Search

Abstract Background Type 1 diabetes (T1D) management exerts a considerable financial burden on patients, caregivers, and developing nations at large. In Ghana, a key governments effort to attenuate the financial burden of T1D on patients was to fashion safety-net mechanisms through financial risk pooling/sharing known as the National Health Insurance Scheme (NHIS). However, there is limited research on patients and caregivers’ experiences with the cost of managing T1D within the NHIS in Ghana. Objective This study explored the cost of T1D management, and the impact of the NHIS policy on mitigating costs of care. Methods A semi-structured interview guide was developed to collect qualitative data from 28 young people living with T1D (PLWD), 12 caregivers, 6 healthcare providers, and other stakeholders in Western, Central and the Greater Accra regions. Multiple data collection techniques including mystery client and in-depth interviews were used to collect data. Thematic content analysis was performed with QSR NVivo 14. Results Five key domains/themes which are: cost of T1D management supplies; cost of clinical care; cost of transportation; cost of diet; and NHIS were identified. The daily cost of blood glucose testing and insulin injection per day was between GHC 5–7 (US$ 0.6 to 1.0). The NHIS did not cover supplies such as strips, glucometers, HbA1c tests, and periodic medical tests. Even for those cost which were covered by the NHIS (mainly pre-mixed insulin), marked government delays in funds reimbursement to accredited NHIS facilities compelled providers to push the financial obligation onto patients and caregivers. Such cost obligations were fulfilled through out-of-pocket top-up or full payment of insulin of about GHC 15–25 (US$ 2–4), and GHC 25–50 (US$4–8) depending on the region and place of residence. Conclusion The cost of managing T1D was a burden for patients and their caregivers. There was a commodification of life-saving insulin on the Ghanaian market, and the NHIS did not function well to ease the cost-burden of T1D management on patients and caregivers. The findings call for the need to scale up NHIS services to include simple supplies, particularly test strips, and always ensure the availability of life-saving insulin in healthcare facilities.

Abstract Background The International Federation for Emergency Medicine (IFEM) published its model curriculum for medical student education in emergency medicine in 2009. Because of the evolving principles of emergency medicine and medical education, driven by societal, professional, and educational developments, there was a need for an update on IFEM recommendations. The main objective of the update process was creating Intended Learning Outcomes (ILOs) and providing tier-based recommendations. Method A consensus methodology combining nominal group and modified Delphi methods was used. The nominal group had 15 members representing eight countries in six regions. The process began with a review of the 2009 curriculum by IFEM Core Curriculum and Education Committee (CCEC) members, followed by a three-phase update process involving survey creation [The final survey document included 55 items in 4 sections, namely, participant & context information (16 items), intended learning outcomes (6 items), principles unique to emergency medicine (20 items), and content unique to emergency medicine (13 items)], participant selection from IFEM member countries and survey implementation, and data analysis to create the recommendations. Results Out of 112 invitees (CCEC members and IFEM member country nominees), 57 (50.9%) participants from 27 countries participated. Eighteen (31.6%) participants were from LMICs, while 39 (68.4%) were from HICs. Forty-four (77.2%) participants have been involved with medical students’ emergency medicine training for more than five years in their careers, and 56 (98.2%) have been involved with medical students’ training in the last five years. Thirty-five (61.4%) participants have completed a form of training in medical education. The exercise resulted in the formulation of tiered ILO recommendations. Tier 1 ILOs are recommended for all medical schools, Tier 2 ILOs are recommended for medical schools based on perceived local healthcare system needs and/or adequate resources, and Tier 3 ILOs should be considered for medical schools based on perceived local healthcare system needs and/or adequate resources. Conclusion The updated IFEM ILO recommendations are designed to be applicable across diverse educational and healthcare settings. These recommendations aim to provide a clear framework for medical schools to prepare graduates with essential emergency care capabilities immediately after completing medical school. The successful distribution and implementation of these recommendations hinge on support from faculty and administrators, ensuring that future healthcare professionals are well-prepared for emergency medical care.

Melodies are full of repeated patterns of pitch, interval, and rhythm. It has been suggested that these repeated patterns aid the listener in creating an efficient encoding; this raises the possibility that compositional practice might have evolved to facilitate this process. I propose three specific hypotheses about compositional practice: 1) Repeated intervallic patterns tend to be metrically parallel, with each instance of the pattern falling at the same position in relation to the metrical structure; 2) Purely intervallic repetitions tend to be confined to short distances (longer-distance repetitions tend to involve repetition of scale-degrees as well); 3) Repeated intervallic patterns tend to involve multiple intervals rather than single ones. In each case, I explain how such a compositional strategy might facilitate efficient encoding. Corpus analyses of classical themes and European folk songs find support for all three hypotheses.

Patients with Borderline Personality Disorder (BPD), particularly with comorbid trauma-disorders, show an attentional bias towards angry facial expressions. This is often interpreted to reflect increased anxiety and sensitivity to social threats. Given BPDs severe problems in reacting to and interpreting social communication, we investigated whether this threat bias extends to social orienting. Using a gaze-cueing task, we assessed whether centrally presented dynamic fearful and happy gaze stimuli promote the detection of peripherally presented targets. Groups with BPD (N = 50) and other personality disorders (OPD, N = 51) were compared to healthy controls (HC, N = 46), and evaluated on the independent influence of traumatic experience, trait anxiety and trait anger. Across groups we find reliable gaze-cueing. In line with earlier evidence, trait anxiety predicts faster detection of targets signaled by a fearful gaze in HCs. This threat bias is however not present in BPDs and OPDs, thus the threat bias in BPD does not extend to social orienting. Instead, self-experienced trauma predicts amplified gaze-cueing in BPDs, but reduced gaze-cueing in OPDs. This not only emphasizes the importance of evaluating trauma exposure in personality disorders, but also suggests that the childhood adversity typically associated with the development of BPD promotes increased social orienting.

Summary: Sphingolipid levels are crucial determinants of neurodegenerative disorders and therefore require tight regulation. The Orm protein family and ceramides inhibit the rate-limiting step of sphingolipid biosynthesis—the condensation of L-serine and palmitoyl-coenzyme A (CoA). The yeast isoforms Orm1 and Orm2 form a complex with the serine palmitoyltransferase (SPT). While Orm1 and Orm2 have highly similar sequences, they are differentially regulated, though the mechanistic details remain elusive. Here, we determine the cryoelectron microscopy structure of the SPT complex containing Orm2. Complementary in vitro activity assays and genetic experiments with targeted lipidomics demonstrate a lower activity of the SPT-Orm2 complex than the SPT-Orm1 complex. Our results suggest a higher inhibitory potential of Orm2, despite the similar structures of the Orm1- and Orm2-containing complexes. The high conservation of SPT from yeast to man implies different regulatory capacities for the three human ORMDL isoforms, which might be key for understanding their role in sphingolipid-mediated neurodegenerative disorders.

