Chronic intermittent hypoxia-induced cardiovascular and renal dysfunction: from adaptation to maladaptation.

Chronic intermittent hypoxia (CIH) is the dominant pathological feature of human obstructive sleep apnoea (OSA), which is highly prevalent and associated with cardiovascular and renal diseases. CIH causes hypertension, centred on sympathetic nervous overactivity, which persists following removal of the CIH stimulus. Molecular mechanisms contributing to CIH-induced hypertension have been carefully delineated. However, there is a dearth of knowledge on the efficacy of interventions to ameliorate high blood pressure in established disease. CIH causes endothelial dysfunction, aberrant structural remodelling of vessels and accelerates atherosclerotic processes. Pro-inflammatory and pro-oxidant pathways converge on disrupted nitric oxide signalling driving vascular dysfunction. In addition, CIH has adverse effects on the myocardium, manifesting atrial fibrillation, and cardiac remodelling progressing to contractile dysfunction. Sympatho-vagal imbalance, oxidative stress, inflammation, dysregulated HIF-1α transcriptional responses and resultant pro-apoptotic ER stress, calcium dysregulation, and mitochondrial dysfunction conspire to drive myocardial injury and failure. CIH elaborates direct and indirect effects in the kidney that initially contribute to the development of hypertension and later to chronic kidney disease. CIH-induced morphological damage of the kidney is dependent on TLR4/NF-κB/NLRP3/caspase-1 inflammasome activation and associated pyroptosis. Emerging potential therapies related to the gut-kidney axis and blockade of aryl hydrocarbon receptors (AhR) are promising. Cardiorenal outcomes in response to intermittent hypoxia present along a continuum from adaptation to maladaptation and are dependent on the intensity and duration of exposure to intermittent hypoxia. This heterogeneity of OSA is relevant to therapeutic treatment options and we argue the need for better stratification of OSA phenotypes.

Control of Arterial Hypertension by the AhR Blocker CH-223191: A Chronopharmacological Study in Chronic Intermittent Hypoxia Conditions.

Chronic intermittent hypoxia (CIH) is a major contributor to the development of hypertension (HTN) in obstructive sleep apnea (OSA). OSA subjects frequently display a non-dipping pattern of blood pressure (BP) and resistant HTN. After discovering that AHR-CYP1A1 axis is a druggable target in CIH-HTN, we hypothesized that CH-223191 could control BP in both active and inactive periods of the animals, recovering the BP dipping profile in CIH conditions.We evaluated the chronopharmacology of the antihypertensive efficacy of the AhR blocker CH-223191 in CIH conditions (21% to 5% of O2, 5.6 cycles/h, 10.5 h/day, in inactive period of Wistar rats). BP was measured by radiotelemetry, at 8 am (active phase) and at 6 pm (inactive phase) of the animals. The circadian variation of AhR activation in the kidney in normoxia was also assessed, measuring the CYP1A1 (hallmark of AhR activation) protein levels.Despite drug administration before starting the inactive period of the animals, CH-223191 was not able to decrease BP during the inactive phase, in CIH conditions, therefore not reverting the non-dipping profile. These results suggest that a higher dose or different time of administration of CH-223191 might be needed for an antihypertensive effect throughout the 24-h cycle.

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine.

In this review encouraged by original data, we first provided in vivo evidence that the kidney, comparative to the liver or brain, is an organ particularly rich in cysteine. In the kidney, the total availability of cysteine was higher in cortex tissue than in the medulla and distributed in free reduced, free oxidized and protein-bound fractions (in descending order). Next, we provided a comprehensive integrated review on the evidence that supports the reliance on cysteine of the kidney beyond cysteine antioxidant properties, highlighting the relevance of cysteine and its renal metabolism in the control of cysteine excess in the body as a pivotal source of metabolites to kidney biomass and bioenergetics and a promoter of adaptive responses to stressors. This view might translate into novel perspectives on the mechanisms of kidney function and blood pressure regulation and on clinical implications of the cysteine-related thiolome as a tool in precision medicine.

AHR canonical pathway: in vivo findings to support novel antihypertensive strategies.

