Pulsed stimulated Brillouin microscopy enables high-sensitivity mechanical imaging of live and fragile biological specimens.

Brillouin microscopy is an emerging optical elastography technique capable of assessing mechanical properties of biological samples in a three-dimensional, all-optical and noncontact fashion. The typically weak Brillouin scattering signal can be substantially enhanced via a stimulated Brillouin scattering (SBS) process; however, current implementations require high pump powers, which prohibit applications to photosensitive or live imaging of biological samples. Here we present a pulsed SBS scheme that takes advantage of the nonlinearity of the pump-probe interaction. In particular, we show that the required pump laser power can be decreased ~20-fold without affecting the signal levels or spectral precision. We demonstrate the low phototoxicity and high specificity of our pulsed SBS approach by imaging, with subcellular detail, sensitive single cells, zebrafish larvae, mouse embryos and adult Caenorhabditis elegans. Furthermore, our method permits observing the mechanics of organoids and C. elegans embryos over time, opening up further possibilities for the field of mechanobiology.

Where are we now in biological drugs for myositis?

Idiopathic inflammatory myopathies (IIM) are a rare and heterogeneous group of chronic autoimmune disorders. Up to 40% of IIM patients have long-term sequelae and significant functional disability. Its management can be challenging. New therapies are badly needed. The small number of cases with diverse presentations, and different diagnostic criteria interfere significantly with clinical trial results. Only intravenous immunoglobulin has been internationally approved for IIM patients. Most clinical trials of new biological therapies have failed to meet their primary endpoints in IIM, with only one biological drug recommended for refractory IIM treatment (rituximab), although not approved. We review several new emerging biological drugs including B cell depletion therapies, abatacept, janus-kinase inhibitors, and aldesleukin. Encouragingly, some phase II randomized controlled trials have evaluated the efficacy and safety of new biologics in IIM, demonstrating an improvement in clinical and laboratory measures.

A large cohort comparison of very late-onset systemic lupus erythematosus with younger-onset patients.

OBJECTIVES: Age has a significant impact on systemic lupus erythematosus (SLE). However, data on very late-onset SLE (vlSLE) are scarce. We have compared the clinical and serological features of vlSLE patients with younger-onset patients. METHODS: We assessed the clinical and laboratory data of all patients fulfilling SLE classification criteria evaluated at a university hospital from 1978 to 2023. Patients were divided into 4 groups according to age at diagnosis: juvenile SLE (jSLE <8 years); adult SLE (aSLE 18-49 years); late SLE (lSLE 50-59 years); vlSLE (≥60 years). RESULTS: 845 patients were enrolled. The jSLE, aSLE, lSLE, and vlSLE groups included 153, 630, 47, and 15 patients, respectively. The vlSLE group tended to have a lower female-to-male ratio (4:1; p=0.282), was mainly Caucasian (93.3%; p<0.001), and had the lowest survival time (20.3 years; p<0.001). vlSLE patients had the lowest prevalence of positive anti-dsDNA antibodies (26.7%; p=0.010) and low C3 levels (13.3%; p<0.001). Although arthritis was less common among vlSLE patients (73.3%; p=0.043), they more commonly developed Sjögren's syndrome (SS 33.3%; p<0.001) and rheumatoid arthritis (RA 13.3%; p<0.001). Infections and malignancy were the main causes of death. CONCLUSIONS: Compared with younger patients, in vlSLE, female predominance is less pronounced. Arthritis, anti-dsDNA antibodies and low C3 levels are less frequent. SS and RA are more common. Despite lower disease activity, vlSLE patients have the lowest survival rate. While uncommon, SLE should not be excluded as a possible diagnosis in the elderly.

Public involvement in chronic respiratory diseases research: A qualitative study of patients', carers' and citizens' perspectives.

