Individual Pathways Research Articles

Built environment professionals’ perspective on digital technology skills

PurposeThis study aims to explore the opinions of Built Environment Professionals (BEP) on the usage of fourth-generation digital technologies in the construction industry.Design/methodology/approachThis study adopts a qualitative research approach and conducts semi-structured interviews with Black, Asian and Minority Ethnic (BAME) professionals to explore the adoption and utilisation of fourth-generation digital technologies in the construction industry. The semi-structured interviews allowed the participants to elaborate on their experiences, and thematic analysis was employed to identify and analyse significant themes related to the topic.FindingsAccounts from BAME construction professionals reveal that the increased popularity of fourth-generation digital technologies, also known as Industry 4.0 technologies, does not necessarily result in increased usage. This is because many of these new technologies have not been embraced and are unpopular in certain circles. A more significant revelation is the impact of BAME community settings on determining the career pathways of most individuals, which often do not support the construction or digital technology pathways within the construction industry.Research limitations/implicationsResearch targeting ethnic minorities may not necessarily yield a large response due to the sensitivity of the issues raised. However, conducting a nationwide research with a larger sample size drawn from various locations in the UK could achieve more robust findings and uncover additional issues. Meanwhile, the results of this research can serve as a framework for more extensive investigations.Practical implicationsThe research offers valuable recommendations to industry and academia regarding the need to address the specific challenges faced by the BAME community in terms of digital technology adoption. These issues are often overlooked in most discussions about digital technology.Originality/valueThe study provides critical recommendations that are relevant to Further and Higher Education (HE) institutions, industries, construction organisations, government bodies, etc. Recommendations include a call for collaboration between educational institutions, industry partners and local communities to facilitate awareness and orientation programmes within the community.

The effect of hydroxychloroquine on cholesterol synthesis depends on the profile of cholesterol metabolism. A controlled clinical study

Background and aimsHydroxychloroquine (HCQ) has a variable effect on cholesterol synthesis. To clarify this, we assessed the effect of HCQ on the cholesterol-synthesis pathway in individuals with low and high cholesterol absorption efficiency. MethodA total of 53 acute myocardial infarction patients with a constant statin dose randomized to receive HCQ or placebo for six months in a double-blind manner, were classified further into low (n = 26) and high (n = 27) cholesterol absorbers based on the median baseline serum cholestanol level. Serum lipids and biomarkers of cholesterol synthesis (squalene, lanosterol, zymostenol, desmosterol, and lathosterol) and absorption efficiency (sitosterol and cholestanol), were measured at baseline and one-, six-, and 12-month follow-up visits. ResultsIn low cholesterol absorbers, serum cholesterol concentration and cholesterol synthesis and absorption biomarkers did not differ between the HCQ and placebo groups. At one month, high cholesterol absorbers with HCQ had lower serum cholesterol concentration and serum lanosterol to cholesterol ratio in comparison to the placebo group (HCQ 3.18 ± 0.62 vs. placebo 3.71 ± 0.65, p = 0.042, and HCQ 10.4 ± 2.55 vs. placebo 13.1 ± 2.36, p = 0.008, respectively). At 12 months, serum desmosterol to cholesterol ratio was lower in HCQ users (HCQ 47.1 ± 7.08 vs. placebo 59.0 ± 13.1, p = 0.011). ConclusionsHCQ affects the cholesterol-synthesis pathway in high cholesterol absorbers. It reduces serum lanosterol and desmosterol ratios and consequently serum cholesterol concentration possibly by inhibiting the activity of lanosterol synthase as described earlier in vitro studies. Trial registrationClinicalTrials.gov Identifier: NCT02648464.

