiltration, UF) operated under aerobic conditions with direct dosing of powdered activated carbon (PAC) in the mixed liquor. In both reactors high COD degradation and nitrification were achieved (>95%), while nitrate removal was only observed after PAC addition. The adsorbent improved the operation of both systems (sludge properties and microbial diversity) which resulted in an enhancement of the quality of the final effluent. The operation with both types of membrane was feasible being the UF system slightly better in terms of the quality of the final effluent. The strategy of 250 mg/L of PAC additions every 35 days was validated according to the results obtained for the removal of the most recalcitrant OMPs, such as diclofenac and carbamazepine. Concerning the type of membrane, only significant differences were observed for diclofenac and roxithromycin, which were better removed in the UF configuration. These differences were attributed to sorption and/or further biotransformation processes occurring in the cake layer.

Gallbladder perforation: morbidity, mortality and preoperative risk prediction.

INTRODUCTION: Gallbladder perforation (GBP) is a life threatening complication of acute cholecystitis occurring in approximately 2-11 % of patients. The aim of this study is to analyse all factors associated with morbidity and mortality and assess the accuracy of preoperative risk prediction scores. METHODS: Medical records of 1,033 patients who underwent cholecystectomy for acute cholecystitis in our centre between 2002 and 2012 were reviewed. Preoperative, intraoperative and postoperative relevant data were analysed with univariate and multivariate statistical methods to identify all factors associated with postoperative complications and mortality. Accuracy of ASA, POSSUM and APACHE II scores was also compared using receiver-operating characteristics methodology. RESULTS: 137 (12.4 %) patients with gallbladder perforation were identified. Morbidity and mortality rates were 57.7 and 9.5 %, respectively. At multivariate analysis, preoperative albumin (P = 0.007, OR 0.175), open surgery (P = 0.011, OR 37.78) and preoperative sepsis (P = 0.002, OR 51.647) were associated with complications, and preoperative sepsis was the only factor independently associated with hospital mortality (P = 0.007, OR 9.127). Both POSSUM and APACHE II scores were superior to ASA score in risk prediction. CONCLUSION: Preoperative severe sepsis is the most important factor associated with postoperative morbidity and mortality following GBP, and it can be helpful to identify those patients needing the highest level of care possible.

[Applications of MALDI-TOF technology in clinical microbiology]. / Applications de la technologie MALDI-TOF en microbiologie clinique.

Until now, the identification of micro-organisms has been based on the cultural and biochemical characteristics of bacterial and fungal species. Recently, Mass Spectrometry type Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF MS) was developed in clinical microbiology laboratories. This new technology allows identification of micro-organisms directly from colonies of bacteria and fungi within few minutes. In addition, it can be used to identify germs directly from positive blood culture bottles or directly from urine samples. Other ways are being explored to expand the use of MALDI-TOF in clinical microbiology laboratories. Indeed, some studies propose to detect bacterial antibiotic resistance while others compare strains within species for faster strain typing. The main objective of this review is to update data from the recent literature for different applications of MALDI-TOF technique in microbiological diagnostic routine.

Light coupling in single-track guiding structures obtained by femtosecond laser writing in lithium niobate.

In this Letter we present a study of light coupling into a pair of Type II waveguides made of lithium niobate crystals by using femtosecond laser writing. Simulations based on the beam propagation method and optical fiber coupling experiments with the guiding structures showed good agreement. The presented results can be a suitable tool for designing high-performance optical circuits using femtosecond laser writing techniques for different technological requirements.

Aromatase and estrogen receptor alpha mRNA expression as prognostic biomarkers in patients with astrocytomas.

Estrogens are oncogenic hormones at a high level in breast, prostate, endometrial and lung cancer. Estrogens are synthesized by aromatase which has been used as a biomarker both in breast and lung cancer. Estrogen biological activities are executed by their classic receptors (ERα and ERß). ERα has been described as a cancer promoter and ERß, as a possible tumor suppressor. Both receptors are present at low levels in primary multiforme glioblastoma (GBM). The GBM frequency is 50 % higher in men than in women. The GBM patient survival period ranges from 7 to 18 months. The purpose of this pilot study was to evaluate aromatase and estrogen receptor expression, as well as 17ß-estradiol concentration in astrocytoma patients biopsies to obtain a prognosis biomarker for these patients. We analyzed 36 biopsies of astrocytoma patients with a different grade (I-IV) of malignity. Aromatase and estrogen receptor mRNA expression were analyzed by semiquantitative RT-PCR, and the E2 levels, by ELISA. E2 concentration was higher in GBM, compared to grade II or III astrocytomas. The number of cells immunoreactive to aromatase and estrogen receptors decreased as the grade of tumor malignity increased. Aromatase mRNA expression was present in all biopsies, regardless of malignity grade or patient age or gender. The highest expression of aromatase mRNA in GBM patients was associated to the worst survival prognostic (6.28 months). In contrast lowest expression of ERα mRNA in astrocytoma patients had a worst prognosis. In conclusion, aromatase and ERα expression could be used as prognosis biomarkers for astrocytoma patients.

