Analysis of the hikikomori phenomenon - an international infodemiology study of Twitter data in Portuguese.

BACKGROUND: Hikikomori refers to the extreme isolation of individuals in their own homes, lasting at least six months. In recent years social isolation has become an important clinical, social, and public health problem, with increased awareness of hikikomori around the globe. Portuguese is one of the six most spoken languages in the world, but no studies have analysed the content regarding this phenomenon expressed in Portuguese. OBJECTIVE: To explore the hikikomori phenomenon on Twitter in Portuguese, utilising a mixed-methods approach encompassing content analysis, emotional analysis, and correlation analysis. METHODS: A mixed methods analysis of all publicly available tweets in the Portuguese language using a specific keyword (hikikomori) between 1st January 2008 and 19th October 2022. The content analysis involved categorising tweets based on tone, content, and user types, while correlation analysis was used to investigate user engagement and geographical distribution. Statistical analysis and artificial intelligence were employed to classify and interpret the tweet data. RESULTS: Among the total of 13,915 tweets generated, in terms of tone 10,731 were classified as "negative", and 3184 as "positive". Regarding content, "curiosities" was the most posted, as well as the most retweeted and liked topic. Worldwide, most of the hikikomori related tweets in Portuguese were posted in Europe, while "individuals with hikikomori" were the users most active posting. Regarding emotion analysis, the majority of tweets were "neutral". CONCLUSIONS: These findings show the global prevalence of the discourse on hikikomori phenomenon among Portuguese speakers. It also indicates an increase in the number of tweets on this topic in certain continents over the years. These findings can contribute to developing specific interventions, support networks, and awareness-raising campaigns for affected individuals.

New azaaurone derivatives as potential multitarget agents in HIV-TB coinfection.

Tuberculosis (TB) disease, caused by Mycobacterium tuberculosis (Mtb) is the leading cause of death among people with human immunodeficiency virus (HIV) infection. No dual-target drug is currently being used to simultaneously treat both infections. This work aimed to obtain new multitarget HIV-TB agents, with the goal of optimizing treatments and preventing this coinfection. These compounds incorporate the structural features of azaaurones as anti-Mtb and zidovudine (AZT) as the antiretroviral moiety. The azaaurone scaffold displayed submicromolar activities against Mtb, and AZT is a potent antiretroviral drug. Six derivatives were synthetically generated, and five were evaluated against both infective agents. Evaluations of anti-HIV activity were carried out in HIV-1-infected MT-4 cells and on endogenous HIV-1 reverse transcriptase (RT) activity. The H37Rv strain was used for anti-Mtb assessments. Most compounds displayed potent antitubercular and moderate anti-HIV activity. (E)-12 exhibited a promising multitarget profile with an MIC90 of 2.82 µM and an IC50 of 1.98 µM in HIV-1-infected T lymphocyte cells, with an 84% inhibition of RT activity. Therefore, (E)-12 could be the first promising compound from a family of multitarget agents used to treat HIV-TB coinfection. In addition, the compound could offer a prototype for the development of new strategies in scientific research to treat this global health issue.

Target Identification in Anti-Tuberculosis Drug Discovery.

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limiting factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bacterial proteins are targeted during the biosynthesis of the cell wall and the energetic metabolism of two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and explains how chemical probes for protein profiling enabled the identification of new targets and biomarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.

The effects of supported housing for individuals with mental disorders.

Societies face the challenge of providing appropriate arrangements for individuals who need living support due to their mental disorders. We estimate the effects of eligibility to the Dutch supported housing program (Beschermd Wonen), which offers a structured living environment in the community as an intermediate alternative to independent housing and inpatient care. For this, we use exogenous variation in eligibility based on conditionally random assignment of applications to assessors, and the universe of applications to supported housing in the Netherlands, linked to rich administrative data. Supported housing eligibility increases the probability of moving into supported housing and decreases the use of home care, resulting in higher total care expenditures. This increase is primarily due to the costs of supported housing, but potentially also higher consumption of curative mental health care. Supported housing eligibility reduces the total personal income and income from work. Findings do also suggest lower participation in the labor market by the individuals granted eligibility, but the labor participation of their parents increases in the long-run. Our study highlights the trade-offs of access to supported housing for those at the margin of eligibility, informing the design of long-term mental health care systems around the world.