Psychopaths are suggested to be more likely to favor utilitarian outcomes over non-utilitarian (i.e., deontological) choices. Here we re-test this hypothesis and investigate whether oxytocin, a hormone associated with empathy, can counter this utilitarian effect. Forensic psychopathic patients and non-psychopathic controls participated in a sacrificial moral decision-making paradigm. Psychopathic patients performed the task in a double-blind cross-over placebo-controlled oxytocin administration paradigm. We found no evidence for psychopathic patients to act more utilitarian (or sacrificial) or any effect of oxytocin administration. Psychopathic traits within the control group, particularly traits associated with lack of empathy and failure to consider consequences, were however associated with more utilitarian choices, but only when these actions were low in emotion. In contrast, psychopathy severity in psychopathic patients, particularly impulsivity-related traits, predicts deontological choices, but only in highly emotional actions. Thus, although psychopathic traits do predict utilitarianism when emotional investment is low, this is not the case in full-blown psychopathy. Instead, there is a link between impulsivity and deontological choices in psychopathic patients, but only when emotional investment is high, and self-interest is not at stake. These preliminary results are discussed to whether utilitarian outcomes align with the personal goals of psychopathic individuals.

Abstract Introduction Type 1 diabetes mellitus (T1DM) is mostly diagnosed among young people. Despite the evidence that T1DM is disruptive, and affects individuals’ health and cognitive ability, there is dearth of knowledge on the impact of T1DM on schooling in LMICs including Ghana. In this research, we explored the impact of T1DM on the schooling of young people living with the disease, and discussed the results within health selection, social support, and artefactual perspectives of inequality. Methods Data were extracted from a qualitative project on T1DM lived experiences in southern Ghana. The study participants were young persons living with T1DM (n = 28) and their caregivers (n = 12). They were purposively recruited to participate in the study using maximum variation and snowball sampling techniques and interviewed in their support group centres, homes, or healthcare facilities using semi-structured interview guides. A computer-assisted qualitative data analysis was performed using QSR NVivo 14 software, and the results were categorised into themes. Results Three themes were identified from the transcripts. These themes were school and classroom attendance, choice of school, and school/academic performance. T1DM was a major reason for patients’ limited contact hours with teachers, school drop-out, preference for day schools rather than boarding, opting for vocational training instead of continuation of formal education, limited concentration at school, and delayed educational progression. Conclusion T1DM impacted the schooling of young people living with the disease. The mechanisms of these impacts, and young peoples lived experiences are not artefactual, but rather support discourses on health selection and inadequate social support for young people living with the disease. The results call for the need to develop educational and social interventions to address these barriers. The full implementation of the Inclusive Education Policy (IEP) may contribute to reducing educational and social inequalities caused by ill-health.

Purpose – This study aimed to evaluate the potential of artificial intelligence (AI) as a tool for knowledge synthesis, the production of written content and the delivery of coaching conversations. Design/methodology/approach – The research employed the use of experts to evaluate the outputs from ChatGPT's AI tool in blind tests to review the accuracy and value of outcomes for written content and for coaching conversations. Findings – The results from these tasks indicate that there is a significant gap between comparative search tools such as Google Scholar, specialist online discovery tools (EBSCO and PsycNet) and GPT-4's performance. GPT-4 lacks the accuracy and detail which can be found through other tools, although the material produced has strong face validity. It argues organisations, academic institutions and training providers should put in place policies regarding the use of such tools, and professional bodies should amend ethical codes of practice to reduce the risks of false claims being used in published work. Originality/value – This is the first research paper to evaluate the current potential of generative AI tools for research, knowledge curation and coaching conversations.

Abstract Objective Studies are paying increasing attention to complex social determinants in explaining the variation in the rates COVID-19 vaccine uptake. This study examines the influence of various individual, contextual, and vaccine-related factors on COVID-19 vaccine uptake behaviour in a resource-scarce and vulnerable setting using a quantitative research approach. Using a multi-staged cluster sampling approach, 408 individuals from 204 households in Cape Coast, Ghana’s tourism hub, were surveyed. Probit and logistic regression models were estimated to test the vaccine-related factors. Results A significant difference is observed between wait time and vaccination status (χ2 = 21.17; p = 0.000). Moreover, age and religion, as controlled variables, equally played significant roles in influencing the adoption of the vaccine. Other factors encompass the perceived risk of contracting COVID-19, the perceived benefits of the vaccine in relation to its side effects, and the level of trust individuals have in the concern of vaccine producers for their health. These findings call for targeted campaigns by the Ministry of Health, health facilities and other institutions promoting the COVID-19 vaccine. These actors should emphasize the benefits of vaccination, prioritize trust-building initiatives, and provide clear guidance on vaccination schedules, and manage waiting time.

Abstract Blue denim, a billion-dollar industry, is currently dyed with indigo in an unsustainable process requiring harsh reducing and alkaline chemicals. Forming indigo directly in the yarn through indican (indoxyl-β-glucoside) is a promising alternative route with mild conditions. Indican eliminates the requirement for reducing agent while still ending as indigo, the only known molecule yielding the unique hue of blue denim. However, a bulk source of indican is missing. Here, we employ enzyme and process engineering guided by techno-economic analyses to develop an economically viable drop-in indican synthesis technology. Rational engineering of PtUGT1, a glycosyltransferase from the indigo plant, alleviated the severe substrate inactivation observed with the wildtype enzyme at the titers needed for bulk production. We further describe a mild, light-driven dyeing process. Finally, we conduct techno-economic, social sustainability, and comparative life-cycle assessments. These indicate that the presented technologies have the potential to significantly reduce environmental impacts from blue denim dyeing with only a modest cost increase.

The banana fruit fly (Bactrocera musae Tryon), belonging to the family Tephritidae and subfamily Dacinae, is the main pest of bananas responsible for significant crop losses. In order to monitor the B. musae infestation, we collected banana fruit samples from four locations on the Gazelle Peninsula: Burit, Kereba, Vudal, and Vunapalading. On each field collection date, twelve banana bunches were chosen at random from the corresponding study sites. Following the removal of 100 individual fruits (fingers) from each fresh bunch at each study site, the fruits were weighed, thoroughly cleaned with rainwater three times, and then incubated in containers until the larval developmental stages were finished. When compared to the other three sites, the number of adults in the Kalapua bananas sampled from Burit was the highest. The banana fruits were divided into three main groups: “mature green”, “mature ripe”, and “immature green”. Mature green fruits produced a higher adult abundance than mature ripe fruits. Compared to the other two stages, immature green had the fewest adults. By fruit weight, Burit had the highest infestation (20.9%), while Vunapalading had the lowest (11.9%). After Kereba (14.7%), Vudal had the second-highest infestation (16.8%). Mature ripe fruit had the highest infestation (37.1%) by fruit weight, while immature green fruits had the lowest infestation (2.04%). A moderate level of infestation was observed in mature green fruits (17.1%). Regarding fruit count, the least infected fruits were immature green fruits (1.8%), moderately infected mature green fruits (17.0%), and highly infected mature ripe fruits (26.9%). Geographically, the Gazelle Peninsula has a Kalapua infestation level ranging from 11.9 to 20.9%, and a different maturity stage infestation level ranging from 2.04 to 26.9%. In general, the degree of infestation has escalated, and B. musae has established itself in the Gazelle Peninsula.