Alternatives for the administration of oral antineoplastics in patients with swallowing difficulties.

Oncology patients often experience swallowing difficulties, which can compromise adherence to treatment and consequently reduce its effectiveness. Improper handling of these hazardous drugs can lead to the risk of inhalation of particles or other exposures endangering the health of the persons involved such as nurses and pharmacists. The aim of this review is to analyse and update the recommendations for the manipulation of oral antineoplastic drugs in patients with swallowing difficulties. A literature review of articles, websites, guidelines and other documents published up to about the conditions of handling and administration of oral antineoplastic agents in oncology and oncohaematology was carried out. A table of 110 active principles was compiled. The information was grouped according to the name of the drug, instructions for oral and nasogastric tube administration and suggested recommendations. Among the drugs reviewed, 66.4% were suitable for dissolution. Although there is a lot of information in the literature, the nonstop development of new oncological drugs requires continuous updating. Therefore, we have collected the most recent data to provide a consultation tool for healthcare professionals and patients with swallowing difficulties.

This review can be used by all types of healthcare professionals, especially nurses, who handle oncological medicinal drugs. In addition, the safest handling methods for the worker have been recommended.

Preventive strategies in paediatric cardiovascular surgery: impact on surgical site infections and beyond.

BACKGROUND: Surgical management of congenital heart disease (CHD) has increased worldwide, but healthcare-associated infections (HAIs) can threaten these efforts. AIM: To analyse the incidence of HAI, the impact of preventive interventions, and microbiological profiles in a paediatric cardiovascular surgery programme. METHODS: Cohort study including children aged <12 years with CHD who underwent cardiovascular surgery between 2010 and 2021 in Medellín, Colombia (a middle-income setting). Data were collected from medical and laboratory records and infection control programme databases. Impact of various preventive interventions was assessed using a Poisson model. P < 0.05 was considered statistically significant. FINDINGS: A total of 2512 surgeries were analysed. Incidence of surgical site infection (SSI) was 5.9%, followed by central line-associated bloodstream infection (CLABSI; 4.7%), catheter-associated urinary tract infection (CAUTI; 2.2%), and ventilator-associated pneumonia (VAP; 1.4%). Most of the strategies focused on preventing SSI, resulting in a reduction from 9.5% in 2010 to 3.0% in 2021 (P = 0.030). Antibiotic prophylaxis based on patient weight and continuous infusion had an impact on reducing SSI (RR: 0.56; 95% CI: 0.32-0.99). Vacuum-assisted closure (VAC) in clean wounds reduced 100% of infections. No significant risk reduction was observed for other HAI with the implemented interventions. CONCLUSION: Preventive strategies effectively reduced SSI but no other infections, emphasizing the need for targeted approaches to address a broader spectrum of HAI successfully.

Occurrence and fate of CECs (OMPs, ARGs and pathogens) during decentralised treatment of black water and grey water.

Decentralised wastewater treatment is becoming a suitable strategy to reduce cost and environmental impact. In this research, the performance of two technologies treating black water (BW) and grey water (GW) fractions of urban sewage is carried out in a decentralised treatment of the wastewater produced in three office buildings. An Anaerobic Membrane Bioreactor (AnMBR) treating BW and a Hybrid preanoxic Membrane Bioreactor (H-MBR) containing small plastic carrier elements, treating GW were operated at pilot scale. Their potential on reducing the release of contaminants of emerging concern (CECs) such as Organic Micropollutants (OMPs), Antibiotic Resistance Genes (ARGs) and pathogens was studied. After 226 d of operation, a stable operation was achieved in both systems: the AnMBR removed 92.4 ± 2.5 % of influent COD, and H-MBR removed 89.7 ± 3.5 %. Regarding OMPs, the profile of compounds differed between BW and GW, being BW the matrix with more compounds detected at higher concentrations (up to µg L-1). For example, in the case of ibuprofen the concentrations in BW were 23.63 ± 3.97 µg L-1, 3 orders of magnitude higher than those detected in GW. The most abundant ARGs were sulfonamide resistant genes (sul1) and integron class 1 (intl1) in both BW and GW. Pathogenic bacteria counts were reduced between 1 and 3 log units in the AnMBR. Bacterial loads in GW were much lower than in BW, being no bacterial re-growth observed for the GW effluents after treatment in the H-MBR. None of the selected enteric viruses was detected in GW treatment line.

Traumatic brain injury promotes neurogenesis at the cost of astrogliogenesis in the adult hippocampus of male mice.