Inflammation as the nexus: exploring the link between acute myocardial infarction and chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD), particularly following acute exacerbations (AE-COPD), significantly heightens the risks and mortality associated with acute myocardial infarction (AMI). The intersection of COPD and AMI is characterised by a considerable overlap in inflammatory mechanisms, which play a crucial role in the development of both conditions. Although extensive research has been conducted on individual inflammatory pathways in AMI and COPD, the understanding of thrombo-inflammatory crosstalk in comorbid settings remains limited. The effectiveness of various inflammatory components in reducing AMI infarct size or slowing COPD progression has shown promise, yet their efficacy in the context of comorbidity with COPD and AMI is not established. This review focuses on the critical importance of both local and systemic inflammation, highlighting it as a key pathophysiological connection between AMI and COPD/AE-COPD.

Diagnosis and admission center : Establishment and evaluation of an integrated translational infrastructure for clinical psychiatric research

The routine in-depth characterization of patients with methods of clinical and scale-based examination, neuropsychology, based on biomaterials, and sensor-based information opens up transformative possibilities on the way to personalized diagnostics, treatment and prevention in psychiatry, psychotherapy, and psychosomatics. Effective integration of the additional temporal and logistical effort into everyday care as well as the acceptance by patients are critical to the success of such an approach but there is little evidence on this to date. We report here on the establishment of the Diagnosis and Admission Center (DAZ) at the Central Institute of Mental Health (ZI) in Mannheim. The DAZ is an outpatient unit upstream of other care structures for clinical and scientific phenotyping across diagnoses as astarting point for data-driven, individualized pathways to further treatment, diagnostics or research. We describe the functions, goals, and implementation of the newly created clinical scientific translational structure, provide an overview of the patient populations it has reached, and provide data on its acceptance. In this context, the close integration with downstream clinical processes enables abetter coordinated and demand-oriented allocation. In addition, DAZ enables afaster start of disorder-specific diagnostics and treatment. Since its launch in April 2021 up to the end of 2022, 1021 patients underwent psychiatric evaluation at DAZ during apilot phase. The patient sample corresponded to arepresentative sample from standard care and the newly established processes were regarded as helpful by patients. In summary, the DAZ uniquely combines the interests and needs of patient with the collection of scientifically relevant data.

The mediating role of child delay of gratification in the link between early and prolonged poverty exposure and adolescent allostatic load

Early and prolonged exposure to poverty disrupts biological processes associated with the body’s stress response system, leading to long-term negative health outcomes, including obesity, autoimmune disorders, and cardiovascular disease. Allostatic load (AL), a composite measure of chronic stress on the body, is a robust predictor of subsequent health outcomes. However, developmental research examining the associations of early poverty exposure with AL in adolescence, as well as the underlying mechanisms of influence is limited. Early poverty exposure also impedes healthy development of child self-regulation, which may increase risk for high AL in adolescence, but this mechanistic pathway has not yet been tested. We used data from the national Study of Early Child Care and Youth Development (SECCYD) to examine the longitudinal associations between prolonged poverty exposure in early childhood (0–3 years) and AL in adolescence (age 15). We also tested the mediating role of child delay of gratification, a behavioral measure of self-regulation (at age 54 months), in the potential association between early poverty exposure and adolescent AL. Accounting for model covariates (i.e., child biological sex and race-ethnicity) and individual differences in child delay of gratification, early and prolonged poverty exposure was significantly associated with higher AL at age 15. The indirect effect through child delay of gratification was not significant, but the individual pathways of the indirect effect were significant, and the overall direct association of early poverty exposure with adolescent AL was significant. Our findings show that prolonged exposure to poverty in early childhood (0–3 years) can have significant negative associations with both child delay of gratification (at 54 months) and AL (at age 15). Given that the detrimental impacts of poverty exposure can be detected at an early age, targeted prevention efforts (e.g., anti-poverty programs such as cash assistance programs) may be able to offset some of the risks of early poverty exposure on self-regulation and AL.

