Tunnelling measured in a very slow ion-molecule reaction.

Quantum tunnelling reactions play an important role in chemistry when classical pathways are energetically forbidden1, be it in gas-phase reactions, surface diffusion or liquid-phase chemistry. In general, such tunnelling reactions are challenging to calculate theoretically, given the high dimensionality of the quantum dynamics, and also very difficult to identify experimentally2-4. Hydrogenic systems, however, allow for accurate first-principles calculations. In this way the rate of the gas-phase proton-transfer tunnelling reaction of hydrogen molecules with deuterium anions, H2 + D- → H- + HD, has been calculated5, but has so far lacked experimental verification. Here we present high-sensitivity measurements of the reaction rate carried out in a cryogenic 22-pole ion trap. We observe an extremely low rate constant of (5.2 ± 1.6) × 10-20 cm3 s-1. This measured value agrees with quantum tunnelling calculations, serving as a benchmark for molecular theory and advancing the understanding of fundamental collision processes. A deviation of the reaction rate from linear scaling, which is observed at high H2 densities, can be traced back to previously unobserved heating dynamics in radiofrequency ion traps.

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.

BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Vascular mimicry as a facilitator of melanoma brain metastasis.

Melanoma has the highest propensity among solid tumors to metastasize to the brain. Melanoma brain metastases (MBM) are a leading cause of death in melanoma and affect 40-60% of patients with late-stage disease. Therefore, uncovering the molecular mechanisms behind MBM is necessary to enhance therapeutic interventions. Vascular mimicry (VM) is a form of neovascularization linked to invasion, increased risk of metastasis, and poor prognosis in many tumor types, but its significance in MBM remains poorly understood. We found that VM density is elevated in MBM compared to paired extracranial specimens and is associated with tumor volume and CNS edema. In addition, our studies indicate a relevant role of YAP and TAZ, two transcriptional co-factors scarcely studied in melanoma, in tumor cell-vasculogenesis and in brain metastasis. We recently demonstrated activation of the Hippo tumor suppressor pathway and increased degradation of its downstream targets YAP and TAZ in a metastasis impaired cell line model. In the current study we establish the utility of anti-YAP/TAZ therapy in mouse models of metastatic melanoma whereby treatment effectively inhibits VM and prolongs survival of mice with MBM. The data presented herein suggest that VM may be an important and targetable mechanism in melanoma and that VM inhibition might be useful for treating MBM, an area of high unmet clinical need, thus having important implications for future treatment regimens for these patients.

Caffeine-induced protein kinase A activation restores cognitive deficits induced by sleep deprivation by regulating O-GlcNAc cycling in adult zebrafish.

Sleep deprivation (SD) is widely acknowledged as a significant risk factor for cognitive impairment. In this study, intraperitoneal caffeine administration significantly ameliorated the learning and memory (L/M) deficits induced by SD and reduced aggressive behaviors in adult zebrafish. SD led to a reduction in protein kinase A (PKA) phosphorylation, phosphorylated-cAMP response element-binding protein (p-CREB), and c-Fos expression in zebrafish brain. Notably, these alterations were effectively reversed by caffeine. In addition, caffeine mitigated neuroinflammation induced by SD, as evident from suppression of the SD-mediated increase in glial fibrillary acidic protein (GFAP) and nuclear factor-κB (NF-κB) activation. Caffeine restored normal O-GlcNAcylation and O-GlcNAc transferase (OGT) levels while reversing the increased expression of O-GlcNAcase (OGA) in zebrafish brain after SD. Intriguingly, rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, effectively mitigated cognitive deficits, restored p-CREB and c-Fos levels, and attenuated the increase in GFAP in brain induced by SD. In addition, rolipram reversed the decrease in O-GlcNAcylation and OGT expression as well as elevation of OGA expression following SD. Treatment with H89, a PKA inhibitor, significantly impaired the L/M functions of zebrafish compared with the control group, inducing a decrease in O-GlcNAcylation and OGT expression and, conversely, an increase in OGA expression. The H89-induced changes in O-GlcNAc cycling and L/M dysfunction were effectively reversed by glucosamine treatment. H89 suppressed, whereas caffeine and rolipram promoted O-GlcNAc cycling in Neuro2a cells. Our collective findings underscore the interplay between PKA signaling and O-GlcNAc cycling in the regulation of cognitive function in the brain, offering potential therapeutic targets for cognitive deficits associated with SD.NEW & NOTEWORTHY Our observation highlights the intricate interplay between cAMP/PKA signaling and O-GlcNAc cycling, unveiling a novel mechanism that potentially governs the regulation of learning and memory functions. The dynamic interplay between these two pathways provides a novel and nuanced perspective on the molecular foundation of learning and memory regulation. These insights open avenues for the development of targeted interventions to treat conditions that impact cognitive function, including SD.