Culture of Pacific white shrimp (Litopenaeus vannamei) and red swamp crayfish (Procambarus clarkii), using an intercropping production strategy, is being used by one shrimp farmer in Alabama. A concern is that crayfish feed on invertebrates. This raises the question of whether crayfish would feed on shrimp, negatively impacting survival and production. Two trials were conducted using different systems to investigate the cohabitation of these species. Trial 1 consisted of a 24-tank clear water system. Treatment 1 served as an experimental control and consisted of 20 shrimp fed a daily ration of shrimp feed. Treatment 2 comprised of 20 shrimp and one adult crayfish per tank, each receiving a calculated daily ration of shrimp feed. Treatment 3 had the same number of shrimp and crayfish as above, but no additional shrimp feed was added to account for the crayfish in the tank. Trial 2 used a green water on-levee flow-through tank system, stocked at an initial mean shrimp stocking weight of 0.15 ± 0.01 g with four replicates and similar treatments as Trial 1. Shrimp survival was 91.9 % when they were reared in a clear water system without crayfish. Adding crayfish significantly decreased shrimp survival, with no difference in survival between crayfish treatments fed a daily crayfish ration (58.8 %) and those not receiving a daily crayfish ration (40.6 %). Shrimp weight gain did not differ between treatments. However, when shrimp were in the presence of crayfish not receiving a daily crayfish ration, tank-to-tank variability in weight gain by >50 % compared to other treatments increased. Shrimp survival was 92.0–97.3% across treatments when reared in a green water system (Trial 2) without crayfish. Results indicate that cohabitation of crayfish and shrimp is feasible.

Sub-Saharan African countries, including Ghana, are disproportionately affected by hepatitis B. In Ghana, the burden of hepatitis B is unevenly distributed, with the Brong Ahafo region having the highest prevalence (13.7%). Given that people with hepatitis B (PWHB) in Ghana have previously been found to have a lack of understanding of the impact of the infection, we sought to explore their health-seeking behaviour using the health belief model as an organising framework. A qualitative exploratory design was used. In total, 18 people were purposively selected for face-to-face interviews. The data was processed and analysed using QSR NVivo version 11.0 and the Braun and Clarke thematic analysis procedure. The belief that hepatitis B can cause liver cancer and death was the most important determinant of health seeking. Furthermore, access to accurate hepatitis B information, particularly information about availability of effective hepatitis B treatment, influenced a number of participants to seek formal care. However, the high cost of clinical monitoring and treatment to use herbal medicine, despite their concerns about the effectiveness of herbal medicines in managing hepatitis B. Given that hepatitis B information was a factor in health seeking, it is recommended that a hepatitis B awareness campaign focusing on the availability of hepatitis B treatment and where it can be obtained be carried out in the study area. Counselling PWHB at the point of diagnosis should highlight the relevance of life-long clinical monitoring. To remove financial barriers to hepatitis B care in Ghana, the government should include the cost of hepatitis B laboratory investigations and treatment in the health insurance scheme.

Abstract Background In pediatric rheumatic diseases (PRD), adalimumab is dosed using fixed weight-based bands irrespective of methotrexate co-treatment, disease activity (DA) or other factors that might influence adalimumab pharmacokinetics (PK). In rheumatoid arthritis (RA) adalimumab exposure between 2–8 mg/L is associated with clinical response. PRD data on adalimumab is scarce. Therefore, this study aimed to analyze adalimumab PK and its variability in PRD treated with/without methotrexate. Methods A two-center prospective study in PRD patients aged 2–18 years treated with adalimumab and methotrexate (GA-M) or adalimumab alone (GA) for ≥ 12 weeks was performed. Adalimumab concentrations were collected 1–9 (maximum concentration; Cmax), and 10–14 days (minimum concentration; Cmin) during ≥ 12 weeks following adalimumab start. Concentrations were analyzed with enzyme-linked immunosorbent assay (lower limit of quantification: 0.5 mg/L). Log-normalized Cmin were compared between GA-M and GA using a standard t-test. Results Twenty-eight patients (14 per group), diagnosed with juvenile idiopathic arthritis (71.4%), non-infectious uveitis (25%) or chronic recurrent multifocal osteomyelitis (3.6%) completed the study. GA-M included more females (71.4%; GA 35.7%, p = 0.13). At first study visit, children in GA-M had a slightly longer exposure to adalimumab (17.8 months [IQR 9.6, 21.6]) compared to GA (15.8 months [IQR 8.5, 30.8], p = 0.8). Adalimumab dosing was similar between both groups (median dose 40 mg every 14 days) and observed DA was low. Children in GA-M had a 27% higher median overall exposure compared to GA, although median Cmin adalimumab values were statistically not different (p = 0.3). Cmin values ≥ 8 mg/L (upper limit RA) were more frequently observed in GA-M versus GA (79% versus 64%). Overall, a wide range of Cmin values was observed in PRD (0.5 to 26 mg/L). Conclusion This study revealed a high heterogeneity in adalimumab exposure in PRD. Adalimumab exposure tended to be higher with methotrexate co-treatment compared to adalimumab monotherapy although differences were not statistically significant. Most children showed adalimumab exposure exceeding those reported for RA with clinical response, particularly with methotrexate co-treatment. This highlights the need of further investigations to establish model-based personalized treatment strategies in PRD to avoid under- and overexposure. Trial registration NCT04042792 , registered 02.08.2019.

Abstract Background In Low-Middle-Income Countries (LMICs), young people living with Type 1 Diabetes Mellitus (T1DM) face structural barriers which undermine adequate T1DM management and lead to poor health outcomes. However, research on the barriers faced by young people living with T1DM have mostly focused on patient factors, neglecting concerns regarding plausible barriers that may exist at the point of healthcare service delivery. Objective This study sought to explore barriers faced by young people living with T1DM and their caregivers at the point of healthcare service delivery. Methods Data were drawn from a qualitative research in southern Ghana. The research was underpinned by a phenomenological study design. Data were collected from 28 young people living with T1DM, 12 caregivers, and six healthcare providers using semi-structured interview guides. The data were collected at home, hospital, and support group centres via face-to-face interviews, telephone interviews, and videoconferencing. Thematic and framework analyses were done using CAQDAS (QSR NVivo 14). Results Eight key barriers were identified. These were: shortage of insulin and management logistics; healthcare provider knowledge gaps; lack of T1DM care continuity; poor healthcare provider-caregiver interactions; lack of specialists’ care; sharing of physical space with adult patients; long waiting time; and outdated treatment plans. The multiple barriers identified suggest the need for an integrated model of T1DM to improve its care delivery in low-resource settings. We adapted the Chronic Care Model (CCM) to develop an Integrated Healthcare for T1DM management in low-resource settings. Conclusion Young people living with T1DM, and their caregivers encountered multiple healthcare barriers in both in-patient and outpatient healthcare facilities. The results highlight important intervention areas which must be addressed/improved to optimise T1DM care, as well as call for the implementation of a proposed integrated approach to T1DM care in low-resource settings.