Biological Evaluation and Mechanistic Studies of Quinolin-(1H)-Imines as a New Chemotype against Leishmaniasis.

Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, making the need for more effective, safer, and less expensive drugs an urgent one. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in-house antiplasmodial libraries against axenic and intracellular forms of Leishmania infantum, Leishmania amazonensis, and Leishmania major. Several of the screened compounds showed half-maximal inhibitory concentrations (IC50s) against intracellular L. infantum parasites in the submicromolar range (compounds 1h, IC50 = 0.9 µM, and 1n, IC50 = 0.7 µM) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major parasites, albeit in the low micromolar range. Mechanistic studies revealed that compound 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that compound 1n is a promising antileishmanial lead and emphasizes the potential of the quinoline-(1H)-imine chemotype for the future development of new antileishmanial agents.

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds.

Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the bacteria to coexist in a state of asymptomatic latency. This last state can be sustained for years or even decades, waiting for a breach in the immune system to become active again. Furthermore, most current therapies are not efficacious against this state, failing to completely clear the infection. Over the years, a series of experimental methods have been developed to mimic the latent state, currently used in drug discovery, both in vitro and in vivo. Most of these methods focus in one specific latency inducing factor, with only a few taking into consideration the complexity of the granuloma and the genomic and proteomic consequences of each physiological factor. A series of targets specifically involved in latency have been studied over the years with promising scaffolds being discovered and explored. Taking in account that solving the latency problem is one of the keys to eradicate the disease, herein we compile current therapies and diagnosis techniques, methods to mimic latency and new targets and compounds in the pipeline of drug discovery.

An Overview of Drug Resistance in Protozoal Diseases.

Protozoan diseases continue to be a worldwide social and economic health problem. Increased drug resistance, emerging cross resistance, and lack of new drugs with novel mechanisms of action significantly reduce the effectiveness of current antiprotozoal therapies. While drug resistance associated to anti-infective agents is a reality, society seems to remain unaware of its proportions and consequences. Parasites usually develops ingenious and innovative mechanisms to achieve drug resistance, which requires more research and investment to fight it. In this review, drug resistance developed by protozoan parasites Plasmodium, Leishmania, and Trypanosoma will be discussed.

Cost Effectiveness of Pembrolizumab for Advanced Melanoma Treatment in Portugal.

BACKGROUND: The aim of this study was to assess the cost-effectiveness of pembrolizumab in treating patients with ipilimumab-naïve advanced melanoma in Portugal. METHODS: A cost-effectiveness model was developed to analyze the costs and consequences of treatment with pembrolizumab compared to treatment with ipilimumab in patients with advanced melanoma not previously treated with ipilimumab. The model was parameterized by using data from a head-to-head phase III randomized clinical trial, KEYNOTE-006. Extrapolation of long-term outcomes was based on approaches previously applied, combining ipilimumab data and melanoma patients' registry data. The analysis was conducted from the perspective of the Portuguese National Health Service, and a lifetime horizon (40 years) was used. Portugal-specific disease management costs were estimated by convening a panel of six clinical experts to derive health state resource use and multiplying the results by national unit costs. To test for the robustness of the conclusions, we conducted deterministic and probabilistic sensitivity analyses. RESULTS: Pembrolizumab increases life expectancy in 1.57 undiscounted life-years (LYs) and is associated with an increase in costs versus that of ipilimumab. The estimated incremental cost-effectiveness ratio is €47,221 per quality-adjusted life-year (QALY) and €42,956 per LY. Deterministic sensitivity analysis showed that the results were robust to the change of most input values or assumptions and were sensitive to time on treatment scenarios. According to the probabilistic sensitivity analysis performed, pembrolizumab is associated with a cost per QALY gained inferior to €50,000 in 75% of the cases. CONCLUSIONS: Considering the usually accepted thresholds in oncology, pembrolizumab is a cost-effective alternative for treating patients with advanced melanoma in Portugal.