Correlation of In Vitro Kinetic Stability to Preclinical In Vivo Pharmacokinetics for a Panel of Anti-PD-1 Monoclonal Antibody Interleukin 21 Mutein Immunocytokines.

The development of therapeutic fusion protein drugs is often impeded by the unintended consequences that occur from fusing together domains from independent naturally occurring proteins, consequences such as altered biodistribution, tissue uptake, or rapid clearance and potential immunogenicity. For therapeutic fusion proteins containing globular domains, we hypothesized that aberrant in vivo behavior could be related to low kinetic stability of these domains leading to local unfolding and susceptibility to partial proteolysis and/or salvage and uptake. Herein we describe an assay to measure kinetic stability of therapeutic fusion proteins by way of their sensitivity to the protease thermolysin. The results indicate that in vivo pharmacokinetics of a panel of anti-programmed cell death protein 1 monocolonal antibody:interleukin 21 immunocytokines in both mice and nonhuman primates are highly correlated with their in vitro susceptibility to thermolysin-mediated proteolysis. This assay can be used as a tool to quickly identify in vivo liabilities of globular domains of therapeutic proteins, thus aiding in the optimization and development of new multispecific drug candidates. SIGNIFICANCE STATEMENT: This work describes a novel assay utilizing protein kinetic stability to identify preclinical in vivo pharmacokinetic liabilities of multispecific therapeutic fusion proteins. This provides an efficient, inexpensive method to ascertain inherent protein stability in vitro before conducting in vivo studies, which can rapidly increase the speed of preclinical drug development.

The impacts of telemedicine on assisted reproduction: a systematic review and meta-analysis.

Telemedicine is being applied in assisted reproduction technology (ART) to provide remote consultations, monitoring and support for patients. This study aimed to evaluate the potential advantages of telemedicine in ART treatment in the form of virtual consultations. Studies in which patients were using telemedicine during ART treatment were identified from four scientific databases (PudMed, EMBASE, Scopus, Web of Science). The success of fertility treatments was compared between telemedicine and in-office care, and patient satisfaction with ART through telemedicine was assessed. Eleven studies, comprising 4697 patients, were identified. Quality assessment (Joanna Briggs Institute Critical Appraisal and revised Cochrane risk-of-bias tools) revealed an acceptable risk of bias for both randomized controlled trials and observational studies. Using a fixed-effects model, telemedicine was comparable to in-person care regarding the pregnancy rate achieved (odds ratio 1.02, 95% confidence intervals 0.83-1.26, P = 0.83). A Q-test suggested that all the included studies were homogeneous. Patients who received telemedicine during fertility treatment reported a high level of satisfaction (91%, 95% confidence intervals 80-96%). Egger's test confirmed that no publication bias was found. Telemedicine could serve as a complementary tool during fertility treatment to facilitate patients' satisfaction and overcome some practical problems without compromising treatment outcomes. Future studies should continue exploring the potential applications of telemedicine in assisted reproduction.

Patterns of brain metastases response to immunotherapy with pembrolizumab.

PURPOSE: Central nervous system (CNS) metastases from lung cancers and melanoma, significantly contribute to morbidity and mortality. Despite advances in local therapies, there is a need for effective systemic treatments. Pembrolizumab, a PD-1 inhibitor, has shown promise for some patients with untreated brain metastases from melanoma and non-small cell lung cancer (NSCLC). This study aims to analyze the response of brain metastasis to pembrolizumab and associate characteristics like size and location with treatment outcome. METHODS: This retrospective study used imaging data from a phase II trial of pembrolizumab in melanoma or NSCLC patients with untreated brain metastases. MRI evaluations were conducted at 2 month intervals, with each brain metastasis treated as a distinct tumor for response assessment, based on modified RECIST criteria (maximum 5 lesions, 5 mm target lesions). RESULTS: Of 130 individual target metastases (> 5 mm), in 65 patients with NSCLC (90 metastases) and Melanoma (40 metastases), 32 (24.6%) demonstrated complete resolution, 24 (18.5%) had partial resolution, 32 (24.6%) were SD and 42 (32.3%) demonstrated PD. Those smaller than 10 mm were more likely to show complete resolution (p = 0.0218), while those ≥ 10 mm were more likely to have PR. There was no significant association between size, number or location (supratentorial vs. infratentorial) and lesion progression. The median time to metastatic lesion progression in the brain was 5.7-7 weeks. CONCLUSION: Pembrolizumab is effective in brain metastases from NSCLC and melanoma, showing response (CR + PR) in 43% and progression (PD) in 32% of metastases. With the median time to CNS progression of 5.7-7 weeks, careful radiographic monitoring is essential to guide timely local treatment decisions.