This study evaluated the phytochemical composition and antioxidant activity of Piliostigma thonningii (Schumach.) Milne-Redh, Psorospermum febrifugum Spach, Inula glomerata Oliv. and Hiern, Zanthoxylum chalybeum Engl. and Monotes africanus A.DC., claimed to treat cancer by Malawian traditional herbal practitioners. Ground and dried plant extracts were analyzed for total phenolic content (TPC), total flavonoid content (TFC), total alkaloid content (TAC), ferric reducing antioxidant power (FRAP) and 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) using standard assays. The TPC, TFC, and TAC ranged from 539 ± 2.70 to 4602 ± 32 mg GAE/g DW, 6.18 ± 0.03 to 64.04 ± 0.16 mg QE/g DW and 19.25 ± 0.07 to 76.05 ± 0.36 mg CE/g DW, respectively, and the variations were significant, p < 0.05. FRAP values ranged from 82.15 ± 0.7 to 687.28 ± 0.71 mg TEAC/g DW and decreased in the following order: P. thoningii (Schumach.) Milne-Redh > P. febrifugum Spach > M. africanus A.DC > Z. chalybeum Engl > I. glomerata Oliv. and Hiern. The scavenging activity (SA50) of the extracts ranged from 0.09 ± 0.01 to 1.57 ± 0.01 μg/mL of extract with P. thonningii (Schumach.) Milne-Redh showing the lowest value. Based on the levels of phenolic compounds and their antioxidant activity, the plants in this study could be considered for use as medicinal agents and sources of natural bioactive compounds and antioxidants.

Abstract To curb HIV infection rate in Tanzania, antiretroviral therapy (ART) has been scaled up since 2006, and in 2019, the country shifted to regimen including dolutegravir as a default first line. We assessed the success of ART and the contribution of HIV drug resistance (HIVDR) to unsuppressed viral loads. Between February and May 2023 a cross-sectional survey with random sampling was conducted in the six clinics in an urban cohort in Dar es Salaam. Patients with unsuppresed viral loads (local criteria viral load (VL) ≥ 1000 copies/mL) were tested for HIVDR mutations using the WHO adapted protocol for plasma samples. Mutations were interpreted using the Stanford HIVDR database. In total 600 individuals participated in this survey, the majority were female (76.83%), mean age ( $$\pm$$ ± standard deviation) was 44.0 ( $$\pm$$ ± 11.6) years. The median duration on ART (interquartile range) was 6.5 (3.9–10.2) years. Approximately 99% were receiving tenofovir + lamivudine + dolutegravir as a fixed dose combination. VL testing was successful in 99.67% (598/600) of survey patients and only 33 had VL ≥ 1000 copies/mL, resulting in a viral suppression level of 94.48% (565/598, 95% CI 92.34–96.17%). For 23 samples, protease and reverse transcriptase (RT) genotyping were successful, with 13 sequences containing RT inhibitor surveillance drug resistance mutations (SDRMs) (56.5%). No SDRM against protease inhibitors were detected. Thirty samples were successfully genotyped for integrase with 3 sequences (10.08%) containing integrase strand transfer inhibitor (INSTI) SDRMs. In samples successfully genotyped in the three genetic regions, 68.18% (16/22) had a genotypic susceptibility score (GSS) ≥ 2.5 for the concurrent regimen, implying factors beyond drug resistance caused the unsuppressed viral load. For five patients, GSS indicated that HIVDR may have caused the unsuppressed viral load. All three patients with INSTI resistance mutations were highly resistant to dolutegravir and accumulated nucleoside and non-nucleoside RT inhibitor HIVDR mutations. Although in this cohort the last 95 UNAIDS target was almost achieved, HIVDR mutations, including INSTIs resistance mutations were detected in HIV-positive individuals taking ART for at least one year. We recommend the design and implementation of high-impact interventions to prevent the increase of HIVDR, failure of dolutegravir and address the non-resistance factors in the study area.

Chagas disease is caused by a protozoan parasite called Trypanosoma cruzi. The infection produces a first clinical phase, commonly asymptomatic or showing non-specific symptoms, and a second chronic phase characterized by cardiac and digestive dysfunctions in some individuals with the disease. This disease affects 7 million people and has been categorized by the World Health Organisation as a neglected tropical disease. In addition, the drugs used to combat it were developed in the 1970s and present major toxicity problems and limited efficacy in the chronicity of the disease. This has led to research into new active compounds that are effective against the disease, with studies on cyanoderivatives showing promising activity. In this work, eight active E-cyanoacrylamides/5-imino pyrrolones were studied. Compounds B and F showed excellent activity, while compounds C and G stood out for their lower cytotoxicity. After correlating the activity and cytotoxicity of the compounds, it was observed that compounds B, C, and G obtained the most favourable results. Various cell death studies were carried out with these compounds, and it was determined that all of them produced programmed cell death, with compound B standing out as being at a late stage in the process.

Abstract Cardiac catheterization remains the gold standard for the diagnosis and management of pediatric pulmonary hypertension (PH). There is lack of consensus regarding optimal anesthetic and airway regimen. This retrospective study describes the anesthetic/airway experience of our single center cohort of pediatric PH patients undergoing catheterization, in which obtaining hemodynamic data during spontaneous breathing is preferential. A total of 448 catheterizations were performed in 232 patients. Of the 379 cases that began with a natural airway, 274 (72%) completed the procedure without an invasive airway, 90 (24%) received a planned invasive airway, and 15 (4%) required an unplanned invasive airway. Median age was 3.4 years (interquartile range [IQR] 0.7–9.7); the majority were either Nice Classification Group 1 (48%) or Group 3 (42%). Vasoactive medications and cardiopulmonary resuscitation were required in 14 (3.7%) and eight (2.1%) cases, respectively; there was one death. Characteristics associated with use of an invasive airway included age

Annona squamosa Linn. (Annonaceae) is a rich source of bioactive compounds, such as alkaloids, tannin, phenolic compounds, aromatic plyketides, steroids, diterpenes and mineral components. Several parts of this plant are traditionally used in the treatment of diabetes and cancer. The current assay evaluates antiproliferative activity of fractions of sugar-apple (A. squamosa) peel and seeds in eight human tumor cell lines (K-562, HT-29, PC-3, NCI-H460, MCF-7, NCI-ADR/RES, UACC-62, U251 e 786-0) and in a non-tumor cell line (HaCat), with doxorubicin as positive control. Cell differentiation was determined by spectrophometric quantification. Seed and peel fractions showed cytostatic and cytocidal effects on cell lines at different concentrations, except for K562. All fractions were selective for the NCI-H460 strain. However, other fractions had an antiproliferative effect on the other strains, especially on the methanol fraction of seeds, which showed the highest cytocidal percentage (up to 100%). Results indicate the potential of these fractions as sources of new chemotherapeutic and/or chemo-preventive agents to be isolated and identified.

Leishmaniasis and Chagas disease are parasitic infections that affect millions of people worldwide, producing thousands of deaths per year. The current treatments against these pathologies are not totally effective and produce some side effects in the patients. Acrylonitrile derivatives are a group of compounds that have shown activity against these two diseases. In this work, four novels synthetic acrylonitriles were evaluated against the intracellular form and extracellular forms of L. amazonensis and T. cruzi. The compounds 2 and 3 demonstrate to have good selectivity indexes against both parasites, specifically the compound 3 against the amastigote form (SI = 6 against L. amazonensis and SI = 7.4 against T. cruzi). In addition, the parasites treated with these two compounds demonstrate to produce a programmed cell death, since they were positive for the events studied related to this type of death, including chromatin condensation, accumulation of reactive oxygen species and alteration of the mitochondrial membrane potential. In conclusion, this work confirms that acrylonitriles is a source of possible new compounds against kinetoplastids, however, more studies are needed to corroborate this activity.

