Metaoptics for aberration correction in microendoscopy.

Compact and minimally invasive scanning fiber endoscopy probes with micron-level resolution have great potential in detailed tissue interrogation and early disease diagnosis, which are key applications of confocal reflectance imaging at visible wavelengths. State-of-the-art imaging probes commonly employ refractive lens triplets or gradient refractive index (GRIN) lenses as the micro-objective. However, off-axis aberration emerges as a critical factor affecting resolution, especially at the extremities of the imaging field. In response to this challenge, we propose what we believe to be a novel design integrating a metasurface with the GRIN micro-objective to address optical aberrations during beam scan. The metasurface acts as a corrector element for optical aberrations in a fiber-scanning endoscope using the same fiber for excitation and collection. Modeling such hybrid refractive-metasurface designs requires the coupling of simulation techniques across macroscale and nanoscale optics, for which we used an Ansys simulation workflow platform. Operating at a wavelength of 644 nm, this metaoptical element serves as a thin and compact aberration correction surface, ensuring uniform resolution across the entire imaging field. Experimental results from our scanning fiber endoscopy system demonstrate a notable enhancement in optical performance both on-axis and off-axis, achieving a resolution of 3 µm at the center of the imaging field. Impressively, the resolution experiences only a modest degradation by a factor of 0.13 at the edge of the field of view compared to the center.

Higher anthocyanin intake is associated with lower depressive symptoms in adults with and without major depressive disorder.

Background: Major depressive disorder (MDD) is a significant cause of disability globally and an emerging body of evidence suggests that dietary components, including flavonoids, may impact depression-related biochemical pathways. Further research that characterizes dietary intake of flavonoids in diverse population groups, including people with MDD and explores the relationship between flavonoid intake and depression is needed. This study aimed to determine dietary flavonoid and subclass intake and assess the association with depressive symptomatology in a sample of adults with and without MDD. Methodology: Participants with and without MDD (determined using DSM 5) completed the Depression, Anxiety, and Stress Scale-21 (DASS-21). Diet history interviews were analyzed using PhenolExplorer to quantify flavonoid subclasses (flavan-3-ols, flavonols, anthocyanins, flavones, flavanones, isoflavones), and total flavonoid intake. Independent t-tests and linear regression, adjusting for age, sex, and BMI were performed. Results: Participants (n = 93; 75% female) had a mean age of 26.0 ± 8.2 years. Participants with MDD had significantly higher DASS-depression scores (n = 44; DASS-depression 27.3 ± 9.8) compared to participants without MDD (n = 49; DASS-depression 3.1 ± 4.4; p < .001). Intakes of total flavonoids and subclasses were similar between groups, except for anthocyanins where participants with MDD reported lower intakes of anthocyanins compared to participants without MDD (median intake: 0.08 mg/day and 11.6 mg/day, respectively; p = .02). In the total sample, higher anthocyanin intake was associated with lower DASS-depression score (B = -4.1; SE = 1.8; 95% CI [-7.7, -0.4]; p = .029). Conclusion: Intake of total flavonoids and most subclasses were similar between people with and without MDD. However, a dietary deficit of anthocyanins (found in purple/red fruits and vegetables) was evident in participants with MDD, and higher anthocyanin intake was associated with lower depressive symptomatology in the total sample. Further research in larger samples is warranted to explore if the documented association is independent of MDD status.

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node.

Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.

Single-cell adhesive profiling in an optofluidic device elucidates CD8+ T lymphocyte phenotypes in inflamed vasculature-like microenvironments.

Tissue infiltration by circulating leukocytes occurs via adhesive interactions with the local vasculature, but how the adhesive quality of circulating cells guides the homing of specific phenotypes to different vascular microenvironments remains undefined. We developed an optofluidic system enabling fluorescent labeling of photoactivatable cells based on their adhesive rolling velocity in an inflamed vasculature-mimicking microfluidic device under physiological fluid flow. In so doing, single-cell level multidimensional profiling of cellular characteristics could be characterized and related to the associated adhesive phenotype. When applied to CD8+ T cells, ligand/receptor expression profiles and subtypes associated with adhesion were revealed, providing insight into inflamed tissue infiltration capabilities of specific CD8+ T lymphocyte subsets and how local vascular microenvironmental features may regulate the quality of cellular infiltration. This methodology facilitates rapid screening of cell populations for enhanced homing capabilities under defined biochemical and biophysical microenvironments, relevant to leukocyte homing modulation in multiple pathologies.

Microengineered In Vitro Assays for Screening and Sorting Manufactured Therapeutic T Cells.