A “Periodic Table” approach to understand the pathophysiology of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction is a complex syndrome that is characterized by symptoms and signs of heart failure without an apparent reduction in left ventricular ejection fraction. Although the main pathophysiologic pathways related to HFpEF are grossly understood, whether all or a specific number of mechanisms are related to the genesis of HFpEF for a given patient remains elusive. Moreover, it has been recently understood that HFpEF is a diverse disease with many phenotypes that have overlapping features, suggesting that a “one-way-fits-all” approach to understand the pathophysiology of this complex syndrome might not be appropriate. In this manuscript, we introduce a “periodic table” approach that incorporates both individual pathophysiologic pathways with consequent hemodynamic alterations, in which combinations of such pathophysiologic “elements” may explain the pathogenetic basis of HFpEF in each phenotype. This approach may held promise for understanding the basis of HFpEF syndrome and may contribute to the personalization of treatment approaches for each individual patient, but further evidence is needed to ascertain whether HFpEF patients have diverse pathogenetic mechanisms as suggested in the periodic table approach.

The Diagnostic Pathway Experiences of People Living with Rare Dementia and Their Family Caregivers: A Cross-Sectional Mixed Methods Study Using Qualitative and Economic Analyses.

The pathways for receiving a diagnosis of a rare type of dementia are poorly understood. Diagnostic challenges decrease access to relevant health promotion activities and post-diagnostic support. This study was focused on pathways experienced by people affected by rare dementia in Wales, United Kingdom (UK), considering the practical, emotional, and economic consequences. Semi-structured interviews were completed with 10 people affected by rare dementia across Wales, UK (nine family caregivers and one person living with rare dementia). The interview data were subject to a thematic analysis and a bottom-up costing approach was used to cost the pathway journeys. Five transitional points occurred across the diagnostic pathway (initial contact, initial referral, further referrals-provider, further referrals-private, and diagnosis) alongside two further themes (i.e., involved in the diagnostic process and disputes between stakeholders). The timeliness of the diagnosis was perceived to often be subject to 'luck', with access to private healthcare a personal finance option to expedite the process. Higher economic costs were observed when, in retrospect, inappropriate referrals were made, or multiple referrals were required. The confusion and disputes relating to individual diagnostic pathways led to further emotional burdens, suggesting that higher economic costs and emotional consequences are interlinked. Clearer diagnostic pathways for rare dementia may prevent unnecessary service contacts, waiting times, and associated distress. Prioritising appropriate and timely service contacts leads to diagnosis and support to families and enables people to increase control over their health. Appropriate diagnostic pathways may be less costly and reduce costs for families.

Understanding and deterring online child grooming: A qualitative study

The prevalence of online child sexual grooming offenses has been on the rise, posing significant risks to children. Child sexual grooming involves sexual communication with minors. This study aims to understand motivations and pathways of individuals who have engaged in online grooming behaviour, as well as propose effective prevention and intervention strategies. A sample of 14 male participants who had engaged in online child grooming were interviewed. Five themes were identified through thematic analysis: Social aspects, Mental health and psychological aspects, Justification for offending, Secrecy and Technology. Within all five themes risk factors and protective factors relating to online grooming behaviour were identified. Three pathways into online grooming behaviour were hypothesised: social connection, addictive behaviour, and fantasy/roleplay. Additionally, the study highlights the complex relationship between online grooming and other child sexual abuse offences, including the sharing and distribution of indecent images of children. The study underscores the need for greater education and awareness about the risks and harms associated with online grooming for those at risk of engaging in this behaviour as well as wider support and situational prevention approaches, including monitoring and use of warning messages on relevant online platforms.

EXPLORING CAREER PATHWAYS FOR PEOPLE WITH SPECIAL NEEDS IN STEM AND BEYOND

This research paper explores the challenges and opportunities in creating inclusive career pathways for individuals with special needs, focusing on Science, Technology, Engineering, and Mathematics (STEM) and beyond. Examining existing literature reveals pervasive societal attitudes, educational barriers, and workplace biases that hinder the seamless integration of individuals with special needs. Acknowledging the importance of diversity and inclusion, the paper discusses initiatives that address these challenges, including mentorship programs, workplace accommodations, and advocacy campaigns. Policy implications underscore the need for systemic reforms to ensure equal opportunities. The paper envisions future directions such as technological advancements, global collaboration, and a holistic approach to inclusion. In conclusion, the collaborative efforts of governments, educational institutions, and the wider community are crucial for shaping a future where individuals with special needs thrive in diverse professional landscapes.
 Keywords: Inclusive Career Pathways, Special Needs, STEM, Diversity and Inclusion.