Essential hypertension (HTN) is a disease where genetic and environmental factors interact to produce a high prevalent set of almost indistinguishable phenotypes. The weak definition of what is under the umbrella of HTN is a consequence of the lack of knowledge on the players involved in environment-gene interaction and their impact on blood pressure (BP) and mechanisms. The disclosure of these mechanisms that sense and (mal)adapt to toxic-environmental stimuli might at least determine some phenotypes of essential HTN and will have important therapeutic implications. In the present manuscript, we looked closer to the environmental sensor aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor involved in cardiovascular physiology, but better known by its involvement in biotransformation of xenobiotics through its canonical pathway. This review aims to disclose the contribution of the AHR-canonical pathway to HTN. For better mirror the complexity of the mechanisms involved in BP regulation, we privileged evidence from in vivo studies. Here we ascertained the level of available evidence and a comprehensive characterization of the AHR-related phenotype of HTN. We reviewed clinical and rodent studies on AHR-HTN genetic association and on AHR ligands and their impact on BP. We concluded that AHR is a druggable mechanistic linker of environmental exposure to HTN. We conclude that is worth to investigate the canonical pathway of AHR and the expression/polymorphisms of its related genes and/or other biomarkers (e.g. tryptophan-related ligands), in order to identify patients that may benefit from an AHR-centered antihypertensive treatment.

The 2-hydroxy-nevirapine metabolite as a candidate for boosting apolipoprotein A1 and for modulating anti-HDL antibodies.

The antiretroviral nevirapine (NVP) is associated to a reduction of atherosclerotic lesions and increases in high-density lipoprotein (HDL)-cholesterol. Despite being a hepatotoxic drug, which forbids its re-purposing to other therapeutic areas, not all NVP metabolites have the same potential to induce toxicity. Our aim was to investigate the effects of NVP and its metabolites in an exploratory study, towards the identification of a candidate to boost HDL. A pilot prospective (n = 11) and a cross-sectional (n = 332) clinical study were performed with the following endpoints: HDL-cholesterol and apolipoprotein A1 (ApoA1) levels, anti-HDL and anti-ApoA1 antibodies titers, paraoxonase, arylesterase and lactonase activities of paraoxonase-1, and NVP's metabolite profile. NVP treatment increased HDL-cholesterol, ApoA1 and paraoxonase-1 activities, and lowered anti-HDL and anti-ApoA1 titers. In the prospective study, the temporal modulation induced by NVP was different for each HDL-related endpoint. The first observation was a decrease in the anti-HDL antibodies titers. In the cross-sectional study, the lower titers of anti-HDL antibodies were associated to the proportion of 2-hydroxy-NVP (p = 0.03). In vitro models of hepatocytes were employed to clarify the individual contribution of NVP's metabolites for ApoA1 modulation. Long-term incubations of NVP and 2-hydroxy-NVP in the metabolically competent 3D model caused an increase in ApoA1 reaching 43 % (p < 0.05) and 86 % (p < 0.001), respectively. These results support the contribution of drug biotransformation for NVP-induced HDL modulation, highlighting the role of 2-hydroxy-NVP as ApoA1 booster and its association to lower anti-HDL titers. This biotransformation-guided approach allowed us to identify a non-toxic NVP metabolite as a candidate for targeting HDL.

Switching from a traditional undergraduate programme in (clinical) pharmacology and therapeutics to a problem-based learning programme.

PURPOSE: The pharmacology and clinical pharmacology and therapeutics (CPT) education during the undergraduate medical curriculum of NOVA Medical School, Lisbon, Portugal, was changed from a traditional programme (i.e. discipline-based, lectures) to a problem-based learning (PBL) programme (i.e. integrated, case-based discussions) without an increase in teaching hours. The aim of this study was to investigate whether this change improved the prescribing competencies of final-year medical students. METHODS: Final-year students from both programmes (2015 and 2019) were invited to complete a validated prescribing assessment and questionnaire. The assessment comprised 24 multiple-choice questions in three subdomains (working mechanism, side-effects and interactions/contraindications), and five clinical case scenarios of common diseases. The questionnaire focused on self-reported prescribing confidence, preparedness for future prescribing task and education received. RESULTS: In total, 36 (22%) final-year medical students from the traditional programme and 54 (23%) from the PBL programme participated. Overall, students in the PBL programme had significantly higher knowledge scores than students in the traditional programme (76% (SD 9) vs 67% (SD 15); p = 0.002). Additionally, students in the PBL programme made significantly fewer inappropriate therapy choices (p = 0.023) and fewer erroneous prescriptions than did students in the traditional programme (p = 0.27). Students in the PBL programme felt more confident in prescribing, felt better prepared for prescribing as junior doctor and completed more drug prescriptions during their medical training. CONCLUSION: Changing from a traditional programme to an integrated PBL programme in pharmacology and CPT during the undergraduate medical curriculum may improve the prescribing competencies of final-year students.