INTRODUCTION: Patient and public involvement (PPI) initiatives involving patients with chronic respiratory disease (CRD) are rare. Therefore, this study aimed to explore the perspectives of patients with CRD, carers and interested citizens regarding the relevance and need for a PPI network and suggestions for its implementation. METHODS: A qualitative study based on focus groups was conducted. Recruitment occurred through invitations on social media platforms and to patients who have participated in previous asthma studies of the team. Three focus groups were conducted, via video conference, using a semi-structured guide. Thematic analysis was performed by two independent researchers and discussed with the extended team. RESULTS: Fifteen patients with CRD, one carer and one interested citizen (13 females, median 36 (range: 18-72) years) participated. All participants acknowledged the importance of implementing a collaborative network and demonstrated interest in being integrated. Participants acknowledged the importance of their involvement in several phases of the research cycle. The main aim identified for this network was to facilitate communication between patients and researchers. Participants regarded the integration of patients, carers, researchers and healthcare professionals from different scientific areas as relevant. The use of digital platforms to attract members and support the work, together with group dynamics and regular meetings, were some of the most relevant practical considerations for implementing the network. The identified facilitators for their engagement were sharing experiences, researchers' and healthcare professionals' support and feedback and schedule flexibility. The identified barriers included the amount of time dedicated, low health/digital literacy and the potential detachment of nondiagnosed patients or those with low symptom impact in daily life. CONCLUSION: Patients, carers and citizens acknowledged the relevance of implementing a collaborative network and demonstrated interest in active participation in every stage of the health research cycle. A deeper knowledge of the barriers and facilitators identified in this study could support implementing these initiatives in Portugal. PATIENT OR PUBLIC CONTRIBUTION: This study was designed by a research team that included one patient with asthma and one carer. They were specifically involved in building the study protocol and the interview guide. They also gave feedback regarding the electronic consent form and the short sociodemographic questionnaire created, namely by removing noncontributing words or phrases and rewording expressions. The lay summary was written by another patient with asthma. All participants of this study were invited to implement and integrate the ConectAR network-a collaborative network of research in respiratory health. PUBLIC SUMMARY: In Portugal, chronic respiratory patients do not have an active role as 'coinvestigators'. This study aimed to acknowledge if patients and citizens considered a patient and public involvement network useful, whose main purpose would be to facilitate communication between patients and researchers. A study based on online group interviews was carried out with patients with chronic respiratory diseases and interested citizens, both recruited on social media platforms. Participants considered that bringing together patients, carers, researchers and healthcare professionals is valuable because sharing different experiences and perspectives may help patients to improve their daily lives and increase research quality. In conclusion, patients agree that implementing a collaborative network with researchers and healthcare professionals and participating in the health research cycle is quite preponderant. Acknowledging what can help and deter this network may be beneficial to implementing this type of initiative in Portugal.

The cost of living crisis - how does it impact the health and life of individuals? A survey exploring perceptions in Italy, Germany, Sweden and the United Kingdom.

BACKGROUND: The Cost of Living Crisis (CoLC), a real term reduction in basic income, risks individuals being unable to afford essentials such as heat, food and clothing. The impact of the CoLC is disproportionate - with different population sub-groups more likely to be negatively affected. The objective of this survey was to evaluate the perceived impact of the CoLC on the life and health of participants across four European countries. METHODS: A survey housing two questions to investigate the relationship between the CoLC and its perceived impact on life and health was developed. Four European countries (U.K., Sweden, Italy and Germany) took part via the YouGov platform. Logistic regression models were created for each country and question to evaluate which population characteristics were associated with a negative reported impact of the CoLC. RESULTS: A total of 8,152 unique individuals responded between 17th March and 30th March 2023. Each country was equally represented. Those aged 36-64 were more likely to report a negative impact of the CoLC on their life and health than younger participants (p < 0.001, p = 0.02 respectively). Across all countries, females were significantly more likely to report a negative impact on their life and health, however, when analysed according to country, in Sweden females were less likely to report a negative impact (p < 0.001). Those in lower income families or who reported poor health in the preceding 12 months were significantly more likely to report a negative impact of the CoLC on their life and health. There was no difference within the participant group on the reported impact of the CoLC based on location (rural vs. urban). CONCLUSIONS: We demonstrate the disproportionate negative impact of the CoLC on both life and health in different population subgroups. Germany and Sweden appeared to be more resilient to the effects of the CoLC, particularly for certain population subgroups. It is important to understand the differing effects of a CoLC, and to learn from successful health and economic strategies in order to create targeted policy and create a population resilient to economic shocks.

