Safety and Efficacy of Triple Therapy With Dolutegravir Plus 2 Nucleoside Reverse Transcriptase Inhibitors in Treatment-Naive Human Immunodeficiency Virus Type 2 Patients: Results From a 48-Week Phase 2 Study.

BACKGROUND: Integrase strand transfer inhibitor-based regimens are recommended for first-line therapy in human immunodeficiency virus type 2 (HIV-2). Nonetheless, dolutegravir (DTG) clinical trial data are lacking. METHODS: We conducted a phase 2, single-arm, open-label trial to evaluate the safety and efficacy of a triple therapy regimen that included DTG in persons with HIV-2 (PWHIV-2) in Portugal. Treatment-naive adults receive DTG in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs). Treatment efficacy was evaluated by the proportion of patients who achieved a plasma viral load (pVL) <40 copies/mL and/or by the change from baseline in CD4+ T-cell count and in CD4/CD8 ratio at week 48. RESULTS: A total of 30 patients were enrolled (22 women; median age, 55 years). At baseline, 17 (56.7%) individuals were viremic (median, pVL 190 copies/mL; interquartile range [IQR], 99-445). The median CD4 count was 438 cells/µL (IQR, 335-605), and the CD4/CD8 ratio was 0.8. Three patients discontinued the study. At week 48, all participants (27) had pVL <40 copies/mL. No virological failures were observed. Mean changes in CD4 count and CD4/CD8 ratio at week 48 were 95.59 cells/µL (95% confidence interval [CI], 28-163) and 0.32 (95% CI, .19 to .46). The most common drug-related adverse events were headache and nausea. One participant discontinued due to central nervous system symptoms. No serious adverse events were reported. CONCLUSIONS: DTG plus 2 NRTIs is safe and effective as first-line treatment for PWHIV-2 with a tolerability profile previously known. No virological failures were observed that suggest a high potency of DTG in HIV-2 as occurs in HIV-1. CLINICAL TRIALS REGISTRATION: M NCT03224338.

Is there a time window for MRI in Wernicke encephalopathy - a decade of experience from a tertiary hospital.

OBJECTIVE: Wernicke encephalopathy (WE) is a neuropsychiatric syndrome caused by thiamine deficiency. Despite its low sensitivity, brain magnetic resonance imaging (MRI) is the most useful diagnostic technique. Our aim was to investigate whether the timing of the imaging study, and thiamine replacement can influence brain MRI findings in these patients. METHODS: Retrospective observational study of hospitalized patients between January/2008 and December/2020 with a clinical diagnosis of WE. Data from clinical presentation, diagnostic features, therapeutic approach, and outcomes were collected. RESULTS: We identified 41 patients (55 ± 13.3 years) with WE. Brain MRI was performed in 36 patients, and one third had T2/FLAIR hyperintensities suggestive of WE. We found an association between a history of poor diet and periventricular hyperintensities (p = 0.023), especially on the ventral surface of the thalamus and the periaqueductal region. It was found that the odds of having a typical imaging of WE decreased by 5.3% for each additional unit (100 mg) of thiamine administered (p = 0.046) (95% CI [0.89, 0.99]). On the other hand, the number of days from clinical presentation was not found to be a viable predictor (p = 0.254) (95% CI [0.88, 1.03]) Recovery was positively correlated with the total dose of thiamine received until discharge (p = 0.020). CONCLUSIONS: MRI hyperintensities seem to be dependent on the timing of thiamine correction and, particularly, on the thiamine dosage prescribed at admission. Nevertheless, thiamine replacement should not be delayed, as its timely prescription is associated with a better prognosis at discharge.

Practitioners' knowledge, acceptability and use of external memory aids with individuals with cognitive deficits: An exploratory study.