A Mechanistic-Based and Non-invasive Approach to Quantify the Capability of Kidney to Detoxify Cysteine-Disulfides.

Our general goal was to non-invasively evaluate kidney tubular dysfunction. We developed a strategy based on cysteine (Cys) disulfide stress mechanism that underlies kidney dysfunction. There is scarce information regarding the fate of Cys-disulfides (CysSSX), but evidence shows they might be detoxified in proximal tubular cells by the action of N-acetyltransferase 8 (NAT8). This enzyme promotes the addition of an N-acetyl moiety to cysteine-S-conjugates, forming mercapturates that are eliminated in urine. Therefore, we developed a strategy to quantify mercapturates of CysSSX in urine as surrogate of disulfide stress and NAT8 activity in kidney tubular cells. We use a reduction agent for the selective reduction of disulfide bonds. The obtained N-acetylcysteine moiety of the mercapturates from cysteine disulfides was monitored by fluorescence detection. The method was applied to urine from mice and rat as well as individuals with healthy kidney and kidney disease.

First evidence of aryl hydrocarbon receptor as a druggable target in hypertension induced by chronic intermittent hypoxia.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) is associated to a high prevalence of resistant arterial hypertension (HTN) justifying the research on novel targets. Chronic intermittent hypoxia (CIH) is a key feature in the development of OSA comorbidities, including HTN. EXPERIMENTAL APPROACH: We used a rat model of CIH-induced HTN to disclose the hypothesis that the aryl hydrocarbon receptor (AHR) is activated by CIH once it shares the same binding partner of HIF-1α and promotes pro-oxidant, pro-inflammatory (NF-kB) and pro-fibrotic events in common with CIH. KEY RESULTS: Upon established hypertension (21 days exposure to CIH), we observed an increase in Cyp1a1 mRNA in kidney cortex (6-fold), kidney medulla (3-fold) and liver (3-fold), but not in other tissues. Increased renal expression of Ahr and markers of inflammation (Rela), epithelial to mesenchymal transition markers, the rate-controlling step of gluconeogenesis, Pepck1, and members of HIF-pathway, namely, Hif3a were also observed. Daily administration (14 days) of AHR antagonist, CH-223191 (5 mg.kg-1.day-1, gavage), simultaneously to CIH prevented the increase in systolic blood pressure (SBP) by 53 ± 12% and in diastolic blood pressure (DBP) by 44 ± 16%. Moreover, its administration (14 days) upon already established HTN reversed the increase in SBP by 52 ± 12%. CONCLUSION AND IMPLICATIONS: CIH caused an activation of AHR signaling particularly in the kidney and its pharmacological blockade had a significant impact reverting already established HTN. This first evidence inspires innovative research opportunities for the understanding and treatment of this particular type of HTN.

Contribution of adenosine and ATP to the carotid body chemosensory activity in ageing.