Development and validity evidence on the scale of perceived social support for university students (EPSSEU) during the period of social restrictions.

AIM: This study aims to validate a Perceived Social Support Scale for University Students (EPSSEU) during periods of social restrictions, by focusing on family and university support. SUBJECT AND METHODS: This cross-sectional study was conducted with undergraduate students from a public higher education institution. The college students who participated in the study-1353 at baseline and 378 after 6 months-answered a virtual questionnaire containing questions on: sociodemographic and lifestyle data, items proposed for the EPSSEU, Satisfaction with Social Support Scale (ESSS), and Depression, Anxiety and Stress Scale (DASS-21). Exploratory factor analysis, Cronbach's alpha reliability analysis, as well as discriminant, convergent, and known-group validations were performed. RESULTS: The results showed two factors support from: i) the university and ii) friends and family- which explained 61.82% of the variance in the data. The EPSSEU showed good reliability (Cronbach's alpha = 0.796) as well as validity, with higher scores among individuals without depression, anxiety, or stress. CONCLUSION: The EPSSEU shows adequate psychometric qualities and may be a useful instrument for assessing university students' social support in pandemics, social distancing, and remote teaching contexts.

A state-of-the-science review of analytical methods for urinary dialkylphosphate metabolites in the assessment of exposure to organophosphate pesticides: From 2000 to 2022.

The general population and workers are exposed to organophosphate insecticides, one of the leading chemical classes of pesticides used in rural and urban areas. This paper aims to conduct an integrative review of the most used analytical methods for identifying and quantifying dialkylphosphate-which are metabolites of organophosphate insecticides-in the urine of exposed workers, discussing their advantages, limitations and applicability. Searches utilized the PubMed, the Scientific Electronic Library Online and the Brazilian Digital Library of Theses and Dissertations databases between 2000 and 2021. Twenty-five studies were selected. The extraction methods most used were liquid-liquid extraction (LLE) (36%) and solid-phase extraction (SPE) (36%), with the SPE being more economical in terms of time and amount of solvents needed, and presenting the best percentage of recovery of analytes, when compared with LLE. Nineteen studies (76%) used the gas chromatography method of separation, and among these, 12 records (63%) indicated mass spectrometry used as a detection technology (analyzer). Studies demonstrate that dialkylphosphates are sensitive and representative exposure biomarkers for environmental and occupational organophosphate exposure.

Association between sequence variants in the FSHR gene and reproductive outcomes following IVF in predicted normoresponders.

RESEARCH QUESTION: Is there an association between FSHR sequence variants and reproductive outcomes following IVF in predicted normoresponders? DESIGN: Multicentre prospective cohort study conducted from November 2016 to June 2019 in Vietnam, Belgium and Spain including patients aged <38 years, and undergoing IVF with a predicted normal response with fixed-dose 150 IU rFSH in an antagonist protocol. Genotyping was performed for three FSHR (c.919A>G, c.2039A>G, c.-29G>A) and one FSHB sequence variants (c.-211G>T). Clinical pregnancy rate (CPR), live birth rate (LBR) and miscarriage rate in the first embryo transfer and cumulative live birth rate (CLBR) were compared between the different genotypes. RESULTS: A total of 351 patients underwent at least one embryo transfer. Genetic model analysis that adjusted for patient age, body mass index, ethnicity, type of embryo transfer, embryo stage and number of top-quality embryos transferred revealed a higher CPR for homozygous patients for the variant allele G of c.919A>G when compared to patients with genotype AA (60.3% versus 46.3%, adjusted odds ratio [ORadj] 1.96, 95% confidence interval [CI] 1.09-3.53). Also, c.919A>G genotypes AG and GG presented a higher CPR and LBR when compared with genotype AA (59.1% versus 46.3%, ORadj 1.80, 95% CI 1.08-3.00, and 51.3% versus 39.0%, ORadj 1.69, 95% CI 1.01-2.80, respectively). Cox regression models revealed a statistically significantly lower CLBR for c.2039A>G genotype GG in the codominant model (hazard ratio [HR] 0.66, 95% CI 0.43-0.99). CONCLUSION: These results demonstrate a previously unreported association between variant c.919A>G genotype GG and higher CPR and LBR in infertile patients and reinforce a potential role for genetic background in predicting the reproductive prognosis following IVF.