From hybrid compounds to targeted drug delivery in antimalarial therapy.

The discovery of new drugs to treat malaria is a continuous effort for medicinal chemists due to the emergence and spread of resistant strains of Plasmodium falciparum to nearly all used antimalarials. The rapid adaptation of the malaria parasite remains a major limitation to disease control. Development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the emergence of resistant parasite strains. This review presents the journey that started with simple combinations of two active moieties into one chemical entity and progressed into a delivery/targeted system based on major antimalarial classes of drugs. The rationale for providing different mechanisms of action against a single or additional targets involved in the multiple stages of the parasite's life-cycle is highlighted. Finally, a perspective for this polypharmacologic approach is presented.

Comorbidity burden assessment in older people admitted to a Portuguese University Hospital.

PURPOSE: To determine the most valuable comorbidity index to apply in a clinical context and its prospective association with 1-year mortality and 3-month readmission. The authors also intend to gauge the evolution of older patients' admission profile over 13 years, in the same clinical setting. SUBJECTS/MATERIALS AND METHODS: The authors analyzed data from 100 consecutive patients admitted in 2012. The Charlson Comorbidity Index (CCI), the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) and the Medication-Based Disease Burden Index (MDBI) were used to evaluate comorbidity. Length of stay, number of diagnoses and of medications, readmission and mortality were assessed. A p value <0.05 was considered significant. RESULTS: Mean age was 80.6 years, mean length of stay was 8.8 days, and mean number of diagnosis per patient was 7.9. Mean values of score were of 3.6 for the CCI, 11.3 for the CIRS-G and 0.552 for the MDBI. Three-month readmission and 1-year mortality rates related to higher CCI and CIRS-G scores. No association was found between MDBI and the outcomes evaluated. One-year mortality reached 24 % and 3-month readmission was of 43 %. Comparing the two samples, mean age increased in 2.1 years and the number of diagnosis by 2.2. Length of stay decreased 2 days. DISCUSSION AND CONCLUSION: CCI was easier to use but the CIRS-G was better at evaluating comorbidity. MDBI did not seem to be a trustworthy tool. Despite an older population with high comorbidity, length of stay decreased over 13 years. However, readmission was high. Introduction of geriatric care standards is required to improve health outcomes for older patients.

Income inequalities beyond access to mental health care: a Dutch nationwide record-linkage cohort study of baseline disease severity, treatment intensity, and mental health outcomes.

BACKGROUND: Existing literature shows low and unequal access to mental health treatment globally, resulting in policy efforts to promote access for vulnerable groups. Yet, there is little evidence about how inequalities develop once individuals start treatment. The greater use of mental health care among individuals with low income, such as in the Dutch system, might be driven by differences in need and might not necessarily lead to better treatment outcomes. In this study, we aimed to examine income inequalities in four stages of the mental health treatment pathway while adjusting for need. METHODS: We constructed a nationwide retrospective cohort study, examining all patients aged older than 18 years with a first specialist mental health treatment record in the Netherlands between 2011 and 2016, excluding those who did not receive any treatment minutes. We linked patient-level data from treatment records to administrative data on income, demographics from municipal registries, and health insurance claims. We used multivariate models to estimate adjusted associations between household income quintile (standardised for household size) and outcomes characterising four stages of mental health treatment: severity at baseline assessment based on the Global Assessment of Functioning (GAF) score, treatment minutes received, functional improvement by the end of the initial record, and additional treatment in a subsequent record. Estimates were adjusted for patient need (97 categories of primary diagnosis and severity at baseline assessment measured by GAF) and demographic covariates. FINDINGS: Our study population consisted of 951 530 adults with a first specialist mental health treatment record in the Netherlands between Jan 1, 2011, and Dec 31, 2016. Patients in our cohort were on average aged 45·0 years (range 19-107) and mostly female (529 859 [55·7%] women and 421 671 [44·3%] men; no ethnicity data were available). First, we found that patients with the lowest income had the greatest initial therapist-assessed disease severity (5·545 GAF points), which was 0·353 GAF points (95% CI 0·347-0·360) lower than those in the highest income quintile. Second, we found that the negative association between income and treatment minutes was reversed once we adjusted for diagnosis and severity at baseline, with patients with the lowest income receiving 1·8% fewer treatment minutes (95% CI 1·1-2·4) than those in the highest quintile. Third, those in the highest income quintile were 17·3 percentage points (95% CI 17·0-17·6) more likely to have functional improvements by the end of the initial record, compared with 25·8% of patients with an improvement in the lowest income quintile. Fourth, while 35·7% of patients in the lowest income quintile received additional treatment in a subsequent record, this was only 3·0 percentage points (95% CI 2·7-3·3) lower for those in the highest quintile. None of these patterns were explained by diagnosis, severity at baseline, or treatment minutes received. INTERPRETATION: Disparities favourable to patients with a higher income persist through the different stages of mental health treatment. These differences highlight the limitations of solely focusing on improving access to care to reduce the mental health gap. Our findings call for a better understanding of the role of social environment and quality of care as complementary mechanisms explaining inequalities during mental health treatment. FUNDING: Erasmus Initiative Smarter Choices for Better Health (Erasmus University Rotterdam), European Union's Horizon 2020, and Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Dutch Research Council). TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability.