Primary sarcoma of the liver: A nationwide analysis of a rare mesenchymal tumor.

BACKGROUND AND OBJECTIVES: Primary liver sarcomas are rare malignancies. Prognostic factors associated with long-term survival remain poorly understood. The objective of this study is to determine factors associated with long-term survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients with visceral sarcoma arising from the liver. Demographic factors, tumor characteristics, resection status, and survival were evaluated. Multivariate Cox regression analysis was performed to determine predictors of survival. RESULTS: A total of 743 patients with primary hepatic sarcoma were identified. The median tumor size was 10 cm. Only 30% (n = 221) of patients in the cohort underwent surgery. The 5-year overall survival rates were 47.9% for localized disease, 29.5% for regional disease, and 16.5% for distant disease, p < 0.001. Among patients who underwent surgical resection, patients with embryonal sarcoma had better 5-year survival compared with angiosarcoma and other histologic subtypes. On multivariate analysis, surgery was associated with improved survival, while older age, higher stage, and angiosarcoma histology were the strongest independent predictors of poor survival. CONCLUSIONS: Surgery remains the mainstay of treatment for this rare malignancy but is performed in less than one-third of patients. Angiosarcoma histology is associated with worse overall survival, while surgical resection remains the strongest predictor of improved overall survival.

Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS. METHODS: From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed. RESULTS: Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation. CONCLUSION: For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

South East Asian Nutrition Surveys (SEANUTS) II - a multi-country evaluation of nutrition and lifestyle indicators in children aged 12 years and below: Rationale and Design.

OBJECTIVE: To assess the nutritional status, growth parameters and lifestyle behaviours of children between 0.5-12 years in nationally representative samples in Malaysia, Indonesia, Thailand, and Vietnam. DESIGN: A cross-sectional study was conducted in the four countries, between May 2019 and April 2021. Data collected can be categorized into four categories: (1) Growth - anthropometry, body composition, development disorder, (2) Nutrient intake and dietary habits - 24-hour dietary recall, child food habits, breast feeding and complementary feeding, (3) Socio-economic status - food insecurity and child health status/environmental, and (4) Lifestyle behaviours - physical activity patterns, fitness, sunlight exposure, sleep patterns, body image and behavioural problems. Blood samples were also collected for biochemical and metabolomic analyses. With the pandemic emerging during the study, a COVID-19 questionnaire was developed and implemented. SETTING: Both rural and urban areas in Malaysia, Indonesia, Thailand, and Vietnam. PARTICIPANTS: Children who were well, with no physical disability or serious infections/injuries and between the age of 0.5-12 years old were recruited. RESULTS: The South East Asian Nutrition Surveys II recruited 13,933 children. Depending on the country, data collection from children were conducted in schools and commune health centres, or temples, or sub-district administrative organizations. CONCLUSIONS: The results will provide up-to-date insights into nutritional status and lifestyle behaviours of children in the four countries. Subsequently, these data will facilitate exploration of potential gaps in dietary intake among Southeast Asian children and enable local authorities to plan future nutrition and lifestyle intervention strategies.

Prevalence, determinants, intervention strategies and current gaps in addressing childhood malnutrition in Vietnam: a systematic review.