Primary care practitioners' priorities for improving the timeliness of cancer diagnosis in primary care: a European cluster-based analysis.

BACKGROUND: Diagnosing cancer at an early stage increases the likelihood of survival, and more advanced cancers are more difficult to treat successfully. Primary care practitioners (PCPs) play a key role in timely diagnosis of cancer. PCPs' knowledge of their own patient populations and health systems could help improve the planning of more effective approaches to earlier cancer recognition and referral. How PCPs act when faced with patients who may have cancer is likely to depend on how their health systems are organised, and this may be one explanation for the wide variation on cancer survival rates across Europe. OBJECTIVES: To identify and characterise clusters of countries whose PCPs perceive the same factors as being important in improving the timeliness of cancer diagnosis. METHODS: A cluster analysis of qualitative data from an online survey was carried out. PCPs answered an open-ended survey question on how the speed of diagnosis of cancer in primary care could be improved. Following coding and thematic analysis, we identified the number of times per country that an item in a theme was mentioned. k-means clustering identified clusters of countries whose PCPs perceived the same themes as most important. Post-hoc testing explored differences between these clusters. SETTING: Twenty-five primary care centres in 20 European countries. Each centre was asked to recruit at least 50 participants. PARTICIPANTS: Primary care practitioners of each country. RESULTS: In all, 1,351 PCPs gave free-text answers. We identified eighteen themes organising the content of the responses. Based on the frequency of the themes, k-means clustering identified three groups of countries. There were significant differences between clusters regarding the importance of: access to tests (p = 0.010); access to specialists (p = 0.014), screening (p < 0.001); and finances, quotas & limits (p < 0.001). CONCLUSIONS: Our study identified three distinct clusters of European countries within which PCPs had similar views on the factors that would improve the timeliness of cancer diagnosis. Further work is needed to understand what it is about the clusters that have produced these patterns, allowing healthcare systems to share best practice and to reduce disparities.

The Impact of Virtual Consultations on the Quality of Primary Care: Systematic Review.

BACKGROUND: The adoption of virtual consultations, catalyzed by the COVID-19 pandemic, has transformed the delivery of primary care services. Owing to their rapid global proliferation, there is a need to comprehensively evaluate the impact of virtual consultations on all aspects of care quality. OBJECTIVE: This study aims to evaluate the impact of virtual consultations on the quality of primary care. METHODS: A total of 6 databases were searched. Studies that evaluated the impact of virtual consultations, for any disease, were included. Title and abstract screening and full-text screening were performed by 2 pairs of investigators. Risk of bias was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis of the results was performed. RESULTS: In total, 30 studies (5,469,333 participants) were included in this review. Our findings suggest that virtual consultations are equally effective to or more effective than face-to-face care for the management of certain conditions, including mental illness, excessive smoking, and alcohol consumption. Overall, 4 studies indicated positive impacts on some aspects of patient-centeredness; however, a negative impact was noted on patients' perceived autonomy support (ie, the degree to which people perceive those in positions of authority to be autonomy supportive). Virtual consultations may reduce waiting times, lower patient costs, and reduce rates of follow-up in secondary and tertiary care settings. Evidence for the impact on clinical safety is extremely limited. Evidence regarding equity was considerably mixed. Overall, it appears that virtual care is more likely to be used by younger, female patients, with disparities among other subgroups depending on contextual factors. CONCLUSIONS: Our systematic review demonstrated that virtual consultations may be as effective as face-to-face care and have a potentially positive impact on the efficiency and timeliness of care; however, there is a considerable lack of evidence on the impacts on patient safety, equity, and patient-centeredness, highlighting areas where future research efforts should be devoted. Capitalizing on real-world data, as well as clinical trials, is crucial to ensure that the use of virtual consultations is tailored according to patient needs and is inclusive of the intended end users. Data collection methods that are bespoke to the primary care context and account for patient characteristics are necessary to generate a stronger evidence base to inform future virtual care policies.