Dimensions of Legal And Moral Use of Artificial Intelligence In Education

The purpose of the research is to critically analyze the legal aspects of the use of artificial intelligence (AI) in the field of education, as well as to study the role of chatbots and the Chat GPT model, plagiarism issues, educational modeling and the impact of AI on the labor market. To achieve this goal, various research methods are used, including the analysis of current legal norms and international legislation that relate to the use of AI in education. The study also includes an analysis of intellectual property issues, data privacy, ethical standards and liability.
 The results of the study highlight the problem of plagiarism in chat rooms and emphasize the importance of careful use of information to ensure academic integrity. Despite the possible misuse of AI by students, such as chatbots and GPT models, for plagiarism, these technologies can also facilitate plagiarism detection. The research also examines the use of machine learning and data analytics to create personalized learning experiences, improve learning effectiveness, and retain knowledge.
 The overall conclusion is that the integration of artificial intelligence in education has the potential to improve the quality and accessibility of education, but this requires a sound legal framework. The article also evaluates the effectiveness of various AI tools, including chatbots that provide information on demand and Chat GPT, useful for processing textual materials. The paper also examines the role of learning simulation in personalizing education, using AI to analyze performance data, and tailoring individual learning pathways.

Exploring synthesis as a vital cognitive skill in complex clinical diagnosis.

Clinicians employ two main cognitive approaches for diagnoses, depending on their expertise. Novices typically use linear hypothetico-deductive methods, while experts rely more on intuitive pattern recognition. These closely correspond to System 1 and System 2 thinking described in behavioral economics. We propose that complex cases additionally require the cognitive skill of synthesis, to visualize and understand the connections between various elements. To illustrate the concept, we describe a 60-year-old individual with a 6 h history of chest pain, fever, cough, accompanying chronic heart failure, atrial fibrillation, COPD, thyrotoxicosis, and ischemic heart disease. Facedwith such a scenario, a bedside approach adapted by clinicians is to generate a list of individual diagnoses or pathways of pathogenesis, and address them individually. For example, this cluster could include: smoking causing COPD, IHD leading to chest pain and heart failure, and thyrotoxicosis causing atrial fibrillation (AF). However, other interconnections across pathways could be considered: smoking contributing to IHD; COPD exacerbating heart failure; IHD and pneumonia triggering atrial fibrillation; thyrotoxicosis and AF, independently worsening heart failure; COPD causing hypoxemia and worsening ventricular function. The second cluster of explanation offers a richer network of relationships and connections across disorders and pathways of pathogenesis. This cognitive process of creatively identifying these relationships is synthesis, described in Bloom's taxonomy of the cognitive domain. It is a crucial skill required for visualizing a comprehensive and holistic view of a patient. The concept of synthesis as a cognitive skill in clinical reasoning warrants further exploration.

PoMeLo: a systematic computational approach to predicting metabolic loss in pathogen genomes