External memory aids (EMA) are within the most effective cognitive rehabilitation techniques, having demonstrated a positive impact in terms of memory functioning in individuals with multiple cognitive deficits. Despite its proven efficacy, there is yet poor dissemination of these techniques in clinical settings. The current study aims to evaluate the level of knowledge, degree of use, and usage expectations of EMAs by health practitioners, responsible to implement these techniques. A quantitative, descriptive, and cross-sectional study was developed, and 120 practitioners working with cognitively impaired patients participated in the study. One questionnaire was developed to assess participants' knowledge and use of EMAs. Results indicate that the level of global knowledge regarding EMAs is poor, despite superior to its actual use. The degree of perceived acceptance of these prosthetics by their users is positive and stronger than the likelihood of practitioners to use these tools with their patients. This study suggests that the actual implementation of EMAs as rehabilitation tools is still poor, despite the growing evidence-based research highlighting its effectiveness to compensate for cognitive deficits. Future studies should target the current factors that are influencing the underutilization of EMAs, to improve and optimize its dissemination and to benefit cognitively impaired patients.

Assessment of Neurocognitive Functions, Olfaction, Taste, Mental, and Psychosocial Health in COVID-19 in Adults: Recommendations for Harmonization of Research and Implications for Clinical Practice.

OBJECTIVE: To propose a set of internationally harmonized procedures and methods for assessing neurocognitive functions, smell, taste, mental, and psychosocial health, and other factors in adults formally diagnosed with COVID-19 (confirmed as SARS-CoV-2 + WHO definition). METHODS: We formed an international and cross-disciplinary NeuroCOVID Neuropsychology Taskforce in April 2020. Seven criteria were used to guide the selection of the recommendations' methods and procedures: (i) Relevance to all COVID-19 illness stages and longitudinal study design; (ii) Standard, cross-culturally valid or widely available instruments; (iii) Coverage of both direct and indirect causes of COVID-19-associated neurological and psychiatric symptoms; (iv) Control of factors specifically pertinent to COVID-19 that may affect neuropsychological performance; (v) Flexibility of administration (telehealth, computerized, remote/online, face to face); (vi) Harmonization for facilitating international research; (vii) Ease of translation to clinical practice. RESULTS: The three proposed levels of harmonization include a screening strategy with telehealth option, a medium-size computerized assessment with an online/remote option, and a comprehensive evaluation with flexible administration. The context in which each harmonization level might be used is described. Issues of assessment timelines, guidance for home/remote assessment to support data fidelity and telehealth considerations, cross-cultural adequacy, norms, and impairment definitions are also described. CONCLUSIONS: The proposed recommendations provide rationale and methodological guidance for neuropsychological research studies and clinical assessment in adults with COVID-19. We expect that the use of the recommendations will facilitate data harmonization and global research. Research implementing the recommendations will be crucial to determine their acceptability, usability, and validity.

Atrial cardiopathy predicts detection of atrial fibrillation in embolic stroke of undetermined source: real-life data.

OBJECTIVES: Atrial cardiopathy (AC) is more frequent in patients with embolic stroke of undetermined source (ESUS) than in patients with non-cardioembolic stroke. The aim of this work was to describe AC in patients with ESUS and to study its impact on detection of atrial fibrillation (AF) during follow-up. METHODS: This is an observational study of 123 consecutive ESUS patients and 55 ESUS patients from a previous cohort. AC was defined according to the presence of one or more of the following criteria: severe left atrial enlargement, p-wave terminal force in lead V1 > 5000 µVxms, and excessive premature atrial complexes. Unadjusted and adjusted survival analyses for the occurrence of AF and stroke or transient ischemic attack (TIA) were performed. Diagnostic performance of AC for the detection of AF was analyzed. RESULTS: Among 178 patients with ESUS, those with AC (42.7%) were older (p < 0.001), and more frequently had hypertension (p = 0.001) and lower total cholesterol levels (p = 0.001) than patients without AC. The detection of AF during follow-up (median 34 months, interquartile range = 12.8-64) was higher in patients with AC (hazard ratio = 7.00, 95% confidence interval = 2.01-24.39, p = 0.002). This association persisted after adjusting for age, arterial hypertension, and other vascular risk factors. The c-statistic for detection of AF during follow-up for AC was 0.719. There were no differences in stroke or TIA recurrence between groups with and without AC. DISCUSSION: ESUS patients with AC have different baseline clinical characteristics than patients without AC and have a higher detection of AF during follow-up.

Bioremediation of Perfluoroalkyl Substances (PFAS) by Anaerobic Digestion: Effect of PFAS on Different Trophic Groups and Methane Production Accelerated by Carbon Materials.