BACKGROUND: Childhood malnutrition in all forms is a major public health issue worldwide. This review systematically examined the prevalence and determinants and identify the potential interventions and current gap in addressing malnutrition including undernutrition, overnutrition and micronutrient deficiencies (MNDs) in Vietnamese children aged 0-18 years old. METHODS: Embase, Scopus, PubMed, and Web of Science were systematically searched through June 2022 to identify relevant articles published within the past 25 years. Study selection and data extraction were performed by one reviewer and checked for accuracy by the other two reviewers in accordance with PRISMA guideline. Risk of publication bias was assessed using American Dietetic Association Quality Criteria Checklist. RESULTS: Seventy-two studies that met the inclusion criteria were included. Undernutrition has decreased over time but still 22.4%, 5.2% and 12.2% of children under 5 were stunted, wasted and underweight, respectively. Anaemia, iron, zinc, and vitamin D deficiencies were the more common forms of MNDs, the prevalence varied by age, region, and socioeconomic group. Population-based surveys reported that 11% and 48% of children aged 0-11 years old were iron and vitamin D deficient, respectively. Zinc deficiency affected almost one-quarter of the children and adolescents. Retinol deficiency was of less concern (< 20%). However, more evidence on MNDs prevalence is needed. Overweight and obesity is now on the rise, affecting one-third of school-aged children. The key determinants of undernutrition included living in rural areas, children with low birth weight, and poor socio-economic status, whereas living in urban and affluent areas, having an inactive lifestyle and being a boy were associated with increased risk of overweight and obesity. Nutrition specific intervention studies including supplementation and food fortification consistently showed improvements in anthropometric indices and micronutrient biomarkers. National nutrition-sensitive programmes also provided nutritional benefits for children's growth and eating behaviours, but there is a lack of data on childhood obesity. CONCLUSION: This finding highlights the need for effective double duty actions to simultaneously address different forms of childhood malnutrition in Vietnam. However, evidence on the potential intervention strategies, especially on MNDs and overnutrition are still limited to inform policy decision, thus future research is warranted.

Relationship between health-related determinants and adherence to breast and colorectal cancer screening: a population-based study in Flanders, Belgium.

BACKGROUND: Despite the recognized benefits of structured cancer screening, tests outside organized screening programs are common. Comprehensive reports on outside program screening in Europe are lacking, but the Flemish breast cancer (BC) and colorectal cancer (CRC) screening programs monitor data on non-organized tests prescribed by GPs and specialists. METHODS: Using data at aggregated level, logistic regression was used to examine the relationship between health care utilization and screening coverage in 308 Flemish municipalities during 2015-18. RESULTS: With regards to BC, municipalities with higher rates of gynecologists' visits had lower odds of coverage inside (-8%) and higher odds of coverage outside (+17%) the program. By contrast, municipalities with higher rates of GP visits, had higher odds of coverage inside (+6%) and lower odds of coverage outside (-7%) the program. As for CRC, municipalities with higher rates of visits gastroenterologists' visits had lower odds of coverage inside (-3%). Instead, municipalities with higher rates of GP visits, had higher odds of coverage both inside (+2%) and outside (+5%) the program. Municipalities with higher percentages of people with chronic conditions had higher odds of coverage within both the BC and CRC programs (+5% and +3%), and lower odds of outside screening (-7% and -6%). Municipalities with higher percentages of people 65+ with dementia and with mood disorders had, respectively, higher odds (+13% and +5%) and lower odds (-3% and -4%) of coverage inside both the BC and CRC programs. CONCLUSION: Our findings underscore the impact of healthcare utilization on cancer screening coverage at the municipal level in Flanders.

Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities.

Discovered as inflammatory cytokines, MIF and DDT exhibit widespread expression and have emerged as critical mediators in the response to infection, inflammation, and more recently, in cancer. In this comprehensive review, we provide details on their structures, binding partners, regulatory mechanisms, and roles in cancer. We also elaborate on their significant impact in driving tumorigenesis across various cancer types, supported by extensive in vitro, in vivo, bioinformatic, and clinical studies. To date, only a limited number of clinical trials have explored MIF as a therapeutic target in cancer patients, and DDT has not been evaluated. The ongoing pursuit of optimal strategies for targeting MIF and DDT highlights their potential as promising antitumor candidates. Dual inhibition of MIF and DDT may allow for the most effective suppression of canonical and non-canonical signaling pathways, warranting further investigations and clinical exploration.

Fragment length profiles of cancer mutations enhance detection of circulating tumor DNA in patients with early-stage hepatocellular carcinoma.

BACKGROUND: Late detection of hepatocellular carcinoma (HCC) results in an overall 5-year survival rate of less than 16%. Liquid biopsy (LB) assays based on detecting circulating tumor DNA (ctDNA) might provide an opportunity to detect HCC early noninvasively. Increasing evidence indicates that ctDNA detection using mutation-based assays is significantly challenged by the abundance of white blood cell-derived mutations, non-tumor tissue-derived somatic mutations in plasma, and the mutational tumor heterogeneity. METHODS: Here, we employed concurrent analysis of cancer-related mutations, and their fragment length profiles to differentiate mutations from different sources. To distinguish persons with HCC (PwHCC) from healthy participants, we built a classification model using three fragmentomic features of ctDNA through deep sequencing of thirteen genes associated with HCC. RESULTS: Our model achieved an area under the curve (AUC) of 0.88, a sensitivity of 89%, and a specificity of 82% in the discovery cohort consisting of 55 PwHCC and 55 healthy participants. In an independent validation cohort of 54 PwHCC and 53 healthy participants, the established model achieved comparable classification performance with an AUC of 0.86 and yielded a sensitivity and specificity of 81%. CONCLUSIONS: Our study provides a rationale for subsequent clinical evaluation of our assay performance in a large-scale prospective study.