Strengths, Weaknesses, Opportunities, and Threats Analysis of the Use of Digital Health Technologies in Primary Health Care in the Sub-Saharan African Region: Qualitative Study.

BACKGROUND: Digital health technologies (DHTs) have become increasingly commonplace as a means of delivering primary care. While DHTs have been postulated to reduce inequalities, increase access, and strengthen health systems, how the implementation of DHTs has been realized in the sub-Saharan Africa (SSA) health care environment remains inadequately explored. OBJECTIVE: This study aims to capture the multidisciplinary experiences of primary care professionals using DHTs to explore the strengths and weaknesses, as well as opportunities and threats, regarding the implementation and use of DHTs in SSA primary care settings. METHODS: A combination of qualitative approaches was adopted (ie, focus groups and semistructured interviews). Participants were recruited through the African Forum for Primary Care and researchers' contact networks using convenience sampling and included if having experience with digital technologies in primary health care in SSA. Focus and interviews were conducted, respectively, in November 2021 and January-March 2022. Topic guides were used to cover relevant topics in the interviews, using the strengths, weaknesses, opportunities, and threats framework. Transcripts were compiled verbatim and systematically reviewed by 2 independent reviewers using framework analysis to identify emerging themes. The COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist was used to ensure the study met the recommended standards of qualitative data reporting. RESULTS: A total of 33 participants participated in the study (n=13 and n=23 in the interviews and in focus groups, respectively; n=3 participants participated in both). The strengths of using DHTs ranged from improving access to care, supporting the continuity of care, and increasing care satisfaction and trust to greater collaboration, enabling safer decision-making, and hastening progress toward universal health coverage. Weaknesses included poor digital literacy, health inequalities, lack of human resources, inadequate training, lack of basic infrastructure and equipment, and poor coordination when implementing DHTs. DHTs were perceived as an opportunity to improve patient digital literacy, increase equity, promote more patient-centric design in upcoming DHTs, streamline expenditure, and provide a means to learn international best practices. Threats identified include the lack of buy-in from both patients and providers, insufficient human resources and local capacity, inadequate governmental support, overly restrictive regulations, and a lack of focus on cybersecurity and data protection. CONCLUSIONS: The research highlights the complex challenges of implementing DHTs in the SSA context as a fast-moving health delivery modality, as well as the need for multistakeholder involvement. Future research should explore the nuances of these findings across different technologies and settings in the SSA region and implications on health and health care equity, capitalizing on mixed-methods research, including the use of real-world quantitative data to understand patient health needs. The promise of digital health will only be realized when informed by studies that incorporate patient perspective at every stage of the research cycle.

Perceptions of chief clinical information officers on the state of electronic health records systems interoperability in NHS England: a qualitative interview study.

BACKGROUND: In the era of electronic health records (EHR), the ability to share clinical data is a key facilitator of healthcare delivery. Since the introduction of EHRs, this aspect has been extensively studied from the perspective of healthcare providers. Less often explored are the day-to-day challenges surrounding the procurement, deployment, maintenance, and use of interoperable EHR systems, from the perspective of healthcare administrators, such as chief clinical information officers (CCIOs). OBJECTIVE: Our study aims to capture the perceptions of CCIOs on the current state of EHR interoperability in the NHS, its impact on patient safety, the perceived facilitators and barriers to improving EHR interoperability, and what the future of EHR development in the NHS may entail. METHODS: Semi-structured interviews were conducted between November 2020 - October 2021. Convenience sampling was employed to recruit NHS England CCIOs. Interviews were digitally recorded and transcribed verbatim. A thematic analysis was performed by two independent researchers to identify emerging themes. RESULTS: Fifteen CCIOs participated in the study. Participants reported that limited EHR interoperability contributed to the inability to easily access and transfer data into a unified source, thus resulting in data fragmentation. The resulting lack of clarity on patients' health status negatively impacts patient safety through suboptimal care coordination, duplication of efforts, and more defensive practice. Facilitators to improving interoperability included the recognition of the need by clinicians, patient expectations, and the inherent centralised nature of the NHS. Barriers included systems usability difficulties, and institutional, data management, and financial-related challenges. Looking ahead, participants acknowledged that realising that vision across the NHS would require a renewed focus on mandating data standards, user-centred design, greater patient involvement, and encouraging inter-organisational collaboration. CONCLUSION: Tackling poor interoperability will require solutions both at the technical level and in the wider policy context. This will involve demanding interoperability functionalities from the outset in procurement contracts, fostering greater inter-organisation cooperation on implementation strategies, and encouraging systems vendors to prioritise interoperability in their products. Only by comprehensively addressing these challenges would the full potential promised by the use of fully interoperable EHRs be realised.