Adoptively transferred T cells constitute a major class of current and emergent cellular immunotherapies for the treatment of disease, including but not limited to cancer. Although key advancements in molecular recognition, genetic engineering, and manufacturing have dramatically enhanced their translational potential, therapeutic potency remains limited by poor homing and infiltration of transferred cells within target host tissues. In vitro microengineered homing assays with precise control over micromechanical and biological cues can address these shortcomings by enabling interrogation, screening, sorting, and optimization of therapeutic T cells based on their homing capacity. In this article, the working principles, application, and integration of microengineered homing assays for the mechanistic study of biophysical and biomolecular cues relevant to homing of therapeutic T cells are reviewed. The potential for these platforms to enable scalable enrichment and screening of next-generation manufactured T cell therapies for cancer is also discussed.

Developing an ontology of non-pharmacological treatment for emotional and mood disturbances in dementia.

Emotional and mood disturbances are common in people with dementia. Non-pharmacological interventions are beneficial for managing these disturbances. However, effectively applying these interventions, particularly in the person-centred approach, is a complex and knowledge-intensive task. Healthcare professionals need the assistance of tools to obtain all relevant information that is often buried in a vast amount of clinical data to form a holistic understanding of the person for successfully applying non-pharmacological interventions. A machine-readable knowledge model, e.g., ontology, can codify the research evidence to underpin these tools. For the first time, this study aims to develop an ontology entitled Dementia-Related Emotional And Mood Disturbance Non-Pharmacological Treatment Ontology (DREAMDNPTO). DREAMDNPTO consists of 1258 unique classes (concepts) and 70 object properties that represent relationships between these classes. It meets the requirements and quality standards for biomedical ontology. As DREAMDNPTO provides a computerisable semantic representation of knowledge specific to non-pharmacological treatment for emotional and mood disturbances in dementia, it will facilitate the application of machine learning to this particular and important health domain of emotional and mood disturbance management for people with dementia.

PBITV3 : A robust and comprehensive tool for screening pathogenic proteomes for drug targets and prioritizing vaccine candidates.

Rise of life-threatening superbugs, pandemics and epidemics warrants the need for cost-effective and novel pharmacological interventions. Availability of publicly available proteomes of pathogens supports development of high-throughput discovery platforms to prioritize potential drug-targets and develop testable hypothesis for pharmacological screening. The pipeline builder for identification of target (PBIT) was developed in 2016 and updated in 2021, with the purpose of accelerating the search for drug-targets by integration of methods like comparative and subtractive genomics, essentiality/virulence and druggability analysis. Since then, it has been used for identification of drugs and vaccine targets, safety profiling of multiepitope vaccines and mRNA vaccine construction against a broad-spectrum of pathogens. This tool has now been updated with functionalities related to systems biology and immuno-informatics and validated by analyzing 48 putative antigens of Mycobacterium tuberculosis documented in literature. PBITv3 available as both online and offline tools will enhance drug discovery against emerging drug-resistant infectious agents. PBITv3 can be freely accessed at http://pbit.bicnirrh.res.in/.

Australian population norms for health-related quality of life measured using the EQ-5D-5L, and relationships with sociodemographic characteristics.

BACKGROUND: Measuring health related quality-of-life (HRQoL) of the general population is essential to establish a reference for health outcome evaluations. This study sought to establish EQ-5D-5L population norms in Australia and to investigate the heterogeneity of HRQoL between sociodemographic variables. METHODS: A cross-sectional study comprising of a representative sample of Australia's general population (n = 9958) aged 18 or older. Recruitment quotas were set for the Australian census population by age, sex, state/territory of residence and rurality. Participants were recruited by Qualtrics through its database of over 800,000 registered panel members and asked to value their own state of health using the EQ-5D-5L domains and the EuroQol-Visual Analogue Scale (EQ-VAS). An Australian value set developed using Discreet Choice Experiment was used to calculate utility scores. RESULTS: The estimated mean EQ-5D-5L index for Australia's general population was 0.86 (standard deviation [SD] 0.19), and the EQ-VAS score was estimated as 73.2 (SD 21.7). 23.9% of the study population reported being in the best health state (11,111). Younger people, current smokers, people who are unemployed and people with more financial stress reported a lower EQ-5D-5L index score (p < 0.001). Residents in the major cities, inner regional and outer regional Australia reported higher health utility scores than those residing in remote and very remote Australia. CONCLUSIONS: This is the first Australian study to apply the EQ-5D-5L in a nationally representative sample. The EQ-5D-5L Australian population norms obtained can be used as reference scores for future population health evaluations and comparisons. The findings facilitate a national reference for clinical, economic, and policy decision-making processes and provide a fuller understanding of the Australian population's HRQoL.

High-Sensitivity Cardiac Troponin I Enhances Preeclampsia Prediction Beyond Maternal Factors and the sFlt-1/PlGF Ratio.