Promoting High-Oxidation-State Metal Active Sites in a Hollow Ternary Metal Fluoride Nanoflake Array for Urea Electrolysis.

The adsorption ability of hydrogen, hydroxide, and oxygenic intermediates plays a crucial role in electrochemical water splitting. Electron-deficient metal-active sites can prompt electrocatalytic activity by improving the adsorption ability of intermediates. However, it remains a significant challenge to synthesize highly abundant and stable electron-deficient metal-active site electrocatalysts. Herein, we present a general approach to synthesizing a hollow ternary metal fluoride (FeCoNiF2) nanoflake array as an efficient and robust bifunctional electrocatalyst for the hydrogen evolution reaction (HER) and urea oxidation reaction (UOR). We find that the F anion withdraws electrons from the metal centers, inducing an electron-deficient metal center catalyst. The rationally designed hollow nanoflake array exhibits the overpotential of 30 mV for HER and 130 mV for UOR at a current density of 10 mA cm-2 and superior stability without decay events over 150 h at a large current density of up to 100 mA cm-2. Remarkably, the assembled urea electrolyzer using a bifunctional hollow FeCoNiF2 nanoflake array catalyst requires cell voltages of only 1.352 and 1.703 V to afford current densities of 10 and 100 mA cm-2, respectively, which are 116 mV less compared with that required for overall water splitting.

Point-of-care testing in private pharmacy and drug retail settings: a narrative review.

BACKGROUND: Point-of-care testing (POCT) using rapid diagnostic tests for infectious disease can potentially guide appropriate use of antimicrobials, reduce antimicrobial resistance, and economise use of healthcare resources. POCT implementation in private retail settings such as pharmacies and drug shops could lessen the burden on public healthcare. We performed a narrative review on studies of POCTs in low- and middle-income countries (LMICs), and explored uptake, impact on treatment, and feasibility of implementation. METHODS: We searched MEDLINE/PubMed for interventional studies on the implementation of POCT for infectious diseases performed by personnel in private retail settings. Data were extracted and analysed by two independent reviewers. RESULTS: Of the 848 studies retrieved, 23 were included in the review. Studies were on malaria (19/23), malaria and pneumonia (3/23) or respiratory tract infection (1/23). Nine randomised controlled studies, four controlled, non-randomised studies, five uncontrolled interventions, one interventional pre-post study, one cross-over interventional study and three retrospective analyses of RCTs were included. Study quality was poor. Overall, studies showed that POCT can be implemented successfully, leading to improvements in appropriate treatment as measured by outcomes like adherence to treatment guidelines. Despite some concerns by health workers, customers and shop providers were welcoming of POCT implementation in private retail settings. Main themes that arose from the review included the need for well-structured training with post-training certification covering guidelines for test-negative patients, integrated waste management, community sensitization and demand generation activities, financial remuneration and pricing schemes for providers, and formal linkage to healthcare and support. CONCLUSION: Our review found evidence that POCT can be implemented successfully in private retail settings in LMICs, but comprehensive protocols are needed. High-quality randomised studies are needed to understand POCTs for infectious diseases other than malaria.

Real-world Experience of Caplacizumab for Adolescents in the First-line Setting: Case Reports.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy resulting in high mortality. Caplacizumab is approved for treatment of adults with acquired thrombotic thrombocytopenic purpura that has shown faster platelet normalization, clinical improvement, and reduced risk of recurrent/refractory disease. We report 2 cases of adolescents treated off-label with caplacizumab who were able to stop before 30 days from end of plasma exchange after platelets normalized and ADAMTS13 activity recovered to >20% to 30%. Our results show similar efficacy to other reports of patients under 18 receiving caplacizumab in first line, regardless of plasma exchange strategy, and may offer insight into early cessation criteria.

Coupled fibromodulin and SOX2 signaling as a critical regulator of metastatic outgrowth in melanoma.