Per- and polyfluoroalkyl substances (PFAS) are recalcitrant pollutants which tend to persist in soils and aquatic environments and their remediation is among the most challenging with respect to organic pollutants. Anaerobic digestion (AD) supplemented with low amounts of carbon materials (CM), acting as electron drivers, has proved to be an efficient process for the removal of organic compounds from wastewater. This work explores the impact of PFAS on different trophic groups in anaerobic communities, and the effect of carbon nanotubes (CNT), activated carbon (AC), and oxidized AC (AC-HNO3), as electron shuttles on the anaerobic bioremoval of these compounds, based on CH4 production. The inhibition of the specific methanogenic activity (SMA) exerted by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), at a concentration of 0.1 mg L-1, was below 10% for acetoclastic and below 15%, for acetogenic communities. Hydrogenotrophic methanogens were not affected by the presence of PFAS. All CM reduced the negative impact of PFAS on the CH4 production rate, but AC was the best. Moreover, the methanization percentage (MP) of sewage sludge (SS) increased 41% in the presence of PFOS (1.2 g L-1) and AC. In addition, AC fostered an increase of 11% in the MP of SS+PFOS, relative to the condition without AC. AC promoted detoxification of PFOA- and PFOS-treated samples by 51% and 35%, respectively, as assessed by Vibrio fischeri assays, demonstrating the advantage of bringing AD and CM together for PFAS remediation.

Effects of restraining measures due to COVID-19: Pre- and post-lockdown cognitive status and mental health.

The COVID-19 pandemic has prompted all countries to adopt restraining measures to mitigate the spread of the disease. Usually, large-scale disasters tend to be accompanied by significant increases of psychological distress, depression and anxiety. Confinement measures imposed during the COVID-19 pandemic are likely to have similar consequences. In the present study we aim to evaluate how COVID-19 affected the overall psychological functioning of Portuguese individuals by providing a comparison of current data with status prior to the COVID-19 pandemic. The study sample was composed of 150 cognitively healthy participants. Results show an overall maintenance of cognitive capacities, although subjective cognitive decline complaints significantly increased during the pandemic. Regarding mental health, restraining measures culminated in an aggravation of depressive and decrease of the perceived quality of life, associated with feelings of loneliness and perceived social isolation. Finally, higher levels of pre-COVID-19 quality of life seem to play a protective role against depression and anxiety and predict less difficulties in emotion regulation, feelings of solitude and cognitive complaints. In sum, confinement due to COVID-19 implied an aggravation of the mental health of the Portuguese population, which appears to have been attenuated in those with higher pre-pandemic levels of perceived quality of life.

Tracking SARS-CoV-2 lineage B.1.1.7 dissemination: insights from nationwide spike gene target failure (SGTF) and spike gene late detection (SGTL) data, Portugal, week 49 2020 to week 3 2021.

We show that the SARS-CoV-2 B.1.1.7 lineage is highly disseminated in Portugal, with the odds of B.1.1.7 proportion increasing at an estimated 89% (95% confidence interval: 83-95%) per week until week 3 2021. RT-PCR spike gene target late detection (SGTL) can constitute a useful surrogate to track B.1.1.7 spread, besides the spike gene target failure (SGTF) proxy. SGTL/SGTF samples were associated with statistically significant higher viral loads, but not with substantial shift in age distribution compared to non-SGTF/SGTL cases.

Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects.

Dextromethorphan (DXM) is a safe and effective antitussive agent present in several over the counter cough and cold medications. At higher doses, it causes psychoactive effects, making it appealing for abuse. In this work, the pharmacokinetics and pharmacodynamics of DXM with clinical and forensic relevance were extensively reviewed. DXM and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Major metabolic pathways include sequential O-demethylation and N-demethylation of DXM, yielding dextrorphan (DXO), the major active metabolite, and 3-hydroxymorphinan, the bi-demethylated product, respectively. The demethylation order described may reverse being the resultant mid product 3-methoxymorphinan. UDP-glucuronosyltranferase produces glucuronide conjugates. Genotypic variations in enzymes and interactions with other drugs can result in large inter-individual variability in the pharmacological and toxicological effects produced. Knowing the metabolism of DXM may help to better understand the inter-individual variability in the pharmacokinetics and pharmacodynamics and to avoid adverse effects.