Purpose: To determine the prevalence of sleep disturbances in patients before and after arthroscopic surgery of the shoulder and to evaluate the association between patient-reported outcomes and standardized sleep disturbance tools after shoulder arthroscopy. Methods: A systematic review, following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, was conducted by searching the PubMed, Embase, and Scopus databases using the terms “arthroscopic surgery” and “sleep.” Two independent reviewers evaluated the studies based on the inclusion criteria focused on the effects of shoulder arthroscopy on sleep disturbance and the use of outcome measures related to sleep. Data on sleep quality and functional outcomes were collected and analyzed using various assessment tools, including the Pittsburgh Sleep Quality Index and American Shoulder and Elbow Surgeons score. The methodologic quality of included studies was assessed using the Methodological Index for Non-randomized Studies (MINORS) criteria. Results: The review included 15 studies (9 Level IV, 5 Level III, and 1 Level II) comprising 1,818 arthroscopic patients (average age, 57.4 ± 8.86 years; follow-up range, 6 months to 75.7 months). The prevalence rates of sleep disturbances before and after shoulder arthroscopy ranged from 75.8% to 100% and from 19% to 62%, respectively. Every study included in this analysis reported an improvement in rates of sleep disturbances postoperatively compared with preoperatively. Improvements in standardized sleep disturbance scores were associated with functional outcomes. Conclusions: Sleep disturbances are commonly observed before and after arthroscopic surgery of the shoulder. Arthroscopic surgery of the shoulder appears to improve sleep quality, and surgeons can expect functional outcomes, specifically the American Shoulder and Elbow Surgeons score, Simple Shoulder Test score, numeric rating scale or visual analog scale score, and Constant-Murley score, to improve in line with sleep quality. Level of Evidence: Level IV, systematic review of Level II to IV studies.

This work explores the biological evaluation of novel cyanomethyl vinyl ether derivatives as antiproliferative agents. Tubulin, crucial to microtubule structure and function, is a target for cancer therapies. In vitro cytotoxicity assessments revealed significant activity in SKOV3 ovarian carcinoma cells and A549 lung carcinoma cells. Structure-Activity Relationship (SAR) analysis indicated that the E isomer and specific substitutions influenced the biological activity. Computational assays predicted favorable ADME properties, highlighting potential as anticancerous agents. Molecular docking studies demonstrated that compound 12E, with the E geometry of the double bond and fused polyaromatic rings such as phenanthrene, has robust interaction with tubulin, suggesting enhanced stability due to diverse amino acid interactions. Comparative spatial distributions with colchicine further indicated potential mechanistic similarities.

Ribosomes stall on truncated or otherwise damaged mRNAs. Bacteria rely on ribosome rescue mechanisms to replenish the pool of ribosomes available for translation. Trans-translation, the main ribosome-rescue pathway, uses a circular hybrid transfer-messenger RNA (tmRNA) to restart translation and label the resulting peptide for degradation. Previous studies have visualized how tmRNA and its helper protein SmpB interact with the stalled ribosome to establish a new open reading frame. As tmRNA presents the first alanine codon via a non-canonical mRNA path in the ribosome, the incoming alanyl-tRNA must rearrange the tmRNA molecule to read the codon. Here, we describe cryo-EM analyses of an endogenous Escherichia coli ribosome-tmRNA complex with tRNAAla accommodated in the A site. The flexible adenosine-rich tmRNA linker, which connects the mRNA-like domain with the codon, is stabilized by the minor groove of the canonically positioned anticodon stem of tRNAAla. This ribosome complex can also accommodate a tRNA near the E (exit) site, bringing insights into the translocation and dissociation of the tRNA that decoded the defective mRNA prior to tmRNA binding. Together, these structures uncover a key step of ribosome rescue, in which the ribosome starts translating the tmRNA reading frame.

Background:. Fracture-related infection is one of the most challenging complications in orthopaedic trauma surgery. However, the effect of infection on functional and pain-related outcomes has not been well established. The aims of this study were to evaluate functional recovery for patients with fracture and a deep surgical site infection compared with patients with fracture without infection and to evaluate whether pain severity, social support, and preinjury mental health have a moderating effect on the magnitude and direction of the relationship between deep surgical site infection and functional recovery. Methods:. This is a secondary retrospective cohort study using prospectively collected data from the VANCO trial (Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection) and the OXYGEN (Supplemental Perioperative Oxygen to Reduce Surgical Site Infection After High Energy Fracture Surgery) trial. In this study, 2,116 patients with tibial plateau, pilon, or calcaneal fractures at high risk for infection were included. Patients were divided into cohorts of patients who experienced a deep surgical site infection and those who did not. The primary outcome measure was the functional outcome using the Veterans RAND 12-Item Health Survey (VR-12). Results:. After controlling for covariates, deep surgical site infection was independently associated with functional outcome, with a 3.3-point reduction in the VR-12 Physical Component Score, and pain severity was independently associated with functional outcome, with a 2.5-point reduction in the VR-12 Physical Component Score. Furthermore, the Brief Pain Inventory pain severity demonstrated an important moderating effect on the relationship between infection and functional outcome. In patients with lower pain scores, infection had a large negative impact on functional outcome, whereas, in patients with higher pain scores, infection had no significant impact on functional outcome. Furthermore, the functional outcome in the entire cohort remains at only 61% of baseline. Conclusions:. This study documents the negative impact of postoperative infection on functional recovery after injury, as well as the novel finding of pain severity as an important moderating factor. This study emphasizes not only the importance of developing effective interventions designed to reduce postoperative infection, but also the role that factors that moderate pain severity plays in limiting recovery of physical function. Level of evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Abstract We consider a heterotic version of six-dimensional Kodaira-Spencer gravity derived from the heterotic superpotential. We compute the one-loop partition function and find it can be expressed as a product of holomorphic Ray-Singer torsions. We discuss its topological properties and potential gauge and gravitational anomalies. We show these anomalies can be cancelled using Green-Schwarz-like counter-terms. We also discuss the dependence on the background geometry, and in particular the choice of hermitian metric needed for quantisation. Given suitable topological constraints, this dependence may again be cancelled by the addition of purely background-dependent counter-terms. We also explain how our methods provide the one-loop partition functions of a large class of more general holomorphic field theories in terms of holomorphic Ray-Singer torsions.

Abstract During the COVID-19 pandemic, the use of face masks has become a daily routine. Studies have shown that face masks increase the ambiguity of facial expressions which not only affects (the development of) emotion recognition, but also interferes with social interaction and judgement. To disambiguate facial expressions, we rely on perceptual (stimulus-driven) as well as preconceptual (top-down) processes. However, it is unknown which of these two mechanisms accounts for the misinterpretation of masked expressions. To investigate this, we asked participants (N = 136) to decide whether ambiguous (morphed) facial expressions, with or without a mask, were perceived as friendly or unfriendly. To test for the independent effects of perceptual and preconceptual biases we fitted a drift–diffusion model (DDM) to the behavioral data of each participant. Results show that face masks induce a clear loss of information leading to a slight perceptual bias towards friendly choices, but also a clear preconceptual bias towards unfriendly choices for masked faces. These results suggest that, although face masks can increase the perceptual friendliness of faces, people have the prior preconception to interpret masked faces as unfriendly.