BackgroundGenome streamlining, the process by which genomes become smaller and encode fewer genes over time, is a common phenomenon among pathogenic bacteria. This reduction is driven by selection for minimized energy expenditure in a nutrient-rich environment. As pathogens evolve to become more reliant on the host, metabolic genes and resulting capabilities are lost in favor of siphoning metabolites from the host. Characterizing genome streamlining, gene loss, and metabolic pathway degradation can be useful in assessing pathogen dependency on host metabolism and identifying potential targets for host-directed therapeutics.ResultsPoMeLo (Predictor of Metabolic Loss) is a novel evolutionary genomics-guided computational approach for identifying metabolic gaps in the genomes of pathogenic bacteria. PoMeLo leverages a centralized public database of high-quality genomes and annotations and allows the user to compare an unlimited number of genomes across individual genes and pathways. PoMeLo runs locally using user-friendly prompts in a matter of minutes and generates tabular and visual outputs for users to compare predicted metabolic capacity between groups of bacteria and individual species. Each pathway is assigned a Predicted Metabolic Loss (PML) score to assess the magnitude of genome streamlining. Optionally, PoMeLo places the results in an evolutionary context by including phylogenetic relationships in visual outputs. It can also initially compute phylogenetically-weighted mean genome sizes to identify genome streamlining events. Here, we describe PoMeLo and demonstrate its use in identifying metabolic gaps in genomes of pathogenic Treponema species.ConclusionsPoMeLo represents an advance over existing methods for identifying metabolic gaps in genomic data, allowing comparison across large numbers of genomes and placing the resulting data in a phylogenetic context. PoMeLo is freely available for academic and non-academic use at https://github.com/czbiohub-sf/pomelo.

Lhx3/4 initiates a cardiopharyngeal-specific transcriptional program in response to widespread FGF signaling.

Individual signaling pathways, such as fibroblast growth factors (FGFs), can regulate a plethora of inductive events. According to current paradigms, signal-dependent transcription factors (TFs), such as FGF/MapK-activated Ets family factors, partner with lineage-determining factors to achieve regulatory specificity. However, many aspects of this model have not been rigorously investigated. One key question relates to whether lineage-determining factors dictate lineage-specific responses to inductive signals or facilitate these responses in collaboration with other inputs. We utilize the chordate model Ciona robusta to investigate mechanisms generating lineage-specific induction. Previous studies in C. robusta have shown that cardiopharyngeal progenitor cells are specified through the combined activity of FGF-activated Ets1/2.b and an inferred ATTA-binding transcriptional cofactor. Here, we show that the homeobox TF Lhx3/4 serves as the lineage-determining TF that dictates cardiopharyngeal-specific transcription in response to pleiotropic FGF signaling. Targeted knockdown of Lhx3/4 leads to loss of cardiopharyngeal gene expression. Strikingly, ectopic expression of Lhx3/4 in a neuroectodermal lineage subject to FGF-dependent specification leads to ectopic cardiopharyngeal gene expression in this lineage. Furthermore, ectopic Lhx3/4 expression disrupts neural plate morphogenesis, generating aberrant cell behaviors associated with execution of incompatible morphogenetic programs. Based on these findings, we propose that combinatorial regulation by signal-dependent and lineage-determinant factors represents a generalizable, previously uncategorized regulatory subcircuit we term "cofactor-dependent induction." Integration of this subcircuit into theoretical models will facilitate accurate predictions regarding the impact of gene regulatory network rewiring on evolutionary diversification and disease ontogeny.

Supporting women's empowerment by changing intra‐household decision‐making: A mixed‐methods analysis of a field experiment in rural south‐west Tanzania

AbstractMotivationIn rural sub‐Saharan Africa, patriarchal social norms and customs often lead to unequal resource access, decision‐making power, and intra‐household power relations between women and men co‐heads of smallholder farm households. Household methodologies are gender‐transformative approaches that aim to achieve gender equality and empower women by improving intra‐household gender relations. Evidence of the impact of such approaches on women's empowerment is still scarce.PurposeWe assess the effects of a programme that introduces participatory intra‐household decision‐making to challenge gender relations within households on women's empowerment. The programme was delivered to monogamous couples who head smallholder coffee‐farming households in rural south‐west Tanzania.Methods and approachWe combine (quasi‐)experimental quantitative and qualitative methods to assess the programme's impact on women's empowerment and how that impact fits with women's valued domains of empowerment and individual pathways to empowerment.FindingsAwareness‐raising couple seminars, the programme's least intensive intervention, increased women's access to livestock. Intensive coaching in participatory decision‐making increased women's control over household coffee income—a priority for women. Couple seminars increased women's highly valued involvement in strategic farm decisions—intensive coaching increased it further. Access to personal income, however, valued by women for independent decision‐making for their households' wellbeing, did not change.Policy implicationsGender‐transformative approaches that challenge domestic gender relations can increase women's access to household income and resources, and increase their participation in farming decisions. Such approaches need to be complemented by interventions to increase women's human capital, knowledge of enterprises, and personal resources. Catering for women's diverse pathways towards empowerment may increase their effectiveness. Challenging deep gender norms requires long‐term engagement and trust between change agents and communities.