KEY POINTS: Adenosine and ATP are excitatory neurotransmitters involved in the carotid body (CB) response to hypoxia. During ageing the CB exhibits a decline in its functionality, demonstrated by decreased hypoxic responses. In aged rats (20-24 months old) there is a decrease in: basal and hypoxic release of adenosine and ATP from the CB; expression of adenosine and ATP receptors in the petrosal ganglion; carotid sinus nerve (CSN) activity in response to hypoxia; and ventilatory responses to ischaemic hypoxia. There is also an increase in SNAP25, ENT1 and CD73 expression. It is concluded that, although CSN activity and ventilatory responses to hypoxia decrease with age, adjustments in purinergic metabolism in the CB in aged animals are present aiming to maintain the contribution of adenosine and ATP. The possible significance of the findings in the context of ageing and in CB-associated pathologies is considered. ABSTRACT: During ageing the carotid body (CB) exhibits a decline in its functionality. Here we investigated the effect of ageing on functional CB characteristics as well as the contribution of adenosine and ATP to CB chemosensory activity. Experiments were performed in 3-month-old and 20- to 24-month-old male Wistar rats. Ageing decreased: the number of tyrosine hydroxylase immune-positive cells, but not type II cells or nestin-positive cells in the CB; the expression of P2X2 and A2A receptors in the petrosal ganglion; and the basal and hypoxic release of adenosine and ATP from the CB. Ageing increased ecto-nucleotidase (CD73) immune-positive cells and the expression of synaptosome associated protein 25 (SNAP25) and equilibrative nucleoside transporter 1 (ENT1) in the CB. Additionally, ageing did not modify basal carotid sinus nerve (CSN) activity or the activity in response to hypercapnia, but decreased CSN activity in hypoxia. The contribution of adenosine and ATP to stimuli-evoked CSN chemosensory activity in aged animals followed the same pattern of 3-month-old animals. Bilateral common carotid occlusions during 5, 10 and 15 s increased ventilation proportionally to the duration of ischaemia, an effect decreased by ageing. ATP contributed around 50% to ischaemic-ventilatory responses in young and aged rats; the contribution of adenosine was dependent on the intensity of ischaemia, being maximal in ischaemias of 5 s (50%) and much smaller in 15 s ischaemias. Our results demonstrate that both ATP and adenosine contribute to CB chemosensory activity in ageing. Though CB responses to hypoxia, but not to hypercapnia, decrease with age, the relative contribution of both ATP and adenosine for CB activity is maintained.

Singularities of nevirapine metabolism: from sex-dependent differences to idiosyncratic toxicity.

Nevirapine (NVP) is a first-generation non-nucleoside reverse transcriptase inhibitor widely used for the treatment and prophylaxis of human immunodeficiency virus infection. The drug is taken throughout the patient's life and, due to the availability of an extended-release formulation, it is administered once daily. This antiretroviral is one of the scarce examples of drugs with prescription criteria based on sex, in order to prevent adverse reactions. The therapy with NVP has been associated with potentially life-threatening liver and idiosyncratic skin toxicity. Multiple evidence has emerged regarding the formation of electrophilic NVP metabolites as crucial for adverse idiosyncratic reactions. The formation of reactive metabolites that yield covalent adducts with proteins has been demonstrated in patients under NVP-based treatment. Interestingly, several pharmacogenetic- and sex-related factors associated with NVP toxicity can be mechanistically explained by an imbalance toward increased formation of NVP-derived reactive metabolites and/or impaired detoxification capability. Moreover, the haptenation of self-proteins by these reactive species provides a plausible link between NVP bioactivation and immunotoxicity, further supporting the relevance of this toxicokinetics hypothesis. In the current paper, we review the existing knowledge and recent developments on NVP metabolism and their relation to NVP toxicity.

Usefulness of zebrafish larvae to evaluate drug-induced functional and morphological renal tubular alterations.

Prediction and management of drug-induced renal injury (DIRI) rely on the knowledge of the mechanisms of drug insult and on the availability of appropriate animal models to explore it. Zebrafish (Danio rerio) offers unique advantages for assessing DIRI because the larval pronephric kidney has a high homology with its human counterpart and it is fully mature at 3.5 days post-fertilization. Herein, we aimed to evaluate the usefulness of zebrafish larvae as a model of renal tubular toxicity through a comprehensive analysis of the renal alterations induced by the lethal concentrations for 10% of the larvae for gentamicin, paracetamol and tenofovir. We evaluated drug metabolic profile by mass spectrometry, renal function with the inulin clearance assay, the 3D morphology of the proximal convoluted tubule by two-photon microscopy and the ultrastructure of proximal convoluted tubule mitochondria by transmission electron microscopy. Paracetamol was metabolized by conjugation and oxidation with further detoxification with glutathione. Renal clearance was reduced with gentamicin and paracetamol. Proximal tubules were enlarged with paracetamol and tenofovir. All drugs induced mitochondrial alterations including dysmorphic shapes ("donuts", "pancakes" and "rods"), mitochondrial swelling, cristae disruption and/or loss of matrix granules. These results are in agreement with the tubular effects of gentamicin, paracetamol and tenofovir in man and demonstrate that zebrafish larvae might be a good model to assess functional and structural damage associated with DIRI.