While N-acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N-acetyl moiety for a N-carbamoyl group led to analogues with sub- and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug-susceptible and drug-resistant M. tuberculosis isolates. The new N-carbamoyl azaaurones exhibited improved microsomal stability, compared to their N-acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10-8 , a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.

Patient cost-sharing, mental health care and inequalities: A population-based natural experiment at the transition to adulthood.

BACKGROUND: Patient cost-sharing has been increasing around the world, despite the evidence that it reduces both unnecessary and necessary health care utilisation. Financial barriers could compound to poor transitional care into adulthood, when forgoing mental health treatment may have long-term consequences on health and development. We evaluate the impact of increasing deductibles on mental health care use by young adults, and the heterogeneous effects for vulnerable groups. METHODS: We use individual administrative records for 1,541,210 individuals between 17 and 19 years of age, living in the Netherlands. We implement a difference-in-discontinuity design that exploits an increase in the deductible of about 180 euros, between 2009 and 2014, and the deductible exemption for those below 18 years old. Finally, we study subgroup effects by household income, level of mental health care expenditure and medication use for mental disorders. RESULTS: Our results show that increasing deductibles reduced the probability of mental health care use at the transition to adulthood by 13.6% for females (-13.6%, CI 95%: -22.1%, -5.2%), and by 5.3% for males (-5.3%, CI 95%: -11.8%, 1.2%). The reduction was larger among females in the lowest (-18.9%, CI 95%: -35.4%, -2.3%) and second lowest (-21.3%, CI 95%: -36.7%, -5.9%) income quartiles. Additionally, we find increased treatment cessation in high deductible years to happen across all levels of mental health care need. CONCLUSIONS: Our findings indicate that cost-sharing is compounding to existing disruptions in care at the transition between children/adolescent and adult services. The larger reductions in mental health care use among low-income females uncover the role of the deductible increase in widening mental health care inequalities. Increased treatment cessation even among high-intensity users suggests potential long-term consequences for individuals, the health system, and society.

Trade-offs during the COVID-19 pandemic: A discrete choice experiment about policy preferences in Portugal.

The need to control the sanitary situation during the COVID-19 pandemic has led governments to implement several restrictions with substantial social and economic impacts. We explored people's trade-offs in terms of their income, life restrictions, education, and poverty in the society, compared to their willingness to avoid deaths. We applied a web-based discrete choice experiment to elicit preferences of the Portuguese citizens for these attributes and computed the marginal rate of substitution in terms of avoided deaths. We recorded 2,191 responses that faced the possibility of having 250 COVID-19 related deaths per day as the worst possible outcome from the choice levels presented. Estimates suggested that individuals would be willing to sacrifice 30% instead of 10% of their income to avoid approximately 47 deaths per day during the first six months of 2021. For the same period, they would also accept 30% of the students' population to become educationally impaired, instead of 10%, to avoid approximately 25 deaths; a strict lockdown, instead of mild life restrictions, to avoid approximately 24 deaths; and 45% of the population to be in risk of poverty, instead of 25%, to avoid approximately 101 deaths. Our paper shows that avoiding deaths was strongly preferred to the remaining societal impacts; and that being a female, as well as working on site, led individuals to be more averse to such health hazards. Furthermore, we show how a DCE can be used to assess the societal support to decision-making during times of crisis.