Meta-analysis reveals obesity associated gut microbial alteration patterns and reproducible contributors of functional shift

ABSTRACT The majority of cohort-specific studies associating gut microbiota with obesity are often contradictory; thus, the replicability of the signature remains questionable. Moreover, the species that drive obesity-associated functional shifts and their replicability remain unexplored. Thus, we aimed to address these questions by analyzing gut microbial metagenome sequencing data to develop an in-depth understanding of obese host-gut microbiota interactions using 3329 samples (Obese, n = 1494; Control, n = 1835) from 17 different countries, including both 16S rRNA gene and metagenomic sequence data. Fecal metagenomic data from diverse geographical locations were curated, profiled, and pooled using a machine learning-based approach to identify robust global signatures of obesity. Furthermore, gut microbial species and pathways were systematically integrated through the genomic content of the species to identify contributors to obesity-associated functional shifts. The community structure of the obese gut microbiome was evaluated, and a reproducible depletion of diversity was observed in the obese compared to the lean gut. From this, we infer that the loss of diversity in the obese gut is responsible for perturbations in the healthy microbial functional repertoire. We identified 25 highly predictive species and 37 pathway associations as signatures of obesity, which were validated with remarkably high accuracy (AUC, Species: 0.85, and pathway: 0.80) with an independent validation dataset. We observed a reduction in short-chain fatty acid (SCFA) producers (several Alistipes species, Odoribacter splanchnicus, etc.) and depletion of promoters of gut barrier integrity (Akkermansia muciniphila and Bifidobacterium longum) in obese guts. Our analysis underlines SCFAs and purine/pyrimidine biosynthesis, carbohydrate metabolism pathways in control individuals, and amino acid, enzyme cofactor, and peptidoglycan biosynthesis pathway enrichment in obese individuals. We also mapped the contributors to important obesity-associated functional shifts and observed that these are both dataset-specific and shared across the datasets. In summary, a comprehensive analysis of diverse datasets unveils species specifically contributing to functional shifts and consistent gut microbial patterns associated to obesity.

Intrahepatic cholangiocarcinoma: Recurrence patterns, genomics and survival.