BACKGROUND: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence. METHODS: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio. RESULTS: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; P=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence. CONCLUSIONS: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers.

Alcohol consumption and health-related quality of life in regional, rural and metropolitan Australia: analysis of cross-sectional data from the Community Health and Rural/Regional Medicine (CHARM) study.

BACKGROUND: Relationships between alcohol consumption and health are complex and vary between countries, regions, and genders. Previous research in Australia has focused on estimating the effect of alcohol consumption on mortality. However, little is known about the relationships between alcohol consumption and health-related quality of life (QoL) in Australia. This study aimed to investigate the levels of alcohol intake and QoL in males and females in rural, regional and metropolitan areas of Australia. METHOD: Participants (n = 1717 Australian adults) completed an online cross-sectional study. Males and females were compared on measures including the AUDIT-C and WHOQOL-BREF. Data were stratified into risk of alcohol use disorder (AUD) and associations were examined between alcohol consumption and QoL, adjusting for sociodemographic variables. RESULTS: Males had higher alcohol consumption and were at greater risk of AUD than females (20% vs 8%). Relationships between alcohol consumption and QoL were positive or non-significant for low-moderate AUD risk categories and negative in the severe AUD risk category. Males in regional communities reported higher alcohol consumption (AUDIT-C score 6.6 vs 4.1, p < 0.01) than metropolitan areas. Regression analyses identified that after adjusting for sociodemographic variables, alcohol consumption was positively related to overall, environmental, and physical QoL and general health. CONCLUSION: The results indicate that alcohol consumption is negatively related to QoL only in those with severe risk of AUD. Males in regional areas reported higher alcohol consumption than those in metropolitan areas. These results provide further information about relationships between alcohol intake and health in Australia that can help inform prevention, screening and delivery of interventions.

Aspirations, apprehensions and the availability of career guidance among dental interns in Kerala, India.

Background: Dental graduates undergo stress owing to factors such as academic pressure and job uncertainty. Additionally, a lack of guidance with regard to clinical entrepreneurship is a cause of great concern. This study aimed to assess the aspirations and apprehensions of dental interns and to determine the availability of career guidance among them. Materials and Methods: A cross-sectional online survey was conducted using a self-designed electronic questionnaire. A total of 480 dental interns from both public and private dental institutions in the state of Kerala were included in this study. The stratified random sampling method was adopted, and the population proportion ratio was used to collect the samples. Data were analysed using the Chi-square test, Student's t-test, analysis of variance and multivariate linear regression. Results: The majority of the interns were females (87.5%); 75% of the participants had graduated from private institutions and 44% resided in rural areas. The apprehension score was high among interns from private institutions and those who belonged to a higher socioeconomic stratum (P < 0.05). However, the level was low among those who expressed strong aspirations (r = -0.213) and satisfaction (r = -0.329). Conclusion: The determinants for apprehension exhibited substantial disparities among the private and public educational sectors. Although the scenario of students who approached dentistry was similar, their plans for the future differed based on gender, sector and socioeconomic status. The lack of effective career guidance from institutions might impact the advancement of dentistry in future.

Feasibility of training primary healthcare workers to identify antenatal depression.

Identifying women with depressive symptoms is the first step to reducing the risk of the short-term and long-term consequences of antenatal depression. Task shifting by training primary healthcare workers may help to reduce the burden in low-resource settings. Twenty health workers in a primary healthcare center in urban Bengaluru were trained to screen and identify antenatal depression. The training had two components: knowledge-based, using the depression module in the Mental Health Gap Action Program; and skills-based hands-on training, using the Patient Health Questionnaire-9. Knowledge about antenatal depression in the health workers improved by three units after training (p < 0.001). Their perceived skills and self-efficacy also improved by one unit each (p = 0.032 and p = 0.036, respectively). Following the training, 25% of the pregnant women who underwent screening by health workers reported depressive symptoms, as compared to no positive screening before training. Training was found to improve the knowledge, perceived skills and self-efficacy of nurses, junior health assistants and Accredited Social Health Activists (ASHAs), and was found to increase the screening rate of depression in an antenatal clinic in urban India. Incorporating screening for depressive symptoms into regular antenatal care is feasible in low-resource settings.

Mammalian cysteine-rich secretory proteins interact with plasma membrane Ca2+ exporter PMCA4b.