Abstract Two types of Carrollian field theories are shown to emerge from finite current-current deformations of toroidal CFT2’s when the deformation coupling is precisely fixed, up to a sign. In both cases the energy and momentum densities fulfill the BMS3 algebra. Applying these results to the bosonic string, one finds that the electric-like deformation (positive coupling) reduces to the standard tensionless string. The magnetic-like deformation (negative coupling) yields to a new theory, still being relativistic, devoid of tension and endowed with an “inner Carrollian structure”. Classical solutions describe a sort of “self-interacting null particle” moving along generic null curves of the original background metric, not necessarily geodesics. This magnetic-like theory is also shown to be recovered from inequivalent limits in the tension of the bosonic string. Electric- and magnetic-like deformations of toroidal CFT2’s can be seen to correspond to limiting cases of continuous exactly marginal (trivial) deformations spanned by an SO(1,1) automorphism of the current algebra. Thus, the absolute value of the current-current deformation coupling is shown to be bounded. When the bound saturates, the deformation ceases to be exactly marginal, but still retains the full conformal symmetry in two alternative ultrarelativistic regimes.

Abstract Breast cancer screening has substantially reduced mortality across screening populations. However, a clinical need persists for more accessible, cost-effective, and robust approaches for increased-risk and diverse patient populations, especially those with dense breasts where screening mammography is suboptimal. We developed and validated a cost-effective, portable, patient-dedicated three-dimensional (3D) automated breast ultrasound (ABUS) system for point-of-care breast cancer screening. The 3D ABUS system contains a wearable, rapid-prototype 3D-printed dam assembly, a compression assembly, and a computer-driven 3DUS scanner, adaptable to any commercially available US machine and transducer. Acquisition is operator-agnostic, involves a 40-second scan time, and provides multiplanar 3D visualization for whole-breast assessment. Geometric reconstruction accuracy was evaluated with a 3D grid phantom and tissue-mimicking breast phantoms, demonstrating linear measurement and volumetric reconstruction errors

Abstract Background Management of type 1 diabetes (T1D) is complex and demanding. It requires patients and their caregivers, particularly those in low-resource settings to adopt productive coping strategies to achieve ideal glycaemic control. Coping and adaptation strategies have far-reaching implications on their behavioural and health outcomes. Yet, it is uncertain how young people living with T1D and their caregivers in low-resource settings cope and adapt to the challenges of T1D management. This study analysed textual and photo evidence on the coping and adaptation strategies employed by young persons living with T1D (warriors) and their caregivers in Ghana. Methods Qualitative data were collected from 28 warriors, 12 caregivers, 6 healthcare providers and other stakeholders in southern Ghana using semi-structured interview guides. Participants were identified at T1D support group centres, hospitals, and their places of residence, and recruited into the study using maximum variation and snowball sampling approaches. Data were collected via face-to-face interviews, photovoice, telephone interviews and videoconferencing and were thematically analysed using QSR NVivo 11. Results Four superordinate themes which are productive coping, non-productive coping, keeping T1D a secret, and coping with costs of care were identified. Productive coping entailed condition acceptance, planning ahead, seeking social support, borrowing insulin, and overcoming the barriers of insulin storage. On the other hand, avoidance, disengagement, and re-use of syringes were the common non-productive coping approaches. Due to stigma and discrimination, the warriors shrouded their condition in secrecy. As a response to the financial burden of T1D care, caregivers/patients borrowed money, took loans, and sold household items. Conclusion Young persons living with T1D and their caregivers adopted coping strategies which both promoted and compromised their T1D management. There was an occasional co-existence of diverse coping strategies (productive and non-productive), and these reflects the personal and contextual stressors they faced. The results call for the need to eliminate barriers of T1D management and equip patients and their caregivers with ongoing T1D coping competencies.

Abstract In this work, we apply the semigroup expansion method of Lie algebras to construct novel and known three-dimensional hypergravity theories. We show that the expansion procedure considered here yields a consistent way of coupling different three-dimensional Chern-Simons gravity theories with massless spin- 5 2 $$ \frac{5}{2} $$ gauge fields. First, by expanding the osp $$ \mathfrak{osp} $$ (1|4) superalgebra with a particular semigroup a generalized hyper-Poincaré algebra is found. Interestingly, the hyper-Poincaré and hyper-Maxwell algebras appear as subalgebras of this generalized hypersymmetry algebra. Then, we show that the generalized hyper-Poincaré CS gravity action can be written as a sum of diverse hypergravity CS Lagrangians. We extend our study to a generalized hyper-AdS gravity theory by considering a different semigroup. Both generalized hyperalgebras are then found to be related through an Inönü-Wigner contraction which can be seen as a generalization of the existing vanishing cosmological constant limit between the hyper-AdS and hyper-Poincaré gravity theories.

Chagas disease causes a problematic pathology that can lead to megacolon and heart disease, and can even cause the death of the patient. Current therapies for this disease are the same as they were 50 years ago, are not fully effective and have strong side effects. The lack of a safe and effective therapy makes it necessary to search for new, less toxic and totally effective compounds against this parasite. In this work, the antichagasic activity of 46 novel cyanomethyl vinyl ether derivatives was studied. In addition, to elucidate the type of cell death that these compounds produce in parasites, several events related to programmed cell death were studied. The results highlight four more selective compounds, E63, E64, E74 and E83, which also appear to trigger programmed cell death, and are therefore postulated as good candidates to use in future therapeutics for Chagas disease.

Background and Objectives: Despite numerous described techniques, laparoscopy has yet to replace open surgery as the gold standard for inguinal hernia (IH) repair in children. This may be due to many variables, including the lack of long-term follow-up and concern for increased recurrence. In this study, we present our long-term follow-up data on children undergoing percutaneous internal ring suturing (PIRS) for IH repair. Materials and Methods: This retrospective cohort study included children who underwent PIRS for IH between May 2013 and May 2021 at three tertiary care institutions, with at least three years of follow-up. Age at surgery, side of IH, presence of contralateral patent processus vaginalis, surgical and anesthesia time, and complications were noted. Parents were contacted to enquire about long-term complications, such as recurrence. Results: Long-term follow-up (average 6.9 ± 2.3 years) was available for 714 patients. For unilateral and bilateral procedures, the average surgical time was 13.6 ± 5.4 and 19.9 ± 3.0, and the average anesthesia time was 27.7 ± 12.9 and 33.9 ± 14.1 min, respectively. Complications were seen in 0.84% of patients and 1.2% of procedures, and recurrence was observed in 0.98% of patients and 0.78% of procedures. Conclusions: Our study, with a nearly 7-year follow-up, provides substantial evidence that PIRS is a safe and effective technique for IH repair in children, with low recurrence and complication rates. Despite the study’s retrospective nature and limited sample size, it contributes valuable data supporting the use of PIRS in pediatric IH repair.