Design and evaluation of primaquine-artemisinin hybrids as a multistage antimalarial strategy.

It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The "magic bullet" thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC(50)], ∼10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.

Identification of new antimalarial leads by use of virtual screening against cytochrome bc1.

Cytochrome bc(1) is a validated drug target in malaria parasites. The spread of Plasmodium falciparum strains resistant to multiple antimalarials emphasizes the urgent need for new drugs. We screened in silico the ZINC and MOE databases, using ligand- and structure-based approaches, to identify new leads for development. The most active compound presented an IC(50) value against cultured P. falciparum of 2 µM and a docking pose consistent with its activity.

Concerns and adjustments: How the Portuguese population met COVID-19.

BACKGROUND: The COVID-19 pandemic has led to disruptive changes worldwide, with different implications across countries. The evolution of citizens' concerns and behaviours over time is a central piece to support public policies. OBJECTIVE: To unveil perceptions and behaviours of the Portuguese population regarding social and economic impacts of the COVID-19 pandemic, allowing for more informed public policies. METHODS: Online panel survey distributed in three waves between March 13th and May 6th 2020. Data collected from a non-representative sample of 7,448 respondents includes socio-demographic characteristics and self-reported measures on levels of concern and behaviours related to COVID-19. We performed descriptive analysis and probit regressions to understand relationships between the different variables. RESULTS: Most participants (85%) report being at least very concerned with the consequences of the COVID-19 pandemic and social isolation reached a high level of adherence during the state of emergency. Around 36% of the sample anticipated consumption decisions, stockpiling ahead of the state of emergency declaration. Medical appointments suffered severe consequences, being re-rescheduled or cancelled. We find important variation in concerns with the economic impact across activity sectors. CONCLUSION: We show that high level of concern and behaviour adaptation in our sample preceded the implementation of lockdown measures in Portugal around mid-March. One month later, a large share of individuals had suffered disruption in their routine health care and negative impacts in their financial status.

Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management.

Human neutrophil elastase (HNE) is a serine protease that degrades matrix proteins. An excess of HNE may trigger several pathological conditions, such as psoriasis. In this work, we aimed to synthesize, characterize and formulate new HNE inhibitors with a 4-oxo-ß-lactam scaffold with less toxicity, as well as therapeutic index in a psoriasis context. HNE inhibitors with 4-oxo-ß-lactam scaffolds were synthesized and characterized by NMR, FTIR, melting point, mass spectrometry and elemental analysis. In vitro cytotoxicity and serine protease assays were performed. The compound with the highest cell viability (AAN-16) was selected to be incorporated in an emulsion (AAN-16 E) and in a microemulsion (AAN-16 ME). Formulations were characterized in terms of organoleptic properties, pH, rheology, droplet size distribution, in vitro drug release and in vivo psoriatic activity. All compounds were successfully synthesized according to analytical methodology, with good yields. Both formulations presented suitable physicochemical properties. AAN-16 E presented the most promising therapeutic effects in a murine model of psoriasis. Overall, new HNE inhibitors were synthesized with high and selective activity and incorporated into topical emulsions with potential to treat psoriasis.

Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition.

A series of artemisinin-vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range.

Design, synthesis and structure-activity relationships of (1H-pyridin-4-ylidene)amines as potential antimalarials.

(1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were prepared as potential clopidol isosteres in the development of antimalarials. Their antiplasmodial activity was evaluated in vitro against the Plasmodium falciparum W2 (chloroquine-resistant) and FCR3 (atovaquone-resistant) strains. The most active of these derivatives, 4m, had an IC(50) of 1microM against W2 and 3microM against FCR3. Molecular modeling studies suggest that (1H-pyridin-4-ylidene)amines may bind to the ubiquinol oxidation Q(o) site of cytochrome bc(1).