Identification and Microbial Production of the Raspberry Phenol Salidroside that Is Active against Huntington's Disease.

Edible berries are considered to be among nature's treasure chests as they contain a large number of (poly)phenols with potentially health-promoting properties. However, as berries contain complex (poly)phenol mixtures, it is challenging to associate any interesting pharmacological activity with a single compound. Thus, identification of pharmacologically interesting phenols requires systematic analyses of berry extracts. Here, raspberry (Rubus idaeus, var Prestige) extracts were systematically analyzed to identify bioactive compounds against pathological processes of neurodegenerative diseases. Berry extracts were tested on different Saccharomyces cerevisiae strains expressing disease proteins associated with Alzheimer's, Parkinson's, or Huntington's disease, or amyotrophic lateral sclerosis. After identifying bioactivity against Huntington's disease, the extract was fractionated and the obtained fractions were tested in the yeast model, which revealed that salidroside, a glycosylated phenol, displayed significant bioactivity. Subsequently, a metabolic route to salidroside was reconstructed in S cerevisiae and Corynebacterium glutamicum The best-performing S cerevisiae strain was capable of producing 2.1 mm (640 mg L-1) salidroside from Glc in shake flasks, whereas an engineered C glutamicum strain could efficiently convert the precursor tyrosol to salidroside, accumulating up to 32 mm (9,700 mg L-1) salidroside in bioreactor cultivations (yield: 0.81 mol mol-1). Targeted yeast assays verified that salidroside produced by both organisms has the same positive effects as salidroside of natural origin.

Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis.

Glutathione peroxidase 4 (GPX4) is unique as it is the only enzyme that can prevent detrimental lipid peroxidation in vivo by reducing lipid peroxides to the respective alcohols thereby stabilizing oxidation products of unsaturated fatty acids. During reticulocyte maturation, lipid peroxidation mediated by 15-lipoxygenase in humans and rabbits and by 12/15-lipoxygenase (ALOX15) in mice was considered the initiating event for the elimination of mitochondria but is now known to occur through mitophagy. Yet, genetic ablation of the Alox15 gene in mice failed to provide evidence for this hypothesis. We designed a different genetic approach to tackle this open conundrum. Since either other lipoxygenases or non-enzymatic autooxidative mechanisms may compensate for the loss of Alox15, we asked whether ablation of Gpx4 in the hematopoietic system would result in the perturbation of reticulocyte maturation. Quantitative assessment of erythropoiesis indices in the blood, bone marrow (BM) and spleen of chimeric mice with Gpx4 ablated in hematopoietic cells revealed anemia with an increase in the fraction of erythroid precursor cells and reticulocytes. Additional dietary vitamin E depletion strongly aggravated the anemic phenotype. Despite strong extramedullary erythropoiesis reticulocytes failed to mature and accumulated large autophagosomes with engulfed mitochondria. Gpx4-deficiency in hematopoietic cells led to systemic hepatic iron overload and simultaneous severe iron demand in the erythroid system. Despite extremely high erythropoietin and erythroferrone levels in the plasma, hepcidin expression remained unchanged. Conclusively, perturbed reticulocyte maturation in response to Gpx4 loss in hematopoietic cells thus causes ineffective erythropoiesis, a phenotype partially masked by dietary vitamin E supplementation.

Ciprofloxacin, diclofenac, ibuprofen and 17α-ethinylestradiol differentially affect the activity of acetogens and methanogens in anaerobic communities.

Pharmaceutical compounds end up in wastewater treatment plants but little is known on their effect towards the different microbial groups in anaerobic communities. In this work, the effect of the antibiotic Ciprofloxacin (CIP), the non-steroidal anti-inflammatory drugs Diclofenac (DCF) and Ibuprofen (IBP), and the hormone 17α-ethinylestradiol (EE2), on the activity of acetogens and methanogens in anaerobic communities, was investigated. Microbial communities were more affected by CIP, followed by EE2, DCF and IBP, but the response of the different microbial groups was dissimilar. For concentrations of 0.01 to 0.1 mg/L, the specific methanogenic activity was not affected. Acetogenic bacteria were sensitive to CIP concentrations above 1 mg/L, while DCF and EE2 toxicity was only detected for concentrations higher than 10 mg/L, and IBP had no effect in all concentrations tested. Acetoclastic methanogens showed higher sensitivity to the presence of these micropollutants, being affect by all the tested pharmaceutical compounds although at different degrees. Hydrogenotrophic methanogens were not affected by any concentration, indicating their lower sensitivity to these compounds when compared to acetoclasts and acetogens.