Evaluating the impact of a pulse oximetry remote monitoring programme on mortality and healthcare utilisation in patients with COVID-19 assessed in emergency departments in England: a retrospective matched cohort study.

BACKGROUND: To identify the impact of enrolment onto a national pulse oximetry remote monitoring programme for COVID-19 (COVID-19 Oximetry @home; CO@h) on health service use and mortality in patients attending Emergency Departments (EDs). METHODS: We conducted a retrospective matched cohort study of patients enrolled onto the CO@h pathway from EDs in England. We included all patients with a positive COVID-19 test from 1 October 2020 to 3 May 2021 who attended ED from 3 days before to 10 days after the date of the test. All patients who were admitted or died on the same or following day to the first ED attendance within the time window were excluded. In the primary analysis, participants enrolled onto CO@h were matched using demographic and clinical criteria to participants who were not enrolled. Five outcome measures were examined within 28 days of first ED attendance: (1) Death from any cause; (2) Any subsequent ED attendance; (3) Any emergency hospital admission; (4) Critical care admission; and (5) Length of stay. RESULTS: 15 621 participants were included in the primary analysis, of whom 639 were enrolled onto CO@h and 14 982 were controls. Odds of death were 52% lower in those enrolled (95% CI 7% to 75%) compared with those not enrolled onto CO@h. Odds of any ED attendance or admission were 37% (95% CI 16% to 63%) and 59% (95% CI 32% to 91%) higher, respectively, in those enrolled. Of those admitted, those enrolled had 53% (95% CI 7% to 76%) lower odds of critical care admission. There was no significant impact on length of stay. CONCLUSIONS: These findings indicate that for patients assessed in ED, pulse oximetry remote monitoring may be a clinically effective and safe model for early detection of hypoxia and escalation. However, possible selection biases might limit the generalisability to other populations.

Development a Low-Cost Wireless Smart Meter with Power Quality Measurement for Smart Grid Applications.

Developing a low-cost wireless energy meter with power quality measurements for smart grid applications represents a significant advance in efficient and accurate electric energy monitoring. In increasingly complex and interconnected electric systems, this device will be essential for a wide range of applications, such as smart grids, by introducing a real-time energy monitoring system. In light of this, smart meters can offer greater opportunities for sustainable and efficient energy use and improve the utilization of energy sources, especially those that are nonrenewable. According to the 2020 International Energy Agency (IEA) report, nonrenewable energy sources represent 65% of the global supply chain. The smart meter developed in this work is based on the ESP32 microcontroller and easily accessible components since it includes a user-friendly development platform that offers a cost-effective solution while ensuring reliable performance. The main objective of developing the smart meters was to enhance the software and simplify the hardware. Unlike traditional meters that calculate electrical parameters by means of complex circuits in hardware, this project performed the calculations directly on the microcontroller. This procedure reduced the complexity of the hardware by simplifying the meter design. Owing to the high-performance processing capability of the microcontroller, efficient and accurate calculations of electrical parameters could be achieved without the need for additional circuits. This software-driven approach with simplified hardware led to benefits, such as reduced production costs, lower energy consumption, and a meter with improved accuracy, as well as updates on flexibility. Furthermore, the integrated wireless connectivity in the microcontroller enables the collected data to be transmitted to remote monitoring systems for later analysis. The innovative feature of this smart meter lies in the fact that it has readily available components, along with the ESP32 chip, which results in a low-cost smart meter with performance that is comparable to other meters available on the market. Moreover, it is has the capacity to incorporate IoT and artificial intelligence applications. The developed smart meter is cost effective and energy efficient, and offers benefits with regard to flexibility, and thus represents an innovative, efficient, and versatile solution for smart grid applications.