Impact of the implementation of electronic health records on the quality of discharge summaries and on the coding of hospitalization episodes.

OBJECTIVE: To determine whether the implementation and use of the electronic health records (EHR) modifies the quality, readability and/or the length of the discharge summaries (DS) and the average number of coded diagnosis and procedures per hospitalization episode. DESIGN: A pre-post-intervention descriptive study conducted between 2010 and 2014. SETTING: The 'Hospital Universitario 12 de Octubre' (H12O) of Madrid (Spain). A tertiary University Hospital of up to 1200 beds. INTERVENTION: Implementation and systematic use of the EHR. MAIN OUTCOME MEASURES: The quality, length and readability of the DS and the number of diagnosis and procedures codes by raw and risk-adjusted data. RESULTS: A total of 200 DS were included in the present work. After the implementation of the EHR the DS had better quality per formal requirements, although were longer and harder to read (P < 0.001). The average number of coded diagnoses and procedures was increased, 9.48 in the PRE-INT and 10.77 in the POST-INT, and the difference was statistically significant (P < 0.001) in both raw and risk-adjusted data. CONCLUSIONS: The implementation of EHR improves the formal quality of DS, although poor use of EHR functionalities might reduce its understandability. Having more clinical information immediately available due to EHR increases the number of diagnosis and procedure codes enhancing their utility for secondary uses.

Cysteine Oxidative Dynamics Underlies Hypertension and Kidney Dysfunction Induced by Chronic Intermittent Hypoxia.

Previous data showed the lack of efficacy of an adrenoceptor antagonist to revert hypertension induced by chronic intermittent hypoxia (CIH). We hypothesized that, in addition to sympathetic activation, CIH may change the availability and dynamics of cysteine. Temporal variation in total cysteine and its fractions, free reduced, free oxidized and protein-bound (CysSSP), were measured in homogenates of kidney cortex and medulla of Wistar rats. Animals were exposed to CIH for 14, 21 and 60 days and cysteine fractions and fibronectin gene expression were assessed at these time-points. Two different phases in cysteine dynamics were identified. An early phase (14d) characterized by an increase in cysteine oxidation and CysSSP forms. Late events (>21d) were characterized by a global reduction in cysteine, minimum level of CysSSP and maximum overexpression of fibronectin in kidney cortex. In conclusion, cysteine dynamics is influenced by the duration of CIH exposure: first there is a cysteine disulfide stress-like adaptive response followed by a progressive loss of cysteine availability and a decrease in CysSSP fraction. Kidney fibrosis associated to an unbalance in cysteine dynamics might contribute to the inefficacy of available antihypertensive drugs in patients with delayed diagnosis of sleep apnea.

Implications of sulfotransferase activity in interindividual variability in drug response: clinical perspective on current knowledge.

The interindividual variability in drug response is a major issue in clinical practice and in drug development. Sulfoconjugation is an important Phase II reaction catalyzed by cytosolic sulfotransferases (SULTs), playing a major role in homeostatic functions, xenobiotic detoxification, and carcinogen bioactivation. SULT display wide interindividual variability, explained only partially by genetic variation, suggesting that other non-genetic, epigenetic, and environmental influences could be major determinants of variability in SULT activity. This review focuses on the factors known to influence SULT variability in expression and activity and the available evidence regarding the impact of SULT variability on drug response.

The impact of chronic intermittent hypoxia on hematopoiesis and the bone marrow microenvironment.

Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder which is associated with patient morbidity and an elevated risk of developing hypertension and cardiovascular diseases. There is ample evidence for the involvement of bone marrow (BM) cells in the pathophysiology of cardiovascular diseases but a connection between OSA and modulation of the BM microenvironment had not been established. Here, we studied how chronic intermittent hypoxia (CIH) affected hematopoiesis and the BM microenvironment, in a rat model of OSA. We show that CIH followed by normoxia increases the bone marrow hypoxic area, increases the number of multipotent hematopoietic progenitors (CFU assay), promotes erythropoiesis, and increases monocyte counts. In the BM microenvironment of CIH-subjected animals, the number of VE-cadherin-expressing blood vessels, particularly sinusoids, increased, accompanied by increased smooth muscle cell coverage, while vWF-positive vessels decreased. Molecularly, we investigated the expression of endothelial cell-derived genes (angiocrine factors) that could explain the cellular phenotypes. Accordingly, we observed an increase in colony-stimulating factor 1, vascular endothelium growth factor, delta-like 4, and angiopoietin-1 expression. Our data shows that CIH induces vascular remodeling in the BM microenvironment, which modulates hematopoiesis, increasing erythropoiesis, and circulating monocytes. Our study reveals for the first time the effect of CIH in hematopoiesis and suggests that hematopoietic changes may occur in OSA patients.

Quality of life of institutionalized older adults by dementia severity.

BACKGROUND: The goal of the study was to analyze the factors associated with quality of life (QoL) in institutionalized older adults with dementia, based on self and proxy ratings, and if these characteristics differ by dementia severity. METHODS: Cross-sectional study of 525 people with dementia (PwD) and their caregivers (professional or family caregivers). Two different QoL questionnaires, leading to three measures, were used: QoL in Alzheimer's disease scale (QOL-AD), self and proxy-rated, and QoL in late-stage dementia scale (QUALID), proxy-rated. Multivariate linear regression models were tested for each QoL measure and for mild/moderate and severe stages of dementia. RESULTS: Multiple regression analyses showed a significant association between the three QoL measures and depression. Functional ability was significantly associated with QoL when assessed by proxy. Other factors such as education level, leisure activities and frequency of visits were significantly related with QOL-AD by proxy. The associated factors that differed by dementia severity were education level for moderate dementia, and frequency of visits and who answered the questionnaire (professional vs. family member) for severe dementia. CONCLUSIONS: QoL was consistently associated with depressive symptoms independently of the measures as well as functional ability and social leisure activities when the QoL questionnaire was rated by proxy. Treating depressive symptoms, increasing social activities and maintaining the functional ability may decrease the deterioration of QoL in institutionalized older adults with dementia.

The Association Between Antihypertensive Medication and Blood Pressure Control in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea and hypertension are closely related diseases. The lowering effect of continuous positive airway pressure (CPAP) on blood pressure (BP) control is modest and concomitant antihypertensive therapy is still required. However, the best antihypertensive regimen for BP control in patients with OSA remains unknown. We aimed to investigate a hypothetical association between ongoing antihypertensive medication and BP control rates in patients with OSA. We conducted a prospective observational study in a cohort of 205 patients with OSA and hypertension who underwent a sleep study and 24-h ambulatory blood pressure monitoring (ABPM). Ongoing antihypertensive medication profile was recorded. Logistic regression models were used to investigate the association between antihypertensive regimen and BP control, before (n = 205) and, when applicable, after CPAP adaptation (n = 90). One hundred and fifty-five patients (155/205) were being treated with 31 different antihypertensive regimens. At baseline, the antihypertensive regimens and the number of antihypertensive drugs were not associated with BP control (p = 0.847; p = 0.991). After CPAP adaptation, a decrease in median night-time systolic and diastolic BP was observed (p = 0.001; p = 0.006). Nevertheless, the lack of association between antihypertensive regimens and the number of antihypertensive drugs and BP control remained (p = 0.864; p = 0.800). Our findings confirm that although CPAP improves nocturnal BP, this improvement is not sufficient to control blood pressure for 24 h. This study shows, for the first time, that in patients with OSA, there is no association between BP control and both the antihypertensive regimen and the number of antihypertensive drugs.

Differences in nevirapine biotransformation as a factor for its sex-dependent dimorphic profile of adverse drug reactions.