There is a myriad of diseases that plague the world ranging from infectious, cancer and other chronic diseases with varying interventions. However, the dynamism of causative agents of infectious diseases and incessant mutations accompanying other forms of chronic diseases like cancer, have worsened the treatment outcomes. These factors often lead to treatment failure via different drug resistance mechanisms. More so, the cost of developing newer drugs is huge. This underscores the need for a paradigm shift in the drug delivery approach in order to achieve desired treatment outcomes. There is intensified research in nanomedicine, which has shown promises in improving the therapeutic outcome of drugs at preclinical stages with increased efficacy and reduced toxicity. Regardless of the huge benefits of nanotechnology in drug delivery, challenges such as regulatory approval, scalability, cost implication and potential toxicity must be addressed via streamlining of regulatory hurdles and increased research funding. In conclusion, the idea of nanotechnology in drug delivery holds immense promise for optimizing therapeutic outcomes. This work presents opportunities to revolutionize treatment strategies, providing expert opinions on translating the huge amount of research in nanomedicine into clinical benefits for patients with resistant infections and cancer.

(1) Background: Assessing phonatory disorders due to laryngeal biomechanical alterations requires aerodynamic analysis, assessing subglottic pressure, transglottic flow, and laryngeal resistance. This study explores whether the acoustic parameter, the relative fundamental frequency (RFF), can be studied using the current acoustic analysis protocol at the University of Navarra’s voice laboratory and its association with pathologies linked to laryngeal biomechanical alterations. (2) Methods: A retrospective cohort study included patients diagnosed with muscular tension dysphonia, organic lesions of the vocal fold, and vocal fold paralysis (VFP) at the Clínica Universidad de Navarra from 2019 to 2021. Each patient underwent endoscopic laryngeal exploration, followed by acoustic study, RFF calculation, and an aerodynamic study. Additionally, a control group was recruited. (3) Results: 79 patients and 22 controls were studied. Two-way ANOVA showed significant effects for groups and cycles in offset and onset cycles. Statistically significant differences were observed in cycle 1 onset among all groups and in cycles 1 and 2 between the control group and non-healthy groups. (4) Conclusions: RFF is a valuable indicator of phonatory biomechanics, distinguishing healthy and pathological voices and different disorders. RFF in onset cycles offers a cost-effective, accurate method for assessing biomechanical disorders without complex aerodynamic analyses. This study describes RFF values in VFP for the first time, revealing differences regardless of aerodynamic patterns.

Abstract People commonly reject unfair offers even if this leaves them worse off. Some explain this as a rational response based on social preferences. Others argue that emotions override self-interest in the determination of rejection behavior. We conducted an experiment in which we measured responders’ biophysical reactions (EEG and EMG) to fair and unfair offers. We measured biophysical trait anger using resting-state EEG (frontal alpha-asymmetry), state anger using facial expressions, offer expectancy processing using event-related EEG (medial-frontal negativity; MFN) and self-reported emotions. We systematically varied whether rejections led proposers to lose their share (Ultimatum Game; UG) or not (Impunity Game; IG). Results favor preference-based accounts: Impunity minimizes rejection despite increasing subjectively reported anger. Unfair offers evoke frowning responses, but frowning does not predict rejection. Prosocial responders reject unfair UG offers more often after unmet fairness expectations. These results suggest that responders do not reject unfairness out of anger. Rather, people seem motivated to reject unfair offers when they violate their behavioral code but only when rejection has payoff consequences for the proposer, allowing them to reciprocate and restore equity. Thus, social preferences trump emotions when responding to unfair offers.

Abstract Background Despite the large volume of scientific evidence on the rapid spread of the COVID-19 pandemic and associated high morbidity and mortality, little is known about the sociocultural disruptions which ensued. The current study explored the nuanced navigation of the COVID-19-related death and burial protocols and its impact on traditional burial and funeral rites in Ghana. Methods This qualitative study was based on the ‘focused’ ethnographic design. Data were collected using key informant interviews from nineteen COVID-19-related bereaved family members and public health officials involved in enforcing adherence to COVID-19-related death and burial protocols in the Cape Coast Metropolis of Central region of Ghana. Recursive analysis was conducted to generate the themes and sub-themes from the data. Results The overarching theme was “Uncultural” connotations ascribed to the COVID-19-related death and burial protocols. The COVID-19-related death and burial protocols were ubiquitously deemed by participants to be ‘uncultural’ as they inhibited deep-rooted indigenous and eschatological rites of separation between the living and the dead. This was fueled by limited awareness and knowledge about the COVID-19 burial protocols, resulting in fierce resistance by bereaved family members who demanded that public health officials release the bodies of their deceased relatives. Such resistance in the midst of resource limitation led to negotiated compromises of the COVID-19-related death and burial protocols between family members and public health officials. Conclusions Insensitivity to socio-cultural practices compromised the implementation of the COVID-19 pandemic control interventions, particularly, the COVID-19-related death and burial protocols. Some compromises that were not sanctioned by the protocols were reached to allow health officials and families respectfully bury their dead. These findings call for the need to prioritize the incorporation of sociocultural practices in future pandemic prevention and management strategies.

Abstract The fatty acids profile has been playing a decisive role in recent years, thanks to technological, sensory and health demands from producers and consumers. The application of NIRS technique on fat tissues, could lead to more efficient, practical, and economical in the quality control. The study aim was to assess the accuracy of Fourier Transformed Near Infrared Spectroscopy technique to determine fatty acids composition in fat of 12 European local pig breeds. A total of 439 spectra of backfat were collected both in intact and minced tissue and then were analyzed using gas chromatographic analysis. Predictive equations were developed using the 80% of samples for the calibration, followed by full cross validation, and the remaining 20% for the external validation test. NIRS analysis of minced samples allowed a better response for fatty acid families, n6 PUFA, it is promising both for n3 PUFA quantification and for the screening (high, low value) of the major fatty acids. Intact fat prediction, although with a lower predictive ability, seems suitable for PUFA and n6 PUFA while for other families allows only a discrimination between high and low values.

A well-known phenomenon in melodic structure is “step inertia”: the tendency for a step to be followed by another step in the same direction. There is strong evidence of step inertia in three corpora of Western common-practice melodies: European folk songs, classical instrumental themes, and English hymn tunes. Surprisingly, modern Western popular music does not reflect step inertia. In Billboard’s Hot 100, and Rolling Stone magazine's list of “greatest songs,” inertial (same-direction) steps are less likely than non-inertial ones. To further explore the role of step inertia in different corpora, we created a generative model that assigns probabilities to melodies, considering just four factors: range, pitch proximity, scale-degree frequency within a key, and step inertia. We optimized the weights of these factors for the Essen Folksong Collection and the Billboard corpus, and compared them with n -gram models. The optimal (normalized) weight of the inertia factor is large and positive for the Essen collection (.51) and small for the Billboard corpus (.02). This is further evidence that step inertia plays a much smaller role in popular melodies than common-practice ones, and that non-inertial steps are slightly favored.