570 Background: Recurrence is common after resection of intrahepatic cholangiocarcinoma (IHC) but how recurrence patterns impact survival remains unclear. This study investigated the clinicopathologic and genomic factors associated with site of first recurrence and their impact on outcome after curative intent resection. Methods: Patients who underwent curative intent hepatectomy for IHC at two medical centers (MSKCC and EMC) with complete follow up and tumor genomic data were included. Documented sites of first disease recurrence were classified as liver only (LO), extrahepatic (EH) only or simultaneous liver and extrahepatic (SIM). Time to recurrence (TTR) and recurrence-free (RFS) were calculated from time of resection while OS was calculated from time of recurrence. Primary tumors underwent targeted next generation sequencing. Clinical, histopathologic and genomic factors associated with site(s) of recurrence, RFS and OS were assessed. Results: A total of 318 patients (n=296 MSK, n=22 EMC) treated between 1993 and 2021 met inclusion criteria and were analyzed; 232 patients (73%) developed recurrence. TTR was 11 (9.8, 12) months; OS and RFS was 26 (20, 33) and 14 (13, 18) months, respectively, among patients that recurred. Sites of first recurrence were LO 93 (40%), EH 80 (34%) and SIM 59 (26%). Median OS was similar in the LO (33 [26,42] months) and EH groups (33 [23,46] months) but much lower in SIM (12 [9.8,18] months) (p < 0.001). Moderate/poor tumor differentiation (p = 0.004), LVI (p = 0.004), N1 disease (p = 0.003), and PNI (p = 0.012) were associated with SIM; only positive resection margin predicted LO (p = 0.007). No individual genomic or pathway alterations predicted site of initial recurrence; however, for all patients, TP53 mut (HR 2.01, 1.4-2.9; p < 0.001), CDKN2A del (HR 1.96, 1.29-2.98; p = 0.003), CDKN2B del (HR 3.2, 2.03-5.05; p < 0.001) and KRAS mut (HR 2.49, 1.56-3.96; p < 0.001) were associated with worse survival. On multivariable analysis, SIM (HR 2.23, 1.49-3.34; p < 0.001), clinical stage III (HR 1.94, 1.26-2.99; p = 0.011), and alterations in TP53 (HR 2.07, 1.4-3.07; p < 0.001), CDKN2B (HR 4.1, 2.53-6.63; p < 0.001) and KRAS (HR 2.72, 1.68-4.43; p < 0.001) were independent predictors of worse OS. Of note, 13 LO patients were treated with regional chemotherapy after recurrence, with an associated median OS of 49 (33, NR) months compared to 28 (20, 39) months in the 80 patients treated with systemic therapy alone. Conclusions: Recurrence after resection of IHC was common, and the liver was the single most common site (66%). Clinicopathologic and genomic variables had limited ability to predict site of first recurrence. While LO and EH were associated with similar OS, simultaneous recurrences were dramatically worse. The data support adjuvant strategies targeting liver recurrence to improve outcome after resection of IHC.

Opsin-Free Activation of Bmp Receptors by a Femtosecond Laser.

Bone morphogenetic protein (BMP) signaling plays a vital role in differentiation, organogenesis, and various cell processes. As a member of TGF-β superfamily, the BMP initiation usually accompanies crosstalk with other signaling pathways and simultaneously activates some of them. It is quite challenging to solely initiate an individual pathway. In this study, an opsin-free optical method to specifically activate BMP receptors (BMPR) and subsequent pSmad1/5/8 cascades by a single-time scan of a tightly-focused femtosecond laser in the near infrared range is reported. Via transient two-photon excitation to intrinsic local flavins near the cell membrane, the photoactivation drives conformational changes of preformed BMPR complexes to enable their bonding and phosphorylation of the GS domain in BMPR-I by BMPR-II. The pSmad1/5/8 signaling is initiated by this method, while p38 and pSmad2 are rarely perturbed. Based on a microscopic system, primary adipose-derived stem cells in an area of 420 × 420µm2 are photoactivated by a single-time laser scanning for 1.5s and exhibit pSmad1/5/8 upregulation and osteoblastic differentiation after 21 days. Hence, an opsin-free, specific, and noninvasive optical method to initiate BMP signaling, easily accomplished by a two-photon microscope system is reported.

Cost-effectiveness of testosterone treatment utilising individual patient data from randomised controlled trials in men with low testosterone levels.