Traumatic brain injury (TBI) can result in long-lasting changes in hippocampal function. The changes induced by TBI on the hippocampus contribute to cognitive deficits. The adult hippocampus harbors neural stem cells (NSCs) that generate neurons (neurogenesis), and astrocytes (astrogliogenesis). While deregulation of hippocampal NSCs and neurogenesis have been observed after TBI, it is not known how TBI may affect hippocampal astrogliogenesis. Using a controlled cortical impact model of TBI in male mice, single cell RNA sequencing and spatial transcriptomics, we assessed how TBI affected hippocampal NSCs and the neuronal and astroglial lineages derived from them. We observe an increase in NSC-derived neuronal cells and a concomitant decrease in NSC-derived astrocytic cells, together with changes in gene expression and cell dysplasia within the dentate gyrus. Here, we show that TBI modifies NSC fate to promote neurogenesis at the cost of astrogliogenesis and identify specific cell populations as possible targets to counteract TBI-induced cellular changes in the adult hippocampus.

[SUNCT/SUNA: frequently misdiagnosed as trigeminal neuralgia?] / SUNCT/SUNA: ¿frecuentemente mal diagnosticada como neuralgia del trigémino?

OBJECTIVE: Identify the number of cases with a possible diagnosis of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) in patients with a previous diagnosis of Trigeminal Neuralgia (TN) at the Neurology Service of the National Medical Center 20 de Noviembre. This will confirm that these trigeminal-autonomic cephalalgias should be ruled out and considered as differential diagnoses of trigeminal neuralgia. PATIENTS AND METHODS: Cross-sectional and retrospective study. The complete electronic medical records of 100 patients with a diagnosis of TN were evaluated during the period from April 2010 to May 2020. Autonomic symptoms were intentionally searched for in these patients and compared with the diagnostic criteria of SUNCT and SUNA of the 3rd edition of the International Classification of Headache Disorders. Chi-square tests and subsequent bivariate regression were performed to determine the association between variables. RESULTS: One hundred patients with a diagnosis of TN were included. After reviewing the clinical manifestations, 12 patients with autonomic symptoms were found and compared with the diagnostic criteria of SUNCT and SUNA. However, they did not meet the absolute criteria to be diagnosed with the previously mentioned diseases, nor to be ruled out. CONCLUSIONS: TN is a painful and frequent entity that can present with autonomic symptoms, therefore making it important to identify SUNCT and SUNA as differential diagnoses, to recognize them and treat them appropriately.

TITLE: SUNCT/SUNA: ¿frecuentemente mal diagnosticada como neuralgia del trigémino?Objetivo. Identificar el número de casos con posible diagnóstico de cefalea neuralgiforme unilateral de corta duración con inyección conjuntival y lagrimeo (SUNCT) o cefalea neuralgiforme unilateral de corta duración con síntomas autonómicos craneales (SUNA) en pacientes con un previo diagnóstico de neuralgia del trigémino (NT) en el servicio de neurología del Centro Médico Nacional 20 de Noviembre, comprobando así que estas cefaleas trigeminoautonómicas deben ser descartadas y consideradas como diagnósticos diferenciales de la NT. Pacientes y métodos. Estudio transversal y retrospectivo. Se evaluaron los expedientes clínicos electrónicos completos de 100 pacientes con diagnóstico de NT durante el período de abril de 2010 a mayo de 2020. Intencionalmente se buscaron síntomas autonómicos en éstos y se compararon con los criterios diagnósticos de SUNCT y SUNA de la Clasificación Internacional de las Cefaleas, tercera edición. Se realizaron pruebas de chi cuadrado y posteriormente de regresión bivariada para determinar la asociación entre las variables. Resultados. Se incluyó a 100 pacientes con diagnóstico de NT. Tras la revisión de las manifestaciones clínicas, se encontró a 12 pacientes con síntomas autonómicos y se compararon con los criterios diagnósticos de SUNCT y SUNA. Estos no cumplieron los criterios absolutos para ser diagnosticados con las enfermedades previamente mencionadas; sin embargo, cumplieron las características del espectro de cefaleas trigeminoautonómicas. Conclusión. La NT es una entidad dolorosa y frecuente que puede presentar síntomas autonómicos, y es importante pensar en diagnósticos diferenciales, como la SUNCT y la SUNA, para la identificación y el tratamiento correctos.

Discovery of endogenous nitroxyl as a new redox player in Arabidopsis thaliana.

Nitroxyl (HNO) is the one-electron reduced and protonated congener of nitric oxide (•NO), owning a distinct chemical profile. Based on real-time detection, we demonstrate that HNO is endogenously formed in Arabidopsis. Senescence and hypoxia induce shifts in the redox balance, triggering HNO decay or formation mediated by non-enzymatic •NO/HNO interconversion with cellular reductants. The stimuli-dependent HNO generation supports or competes with •NO signalling, depending on the local redox environment.