Abstract PF‐06835919, a ketohexokinase inhibitor, presented as an inducer of cytochrome P450 3A4 (CYP3A4) in vitro (human primary hepatocytes), and static mechanistic modeling exercises predicted significant induction in vivo (oral midazolam area under the plasma concentration‐time curve [AUC] ratio [AUCR] = 0.23–0.79). Therefore, a drug–drug interaction study was conducted to evaluate the effect of multiple doses of PF‐06835919 (300 mg once daily × 10 days; N = 10 healthy participants) on the pharmacokinetics of a single oral midazolam 7.5 mg dose. The adjusted geometric means for midazolam AUC and its maximal plasma concentration were similar following co‐administration with PF‐06835919 (vs. midazolam administration alone), with ratios of the adjusted geometric means (90% confidence interval [CI]) of 97.6% (90% CI: 79.9%–119%) and 98.9% (90% CI: 76.4%–128%), respectively, suggesting there was minimal effect of PF‐06835919 on midazolam pharmacokinetics. Lack of CYP3A4 induction was confirmed after the preparation of subject plasma‐derived small extracellular vesicles (sEVs) and conducting proteomic and activity (midazolam 1′‐hydroxylase) analysis. Consistent with the midazolam AUCR observed, the CYP3A4 protein expression fold‐induction (geometric mean, 90% CI) was low in liver (0.9, 90% CI: 0.7–1.2) and non‐liver (0.9, 90% CI: 0.7‐1.2) sEVs (predicted AUCR = 1.0, 90% CI: 0.9–1.2). Likewise, minimal induction of CYP3A4 activity (geometric mean, 90% CI) in both liver (1.1, 90% CI: 0.9–1.3) and non‐liver (0.9, 90% CI: 0.5‐1.5) sEVs was evident (predicted AUCR = 0.9, 90% CI: 0.6‐1.4). The results showcase the integrated use of an oral CYP3A probe (midazolam) and plasma‐derived sEVs to assess a drug candidate as inducer.

BackgroundEmployment is a major contributor to quality of life. However, autistic people are often unemployed and underemployed. One potential barrier to employment is the job interview. However, the availability of psychometrically-evaluated assessments of job interviewing skills is limited for autism services providers and researchers.ObjectiveWe analyzed the psychometric properties of the Mock Interview Rating Scale that was adapted for research with autistic transition-age youth (A-MIRS; a comprehensive assessment of video-recorded job interview role-play scenarios using anchor-based ratings for 14 scripted job scenarios).MethodsEighty-five transition-age youth with autism completed one of two randomized controlled trials to test the effectiveness of two interventions focused on job interview skills. All participants completed a single job interview role-play at pre-test that was scored by raters using the A-MIRS. We analyzed the structure of the A-MIRS using classical test theory, which involved conducting both exploratory and confirmatory factor analyzes, Rasch model analysis and calibration techniques. We then assessed internal consistency, inter-rater reliability, and test–retest reliability. Pearson correlations were used to assess the A-MIRS’ construct, convergent, divergent, criterion, and predictive validities by comparing it to demographic, clinical, cognitive, work history measures, and employment outcomes.ResultsResults revealed an 11-item unidimensional construct with strong internal consistency, inter-rater reliability, and test–retest reliability. Construct [pragmatic social skills (r = 0.61, p

Childhood immune thrombocytopenia (ITP) is a rare autoimmune disorder characterized by isolated thrombocytopenia. Prolonged ITP (persistent and chronic) leads to a reduced quality of life for children in many domains. To provide optimal support for children, with ITP, it is important to be able to predict those who will develop prolonged ITP. This study aimed to develop a mathematical model based on platelet recovery that allows the early prediction of prolonged ITP. In this retrospective study, we used platelet counts from the 6 months following the diagnosis of ITP to model the kinetics of change in platelet count using a pharmacokinetic–pharmacodynamic model. In a learning set (n = 103), platelet counts were satisfactorily described by our kinetic model. The Kheal parameter, which describes spontaneous platelet recovery, allowed a distinction between acute and prolonged ITP with an area under the curve (AUC) of 0.74. In a validation set (n = 58), spontaneous platelet recovery was robustly predicted using platelet counts from 15 (AUC = 0.76) or 30 (AUC = 0.82) days after ITP diagnosis. In our model, platelet recovery quantified using the kheal parameter allowed prediction of the clinical course of ITP. Future prospective studies are needed to improve the predictivity of this model, in particular, by combining it with the predictive scores previously reported in the literature.

Abstract Aims and Objective We sought to investigate knowledge and skills of type 1 diabetes (T1D) management among young people living with the disease and their caregivers. Our aim is to provide baseline evidence to inform T1D self‐management education for young people living with the disease and their caregivers. Background Both local and international guidelines recommend ongoing T1D self‐management education for people living with the disease. This is because T1D often develops among young people who rarely have the competencies to adequately manage their condition. However, the extent to which young people living with T1D and their caregivers can self‐manage this chronic disease in a low‐resource country like Ghana is unknown. Methods Using a phenomenological study design, semi‐structured interviews were conducted with 28 young people living with type 1 diabetes, 12 caregivers and 6 healthcare providers in southern Ghana. Data were collected at homes, hospitals and support group centres of participants via face‐to‐face interviews, photovoice and video‐conferencing. The data were analysed thematically using QSR NVivo 11. Results The young people living with T1D and their caregivers demonstrated knowledge and skills in the self‐monitoring of blood glucose, and the treatment of hyperglycaemia. Areas of more marginal or lack of knowledge were concerning carbohydrate counting, severe hypoglycaemia and the management of intercurrent illnesses. Young persons living with T1D and their caregivers received their management information from healthcare and non‐healthcare providers. Access to diabetes self‐management education influenced T1D management knowledge and practices. Conclusion Young people living with type 1 diabetes and their caregivers possessed limited scope of knowledge on type 1 diabetes self‐management. Multiple sources of T1D knowledge were found, some of which may not be helpful to patients. The knowledge gaps identified compromises transitional independence and self‐management capacity. Relevance to Clinical Practice It is important for clinicians and organizations that provide T1D education to provide diabetes self‐management education also on managing hypoglycaemia, carbohydrate counting and managing T1D during intercurrent life events among young people living with T1D. No Patient or Public Contribution Patients and their caregivers were interviewed as research participants. They did not conceptualize, analyse, interpret or prepare the manuscript.

Abstract The environment contributes to the screening of Coulomb interactions in two-dimensional semiconductors. This can potentially be exploited to tailor material properties as well as for sensing applications. Here, we investigate the tuning of the band gap and the exciton binding energy in the two-dimensional semiconductor WS2 via the external dielectric screening. Embedding WS2 in van der Waals heterostructures with graphene and hBN spacers of thicknesses between one and 16 atomic layers, we experimentally determine both energies as a function of the WS2-to-graphene interlayer distance and the charge carrier density in graphene. We find that the modification to the band gap as well as the exciton binding energy are well described by a one-over-distance dependence, with a significant effect remaining at several nanometers distance, at which the two layers are electrically well isolated. This observation is explained by a screening arising from an image charge induced by the graphene layer. Furthermore, we find that the effectiveness of graphene in screening Coulomb interactions in nearby WS2 depends on its doping level and can therefore be controlled via the electric field effect. We determine that, at room temperature, it is modified by approximately 20% for charge carrier densities of 2 × 1012 cm−2.