Testosterone is safe and highly effective in men with organic hypogonadism, but worldwide testosterone prescribing has recently shifted towards middle-aged and older men, mostly with low testosterone related to age, diabetes and obesity, for whom there is less established evidence of clinical safety and benefit. The value of testosterone treatment in middle-aged and older men with low testosterone is yet to be determined. We therefore evaluated the cost-effectiveness of testosterone treatment in such men with low testosterone compared with no treatment. A cost-utility analysis comparing testosterone with no treatment was conducted following best practices in decision modelling. A cohort Markov model incorporating relevant care pathways for individuals with hypogonadism was developed for a 10-year-time horizon. Clinical outcomes were obtained from an individual patient meta-analysis of placebo-controlled, double-blind randomised studies. Three starting age categories were defined: 40, 60 and 75 years. Cost utility (quality-adjusted life years) accrued and costs of testosterone treatment, monitoring and cardiovascular complications were compared to estimate incremental cost-effectiveness ratios and cost-effectiveness acceptability curves for selected scenarios. Ten-year excess treatment costs for testosterone compared with non-treatment ranged between £2306 and £3269 per patient. Quality-adjusted life years results depended on the instruments used to measure health utilities. Using Beck depression index-derived quality-adjusted life years data, testosterone was cost-effective (incremental cost-effectiveness ratio <£20,000) for men aged <75 years, regardless of morbidity and mortality sensitivity analyses. Testosterone was not cost-effective in men aged >75 years in models assuming increased morbidity and/or mortality. Our data suggest that testosterone is cost-effective in men <75 years when Beck depression index-derived quality-adjusted life years data are considered; cost-effectiveness in men >75 years is dependent on cardiovascular safety. However, more robust and longer-term cost-utility data are needed to verify our conclusion.

Exploring German High School Students’ Conceptual Learning Pathways of Space and Place

Space and place, fundamental concepts in geography, uniquely contribute to the development of students’ geographical thinking. Despite this, these concepts are underrepresented in German geography classrooms, partly due to a distinct lack of empirical evidence concerning the learning processes associated with learning complex geographical concepts. This study employed videography to explore how n = 64 grade twelve students from various school types in Germany develop a more sophisticated understanding of space and place during a 90 min. teaching experiment. To delve into the micro-level of students’ learning processes, qualitative content analysis was employed to analyse the data. The subsequent detailed reconstruction of an individual learning pathway unveiled several pivotal moments. Notably, the concepts demonstrated significant potential for restructuring students’ existing knowledge into a more conceptual and systematic framework. Moreover, barriers to learning were identified as well. For example, conceptual interferences between the concepts of space/place and other geographical key concepts such as sustainability were observed, partially impeding the formation of a clear conceptual framework in students’ minds. The results provide insights for teaching implications, such as emphasising a single key concept to avoid conceptual interferences, and suggest further research avenues, including longitudinal studies to empirically derive learning progressions related to space and place.

Care pathways of individuals with tuberculosis before and during the COVID-19 pandemic in Bandung, Indonesia.

The COVID-19 pandemic is thought to have undone years' worth of progress in the fight against tuberculosis (TB). For instance, in Indonesia, a high TB burden country, TB case notifications decreased by 14% and treatment coverage decreased by 47% during COVID-19. We sought to better understand the impact of COVID-19 on TB case detection using two cross-sectional surveys conducted before (2018) and after the onset of the pandemic (2021). These surveys allowed us to quantify the delays that individuals with TB who eventually received treatment at private providers faced while trying to access care for their illness, their journey to obtain a diagnosis, the encounters individuals had with healthcare providers before a TB diagnosis, and the factors associated with patient delay and the total number of provider encounters. We found some worsening of care seeking pathways on multiple dimensions. Median patient delay increased from 28 days (IQR: 10, 31) to 32 days (IQR: 14, 90) and the median number of encounters increased from 5 (IQR: 4, 8) to 7 (IQR: 5, 10), but doctor and treatment delays remained relatively unchanged. Employed individuals experienced shorter delays compared to unemployed individuals (adjusted medians: -20.13, CI -39.14, -1.12) while individuals whose initial consult was in the private hospitals experienced less encounters compared to those visiting public providers, private primary care providers, and informal providers (-4.29 encounters, CI -6.76, -1.81). Patients who visited the healthcare providers >6 times experienced longer total delay compared to those with less than 6 visits (adjusted medians: 59.40, 95% CI: 35.04, 83.77). Our findings suggest the need to ramp up awareness programs to reduce patient delay and strengthen private provide engagement in the country, particularly in the primary care sector.