The Role of Biological Rhythms in New Drug Formulations to Cross the Brain Barriers.

For brain protection, the blood-brain barrier and blood-cerebrospinal fluid barrier limit the traffic of molecules between blood and brain tissue and between blood and cerebrospinal fluid, respectively. Besides their protective function, brain barriers also limit the passage of therapeutic drugs to the brain, which constitutes a great challenge for the development of therapeutic strategies for brain disorders. This problem has led to the emergence of novel strategies to treat neurological disorders, like the development of nanoformulations to deliver therapeutic agents to the brain. Recently, functional molecular clocks have been identified in the blood-brain barrier and in the blood-cerebrospinal fluid barrier. In fact, circadian rhythms in physiological functions related to drug disposition were also described in brain barriers. This opens the possibility for chronobiological approaches that aim to use time to improve drug efficacy and safety. The conjugation of nanoformulations with chronobiology for neurological disorders is still unexplored. Facing this, here, we reviewed the circadian rhythms in brain barriers, the nanoformulations studied to deliver drugs to the brain, and the nanoformulations with the potential to be conjugated with a chronobiological approach to therapeutic strategies for the brain.

Urinary dialkylphosphate metabolites in the assessment of exposure to organophosphate pesticides: from 2000 to 2022.

The general population and workers are exposed to organophosphate insecticides, one of the leading chemical classes of pesticides used in rural and urban areas, in the control of arboviruses and agriculture. These pesticides cause environmental/occupational exposure and associated risks to human and environmental health. The objective of this study was to carry out an integrative review of epidemiological studies that identified and quantified dialkylphosphate metabolites in the urine of exposed populations, focusing on the vector control workers, discussing the application and the results found. Searches utilized the Pubmed, Scielo, and the Brazilian Digital Library of Theses and Dissertations (BDTD) databases between 2000 and 2021. From the 194 selected studies, 75 (39%) were with children/adolescents, 48 (24%) with rural workers, 36 (19%) with the general population, 27 (14%) with pregnant women, and 9 (4%) with vector control workers. The total dialkylphosphate concentrations found in the occupationally exposed population were higher than in the general population. Studies demonstrate that dialkylphosphates are sensitive and representative exposure biomarkers for environmental and occupational organophosphate exposure. The work revealed a lack of studies with vector control workers and a lack of studies in developing countries.

Circadian rhythm and disease: Relationship, new insights, and future perspectives.

The circadian system is responsible for internal functions and regulation of the organism according to environmental cues (zeitgebers). Circadian rhythm dysregulation or chronodisruption has been associated with several diseases, from mental to autoimmune diseases, and with life quality change. Following this, some therapies have been developed to correct circadian misalignments, such as light therapy and chronobiotics. In this manuscript, we describe the circadian-related diseases so far investigated, and studies reporting relevant data on this topic, evidencing this relationship, are included. Despite the actual limitations in published work, there is clear evidence of the correlation between circadian rhythm dysregulation and disease origin/development, and, in this way, clock-related therapies emerge as great progress in the clinical field. Future improvements in such interventions can lead to the development of successful chronotherapy strategies, deeply contributing to enhanced therapeutic outcomes.

Genome-Scale Metabolic Modeling Combined with Transcriptome Profiling Provides Mechanistic Understanding of Streptococcus thermophilus CH8 Metabolism.