We aimed to study mechanisms controlling metastatic outgrowth of melanoma into clinically relevant lesions, a critical process responsible for the majority of melanoma deaths. To this end, we developed novel in vivo models and identified molecular events that can be ascribed to their distinct phenotypes, indolent or highly metastatic. Induction of a proliferative state at distant sites was associated with high levels of the stem-like/progenitor marker, SOX2, and required the upregulation of FMOD, an extracellular matrix component, which modulates tumor-stroma interactions. Functional studies revealed a possible link between FMOD and SOX2; dual FMOD and SOX2 silencing nearly abolished brain metastasis and had a similar effect on distant metastasis to other sites. Our in vitro data suggests that FMOD and SOX2 cooperation plays an important role in tumor vasculogenic mimicry. Furthermore, we found that FMOD and SOX2 functional roles might converge at the activation of transcriptional co-factors YAP and TAZ, possibly via crosstalk with the tumor suppressor Hippo pathway. Finally, high expression of both genes in patient specimens predicted early development of brain metastasis. Thus, our study identifies FMOD and SOX2 cooperation as a novel regulatory mechanism that might be linked functionally to melanoma metastatic competence.

Dementia care practices among community healthcare workers in Vietnam: a qualitative descriptive study.

BACKGROUND: Vietnam is one of the most rapidly aging countries in the world and the likelihood that someone may have dementia rises dramatically as the population ages. Although caring for persons living with dementia is important, little is known about the circumstances under which community healthcare professionals in Vietnam provide dementia care. This study aimed to describe the practice of caring for persons with dementia among community healthcare professionals in Vietnam. METHODS: This qualitative descriptive study was conducted with 23 community healthcare professionals recruited from 10 primary healthcare centers, representing 10 of 24 districts in Ho Chi Minh City, Vietnam. Participants were physicians (n = 11), physician's assistants (n = 8) and community nurses (n = 4). Data were collected through in-depth face-to-face semi-structured interviews. Interview data were audio recorded, transcribed verbatim, and analyzed using content analysis. RESULTS: The mean age of the 23 participants was 44.6 ± 8.8 years; most were female (n = 16, 69.6%); and the mean time of working in the field of dementia care was 15.9 ± 8.4 years. Analysis of the interview data revealed five categories, which informed how care was provided: 1) Knowledge about dementia and its prevalence among older adults; 2) Identification of dementia in Vietnam; 3) Lack of attention to early diagnosis of dementia and difficulty in providing continuous care; 4) Dependence on family members for prompt and continuous care; and 5) challenges to providing dementia care. Despite having knowledge about dementia, some healthcare professionals incorrectly viewed dementia as an inevitable part of the ageing process. Participants reported that their limited training and practical experience in caring for persons with dementia caused a lack of confidence in dementia care. CONCLUSIONS: The quality of care provided to persons living with dementia was negatively impacted by the limited training of healthcare personnel. The diagnosis, treatment, and provision of supportive services to persons living with dementia and their families are substantial challenges for the Vietnamese healthcare system. It is crucial to initiate and cultivate dementia care education programs aimed at expanding curricula for physicians, physicians' assistants, and nurses.

Development of oral oncolytic nonadherence estimator (ORACLE): A pretreatment nonadherence risk assessment for oral oncolytics.

INTRODUCTION: To date, there is no adherence estimator to identify risk of nonadherence prior to initiating oral oncolytics. METHODS: A workgroup was assembled through the National Community Oncology Dispensing Association and tasked with creating a tool to meet this need. Tool constructs were defined after a review of the literature identifying top barriers to adherence. A second literature search was conducted to identify questions targeting specific barriers from validated adherence questionnaires. Once a finalized draft was complete, the risk assessment tool was built into an electronic survey where a risk category can be automatically calculated for the patient. RESULTS: The six most impactful factors affecting compliance to oral oncolytics were identified as patient's confidence, health literacy, perception of treatment, quality of life, social support, and complexity of chemotherapy regimen. A six-item questionnaire was created with five patient-directed questions and one clinician-directed question. Examples and descriptions were provided for clinicians to consider when categorizing complexity of a regimen. The tool was designed for responses to each question to be indexed into categories through a 10-point system. Results will be stratified into low, moderate, or high risk for nonadherence. CONCLUSION: The creation of a tool to predict nonadherence prior to starting therapy is an unmet need for patients initiating oral oncolytics. The aim of this tool is to meet those needs and better guide clinicians to provide patients with strategies to better manage nonadherence. Next steps include tool validation and piloting in clinical practice.