OBJECTIVES: Nevirapine is widely used for the treatment of HIV-1 infection; however, its chronic use has been associated with severe liver and skin toxicity. Women are at increased risk for these toxic events, but the reasons for the sex-related differences are unclear. Disparities in the biotransformation of nevirapine and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in nevirapine biotransformation as a potential factor in nevirapine-induced toxicity. METHODS: All included subjects were adults who had been receiving 400 mg of nevirapine once daily for at least 1 month. Blood samples were collected and the levels of nevirapine and its phase I metabolites were quantified by HPLC. Anthropometric and clinical data, and nevirapine metabolite profiles, were assessed for sex-related differences. RESULTS: A total of 52 patients were included (63% were men). Body weight was lower in women (P = 0.028) and female sex was associated with higher alkaline phosphatase (P = 0.036) and lactate dehydrogenase (P = 0.037) levels. The plasma concentrations of nevirapine (P = 0.030) and the metabolite 3-hydroxy-nevirapine (P = 0.035), as well as the proportions of the metabolites 12-hydroxy-nevirapine (P = 0.037) and 3-hydroxy-nevirapine (P = 0.001), were higher in women, when adjusted for body weight. CONCLUSIONS: There was a sex-dependent variation in nevirapine biotransformation, particularly in the generation of the 12-hydroxy-nevirapine and 3-hydroxy-nevirapine metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex-dependent dimorphic profile of nevirapine toxicity.

Change and predictors of quality of life in institutionalized older adults with dementia.

PURPOSE: This study aims to assess the change in and predictive factors of the quality of life (QoL) of institutionalized older adults with dementia over a 20-month period. METHODS: Information was used from a follow-up study conducted over an average period of 19.61 ± 1.93 months on a sample of 274 institutionalized older adults aged 60 or over, diagnosed with dementia. Two linear regression models were built to predict change in the EQ-5D index and the quality of life in Alzheimer's disease (QOL-AD) scale, taking as independent variables: sociodemographic characteristics and measures of functional ability (Barthel Index), depression in dementia (Cornell Scale), number of chronic health problems, cognitive level (MEC, the Spanish Mini-Mental State Examination) and severity of dementia (Clinical Dementia Rating) at baseline. RESULTS: The majority of the participants were women (81.75 %) with an average age of 84.70 ± 6.51 years, single (78.15 %), with severe dementia and moderate functional dependence. There was a significant decrease on the EQ-5D, EQ-VAS and QOL-AD between baseline and follow-up scores. The main predictors of QoL of the institutionalized older adults with dementia were the number of chronic problems and baseline scores of the QoL measures. CONCLUSIONS: A significant decrease in the QoL of institutionalized older adults was observed over a 20-month period. Results suggest that interventions aimed at reducing the number of chronic medical conditions may have a beneficial effect on older adults' QoL.

Night-Time Noise and Sleep Quality in an Internal Medicine Ward in Portugal: An Observational Study.

INTRODUCTION: Hospitals should provide a quiet environment to promote patient healing and well-being. However, published data indicates that World Health Organization's guidelines are frequently not met. The aim of the present study was to quantify night-time noise levels in an internal medicine ward and evaluate sleep quality, as well as the use of sedative drugs. MATERIAL AND METHODS: Prospective observational study in an acute internal medicine ward. Between April 2021 and January 2022, on random days, noise was recorded using a smartphone app (Apple® iOS, Decibel X). Night-time noise was recorded from 10 p.m. to 8 a.m. During the same period, hospitalized patients were invited to respond to a questionnaire regarding their sleep quality. RESULTS: A total of 59 nights were recorded. The average noise level recorded was 55 dB with a minimum of 30 dB and a maximum of 97 dB. Fifty-four patients were included. An intermediate score for night-time sleep quality (35.45 out of 60) and noise perception (5.26 out of 10) was reported. The main reasons for poor sleep were related to the presence of other patients (new admission, acute decompensation, delirium, and snoring), followed by equipment, staff noise and surrounding light. Nineteen patients (35%) were previous users of sedatives, and during hospitalization 41 patients (76%) were prescribed sedatives. CONCLUSION: The noise levels detected in the internal medicine ward were higher than the levels recommended by the World Health Organization. Most patients were prescribed sedatives during hospitalization.