Effects of abamectin-based and difenoconazole-based formulations and their mixtures in Daphnia magna: a multiple endpoint approach.

This study evaluated the toxicity of pesticide formulations Kraft® 36 EC (active ingredient-a.i. abamectin) and Score® 250 EC (a.i. difenoconazole), and their mixtures in Daphnia magna at different biological levels of organization. Survival, reproduction and biochemical markers (cholinesterase (ChE), catalase (CAT) and lipid peroxidation (LPO)) were some of the endpoints evaluated. Total proteins and lipids were also studied together with energy consumption (Ec). D. magna neonates were exposed for 96 h to Kraft (2, 4, and 6 ng a.i./L) and Score (12.5, 25, and 50 µg a.i./L) for the biochemical experiments, and for 15 days to abamectin (1-5 ng a.i./L) and to difenoconazole (3.12-50 µg a.i./L) to assess possible changes in reproduction. Exposures of organisms to both single compounds did not cause effects to antioxidant and detoxifying enzymes, except for LPO occurring at the highest concentration of difenoconazole tested. For ChE and CAT there was enzymatic induction in mixture treatments organisms, occurring at minor pesticides concentrations for CAT and at the two highest concentrations for ChE. There were no significant differences for total protein in D. magna but lipids showed an increase at the highest concentrations of pesticide mixture combinations. There was a significant increase of Ec in individuals of all treatments tested. In the chronic test, increased fecundity occurred for D. magna under difenoconazole exposures and mixtures. This study demonstrated that mixtures of these pesticides caused greater toxicity to D. magna than when tested individually, except for Ec. Therefore, effects of mixtures are very hard to predict only based on information from single compounds, which most possibly is the result of biological complexity and redundancy in response pathways, which need further experimentation to become better known.

Impact of a High Coverage Vaccination Rate on Human Papillomavirus Infection Prevalence in Young Women: A Cross-sectional Study.

OBJECTIVE: The aim of the study was to compare the rate of high-risk human papillomavirus (HR-HPV) genotypes in vaccinated (Gardasil [quadrivalent]) and unvaccinated cohorts of young women. MATERIALS AND METHODS: This is a retrospective, cross-sectional study, consisting of the comparison of the prevalence of HPV 16, 18, and other HR genotypes in 2183 women younger than 25 years, according to their birth year (born >1994 [mostly vaccinated <13 years]; born 1992-1994 [vaccinated at 17 years]; born <1992 [not vaccinated/vaccinated >17 years]), in a private laboratory. RESULTS: The rates of HPV 16, 18, 16/18, and others in the cohort born before 1992 (n = 331) were 6.3%, 1.5%, 7.9%, and 31.7%. In those born 1992-1994 (n = 901), the rates were 3.3%, 0.4%, 3.6%, and 32.5%; in the ones born after 1994 (n = 951), the rates were 0.7%, 0.2%, 0.9%, and 33.2%, respectively.There were no changes in the relative risk (RR) of HR-HPV infection by genotypes other than HPV 16/18 in any cohort.The RR was significantly reduced in the cohort born after 1994 for HPV 16 (0.12 [0.050-0.270], p < .0001), HPV 18 (0.14 [0.027-0.714], p = .02), and HPV 16/18 (0.12 [0.057-0.254], p < .0001).In those born 1992-1994, there was a nearly significant reduction in the RR of HPV 18 infection (0.29 [0.079-1.09], p = .07); the reduction was significant for HPV 16 (0.52 [0.305-0.904], p = .02) and HPV 16/18 (0.45 [0.274-0.747], p = .0018). CONCLUSIONS: Young women vaccinated before 13 years had a nearly 90% risk reduction of HPV 16/18, whereas if vaccinated at 17 years, the decrease was of 50%. There was no impact in the nonvaccine genotypes.Our data highlight the importance of vaccinating at young age and of introducing vaccines covering more HR genotypes.