Streptococcus thermophilus is a lactic acid bacterium adapted toward growth in milk and is a vital component of starter cultures for milk fermentation. Here, we combine genome-scale metabolic modeling and transcriptome profiling to obtain novel metabolic insights into this bacterium. Notably, a refined genome-scale metabolic model (GEM) accurately representing S. thermophilus CH8 metabolism was developed. Modeling the utilization of casein as a nitrogen source revealed an imbalance in amino acid supply and demand, resulting in growth limitation due to the scarcity of specific amino acids, in particular sulfur amino acids. Growth experiments in milk corroborated this finding. A subtle interdependency of the redox balance and the secretion levels of the key metabolites lactate, formate, acetoin, and acetaldehyde was furthermore identified with the modeling approach, providing a mechanistic understanding of the factors governing the secretion product profile. As a potential effect of high expression of arginine biosynthesis genes, a moderate secretion of ornithine was observed experimentally, augmenting the proposed hypothesis of ornithine/putrescine exchange as part of the protocooperative interaction between S. thermophilus and Lactobacillus delbrueckii subsp. bulgaricus in yogurt. This study provides a foundation for future community modeling of food fermentations and rational development of starter strains with improved functionality. IMPORTANCE Streptococcus thermophilus is one the main organisms involved in the fermentation of milk and, increasingly, also in the fermentation of plant-based foods. The construction of a functional high-quality genome-scale metabolic model, in conjunction with in-depth transcriptome profiling with a focus on metabolism, provides a valuable resource for the improved understanding of S. thermophilus physiology. An example is the model-based prediction of the most significant route of synthesis for the characteristic yogurt flavor compound acetaldehyde and identification of metabolic principles governing the synthesis of other flavor compounds. Moreover, the systematic assessment of amino acid supply and demand during growth in milk provides insights into the key challenges related to nitrogen metabolism that is imposed on S. thermophilus and any other organism associated with the milk niche.

Androgens and diminished ovarian reserve: the long road from basic science to clinical implementation. A comprehensive and systematic review with meta-analysis.

OBJECTIVE: This study aimed to present a narrative review regarding androgen production, androgens' role in folliculogenesis, and the available therapeutic approaches for androgen supplementation, and to perform a systematic review and meta-analysis regarding the impact of androgens (dehydroepiandrosterone/testosterone) compared with placebo or no treatment on ovarian response and pregnancy outcomes in patients with diminished ovarian reserve and/or poor ovarian responders. DATA SOURCES: An electronic search of MEDLINE, Embase, Cochrane Library, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, the ISRCTN registry, and the World Health Organization International Clinical Trials Registry, was conducted for studies published until September 2021. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that compared ovarian response and/or pregnancy outcomes between the different in vitro fertilization protocols using androgens (ie, dehydroepiandrosterone and testosterone) and conventional in vitro fertilization stimulation in patients with diminished ovarian reserve and/or poor ovarian responders were included. METHODS: The quality of each study was evaluated with the revised Cochrane risk-of-bias tool for randomized trials (RoB 2). The meta-analysis used random-effects models. All results were interpreted on the basis of intention-to-treat analysis (defined as the inclusion of all randomized patients in the denominator). Risk ratios and 95% confidence intervals were used and combined for meta-analysis. RESULTS: No significant differences were found regarding the number of oocytes retrieved (mean difference, 0.76; 95% confidence interval, -0.35 to 1.88), mature oocytes retrieved (mean difference, 0.25; 95% confidence interval, -0.27 to 0.76), clinical pregnancy rate (risk ratio, 1.17; 95% confidence interval, 0.87-1.57), live-birth rate (risk ratio, 0.97; 95% confidence interval, 0.47-2.01), or miscarriage rate (risk ratio, 0.80; 95% confidence interval, 0.29-2.22) when dehydroepiandrosterone priming was compared with placebo or no treatment. Testosterone pretreatment yielded a higher number of oocytes retrieved (mean difference, 0.94; 95% confidence interval, 0.46-1.42), a higher clinical pregnancy rate (risk ratio, 2.07; 95% confidence interval, 1.33-3.20), and higher live-birth rate (risk ratio, 2.09; 95% confidence interval, 1.11-3.95). CONCLUSION: Although dehydroepiandrosterone did not present a clear effect on outcomes of assisted reproductive techniques, we found a potentially beneficial effect of testosterone priming on ovarian response and pregnancy outcomes. However, results should be interpreted with caution, taking into account the low to moderate quality of the available evidence.