BACKGROUND: Mammalian cysteine-rich secretory proteins (CRISPs) are predominantly expressed in the male reproductive tract. Knockout mice lacking two or more CRISPs show defects in sperm transport, sperm-egg interaction and Ca2+ homeostasis. CRISPs play redundant and specific roles via their binding partners. To understand this, a comprehensive analysis of CRISP interactome needs to be undertaken. OBJECTIVES: This study aimed to analyse CRISP4 binding partners on the plasma membrane of rat caudal spermatozoa. MATERIALS AND METHODS: Total proteins from rat caudal spermatozoa were subjected to immunoprecipitation using anti-CRISP4 antibody followed by liquid chromatography-mass spectrophotometry analysis. Plasma membrane localised proteins were shortlisted, and a key target was validated by co-immunoprecipitation and co-localisation. Co-transfection followed by co-immunoprecipitation was carried out for studying the interaction of full-length as well as deletion mutants of CRISPs with human plasma membrane calcium ATPase, isoform b (hPMCA4b). Calcium assays were performed using Fura-2-AM. The cholesterol binding ability of different CRISPs was evaluated in silico. RESULTS: The membrane-specific interactome of rat CRISP4 (rCRISP4) from caudal spermatozoa revealed PMCA4b as a novel binding partner, and their interaction was validated in rat spermatozoa. Human CRISP1 (hCRISP1) and hCRISP3 also interacted with PMCA4b via the N-terminal domain. Interestingly, hCRISP1 and rCRISP4 delayed PMCA4b-mediated calcium extrusion but hCRISP3 did not. In silico analysis demonstrated that hCRISP1 and rCRISP4 have higher binding affinity towards cholesterol than hCRISP3. The secretion profile of different CRISPs also showed that the ratio of secreted to cell-associated proteins was highest for hCRISP3. CONCLUSION: Our study identifies PMCA4b as a target of multiple mammalian CRISPs and unravels a new role of CRISPs in regulating calcium homeostasis. Differences in the interaction of different CRISPs with cholesterol may regulate their enrichment in the lipid rafts and redistribution in the membrane post-capacitation, thereby affecting their interaction with PMCA4b.

Smartphone application use patterns for mental health disorders: A systematic literature review and meta-analysis.

BACKGROUND: Mobile mental health applications play a significant role in mental health care to fill gaps in care for mental disorders. Despite the growth in mobile phone apps for mental health conditions, patients' mental health smartphone application use, perceived usefulness, and future interest in using apps for mental disorders have not been systematically examined. METHODS: The authors designed and conducted this systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. Articles reporting mobile/smartphone applications used for mental disorders describing ownership, application use, perceived helpfulness, future interest to use, use patterns, and attitudes were included. PubMed/MEDLINE, EMBASE, PsychINFO, Scopus, and Google Scholar were searched. Published articles from 2014 up to October 2022 were included. The methodological quality was assessed using the Joanna Briggs Institute critical appraisal tool. The heterogeneity test, publication bias, funnel plots and Egger's test were applied. The outcome was calculated by metaprop command using a random-effects model. RESULTS: Ten studies met the eligibility criteria. The pooled prevalence of smartphone ownership, application use for current mental health disorders, perceived usefulness, and future interest in using the app for their mental health problem was 88.63%, 23.29%, 72.80%, and 78.97%, respectively. Heterogeneity and publication bias were detected. CONCLUSIONS: The results of this study indicate that despite a considerable number of smartphone users, perceived usefulness, and future interest in using smartphone mental health applications among patients with mental disorders, only about one-fifth use an application for mental health disorders. The results show that there is a large potential to increase the use of apps for patients to support self-care in the growing era of digital mental health. Further research with consumers and mental health professionals is recommended to address barriers and improve mhealth app utilization. REGISTRATION: Prospero international prospective register of systematic reviews with ID: CRD42022359416.

Salivary testosterone and cortisol levels in borderline personality disorder before and after a 12-week group dialectical behavior therapy intervention.

Background: Borderline Personality Disorder (BPD) is a chronic, debilitating, and difficult to treat condition. BPD has recently been linked to steroid hormone dysregulation and medical conditions characterized by disturbed androgen metabolism. This study aimed to investigate cortisol and testosterone levels in BPD, and changes in hormones following psychological treatment. Methods: Participants with BPD (n = 33) completed a 12-week Dialectical Behavior Therapy group program. Pre and post salivary testosterone and cortisol were analyzed. Baseline hormones in the BPD group were compared to age-and-sex matched controls (n = 33). Non-parametric tests were utilized to investigate group differences, pre-post treatment hormone and symptom changes, and associations between symptoms and hormone levels. Results: Participants with BPD had significantly higher testosterone levels than controls. Mean testosterone levels in females with BPD were double that of female controls. Testosterone and cortisol levels were related, and some BPD symptoms were associated with with hormone levels. BPD symptoms reduced significantly with treatment, however pre to post hormone levels did not change. Conclusions: This study supports an association between BPD symptoms and neuroendocrine dysfunction at baseline, however we found no reduction in hormone dysfunction post treatment. Further research into relationships between stress signaling and neuroendocrine disturbances in BPD may inform aetiological and treatment models. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12618000477224. Registered on 3 April 2018.