Modulation of the central carbon metabolism of Corynebacterium glutamicum improves malonyl-CoA availability and increases plant polyphenol synthesis.

In recent years microorganisms have been engineered towards synthesizing interesting plant polyphenols such as flavonoids and stilbenes from glucose. Currently, the low endogenous supply of malonyl-CoA, indispensable for plant polyphenol synthesis, impedes high product titers. Usually, limited malonyl-CoA availability during plant polyphenol production is avoided by supplementing fatty acid synthesis-inhibiting antibiotics such as cerulenin, which are known to increase the intracellular malonyl-CoA pool as a side effect. Motivated by the goal of microbial polyphenol synthesis being independent of such expensive additives, we used rational metabolic engineering approaches to modulate regulation of fatty acid synthesis and flux into the tricarboxylic acid cycle (TCA cycle) in Corynebacterium glutamicum strains capable of flavonoid and stilbene synthesis. Initial experiments showed that sole overexpression of genes coding for the native malonyl-CoA-forming acetyl-CoA carboxylase is not sufficient for increasing polyphenol production in C. glutamicum. Hence, the intracellular acetyl-CoA availability was also increased by reducing the flux into the TCA cycle through reduction of citrate synthase activity. In defined cultivation medium, the constructed C. glutamicum strains accumulated 24 mg·L -1 (0.088 mM) naringenin or 112 mg·L -1 (0.49 mM) resveratrol from glucose without supplementation of phenylpropanoid precursor molecules or any inhibitors of fatty acid synthesis.

Cytinus hypocistis (L.) L. subsp. macranthus Wettst.: Nutritional Characterization.

The habit of eating wild plants in Europe is often associated with times of famine; an example of such is the nectar of Cytinus hypocistis (L.) L., a parasitic plant. To the authors' best knowledge, there are no studies on its nutritional and chemical composition; thus, the whole C. hypocistis (L.) L. subsp. macranthus Wettst. plant (CH) and its nectar (NCH) were nutritionally and chemically characterized. The proximate composition of CH and NCH were very similar in terms of energy, ash, and carbohydrate content. Protein and fat were approximately 2-fold higher in NCH, and crude fiber was 4.6-fold higher in CH compared to NCH. Fructose, glucose, sucrose, and trehalose were the free sugars present in both samples. Oxalic, malic, and citric acids were the identified organic acids in both samples, with citric acid as the most abundant molecule. For both samples, polyunsaturated and saturated fatty acids (PUFA and SFA, respectively) predominate over monounsaturated fatty acids (MUFA) due to the significant contribution of linoleic and palmitic acids, respectively. However, unsaturated fatty acids (UFA) prevail over SFA in CH and NCH. Therefore, CH proved to be an excellent source of nutritional compounds, which supports its use during past periods of scarcity.

Imatinib and spironolactone suppress hepcidin expression.

Disorders of iron metabolism are largely attributed to an excessive or insufficient expression of hepcidin, the master regulator of systemic iron homeostasis. Here, we investigated whether drugs targeting genetic regulators of hepcidin can affect iron homeostasis. We focused our efforts on drugs approved for clinical use to enable repositioning strategies and/or to reveal iron-related side effects of widely prescribed therapeutics. To identify hepcidin-modulating therapeutics, we re-evaluated data generated by a genome-wide RNAi screen for hepcidin regulators. We identified 'druggable' screening hits and validated those by applying RNAi of potential drug targets and small-molecule testing in a hepatocytic cell line, in primary murine and human hepatocytes and in mice. We initially identified spironolactone, diclofenac, imatinib and Suberoylanilide hydroxamic acid (SAHA) as hepcidin modulating drugs in cellular assays. Among these, imatinib and spironolactone further suppressed liver hepcidin expression in mice. Our results demonstrate that a commonly used anti-hypertensive drug, spironolactone, which is prescribed for the treatment of heart failure, acne and female hirsutism, as well as imatinib, a first-line, lifelong therapeutic option for some frequent cancer types suppress hepcidin expression in cultured cells and in mice. We expect these results to be of relevance for patient management, which needs to be addressed in prospective clinical studies.

It is not only memory: effects of sensecam on improving well-being in patients with mild alzheimer disease.

BACKGROUND: Cognitive interventions (either restorative or compensatory) developed for mild Alzheimer's Disease (AD) have been tested widely with cognitive measures, but less is known about how the effects of such interventions are generalizable to daily functioning. In the present study, we looked at affective state and perceived functionality and quality of life indicators, for three different cognitive rehabilitation programs. METHODS: Fifty-one AD patients in the mild stage of the disease were selected for the study and were randomly assigned to one of three cognitive training groups: (1) Memo+ (a paper and pencil memory training program); (2) SenseCam (wearable camera used as a passive external memory aid); (3) Written diary (a personal journal, used as control condition). All patients attended 11 sessions, twice a week, of 1-hour length. The three outcome indicators were examined with standardized instruments applied before the intervention, one week after and at six months follow-up. RESULTS: After treatment, the SenseCam and Memo+ groups had significantly reduced depressive symptoms compared to the Diary control condition. The same was found for measures of perceived functional capacity. No intervention effects were found for quality of life measures. The immediate effects of the interventions were not maintained at follow-up. CONCLUSIONS: Our results suggest that two types of memory rehabilitation can improve depressive symptomology and instrumental activities of daily living, suggesting that these interventions can stimulate not only cognition but also well-being, at least in the short term.

Late presentation increases risk and costs of non-infectious comorbidities in people with HIV: an Italian cost impact study.

BACKGROUND: Late presentation (LP) at the time of HIV diagnosis is defined as presentation with AIDS whatever the CD4 cell count or with CD4 <350 cells/mm. The objective of our study was to assess the prevalence of non-infectious comorbidities (NICM) and multimorbidity among HIV-positive individuals with and without a history of LP (HIV + LP and HIV + EP, respectively), and compare them to matched HIV-negative control participants from a community-based cohort. The secondary objective was to provide estimates and determinants of direct cost of medical care in HIV patients. METHODS: We performed a matched cohort study including HIV + LP and HIV + EP among people attending the Modena HIV Metabolic Clinic (MHMC) in 2014. HIV-positive participants were matched in a 1:3 ratio with HIV-negative participants from the CINECA ARNO database. Multimorbidity was defined as the concurrent presence of ≥2 NICM. Logistic regression models were constructed to evaluate associated predictors of NICM and multimorbidity. RESULTS: We analyzed 452 HIV + LP and 73 HIV + EP participants in comparison to 1575 HIV-negative controls. The mean age was 46 ± 9 years, 27.5% were women. Prevalence of NICM and multimorbidity were fourfold higher in the HIV + LP compared to the general population (p < 0.001), while HIV + EP present an intermediate risk. LP was associated with increased total costs in all age strata, but appear particularly relevant in patients above 50 years of age, after adjusting for age, multimorbidity, and antiretroviral costs. CONCLUSIONS: LP with HIV infection is still very frequent in Italy, is associated with higher prevalence of NICM and multimorbidity, and contributes to higher total care costs. Encouraging early testing and access to care is still urgently needed.

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling.

The hepatic hormone hepcidin is a key regulator of systemic iron metabolism. Its expression is largely regulated by 2 signaling pathways: the "iron-regulated" bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways. To obtain broader insights into cellular processes that modulate hepcidin transcription and to provide a resource to identify novel genetic modifiers of systemic iron homeostasis, we designed an RNA interference (RNAi) screen that monitors hepcidin promoter activity after the knockdown of 19 599 genes in hepatocarcinoma cells. Interestingly, many of the putative hepcidin activators play roles in signal transduction, inflammation, or transcription, and affect hepcidin transcription through BMP-responsive elements. Furthermore, our work sheds light on new components of the transcriptional machinery that maintain steady-state levels of hepcidin expression and its responses to the BMP- and interleukin-6-triggered signals. Notably, we discover hepcidin suppression mediated via components of Ras/RAF MAPK and mTOR signaling, linking hepcidin transcriptional control to the pathways that respond to mitogen stimulation and nutrient status. Thus using a combination of RNAi screening, reverse phase protein arrays, and small molecules testing, we identify links between the control of systemic iron homeostasis and critical liver processes such as regeneration, response to injury, carcinogenesis, and nutrient metabolism.