Informal caregiving among people supporting a person with type 2 diabetes in rural communities of Northern Vietnam: A cross-sectional study of caregiver burdens.

OBJECTIVE: The prevalence of type 2 diabetes mellitus (T2DM) in Vietnam has doubled from 3% to 6% over the last decades, with potential consequences for persons with diabetes and their caregivers. This study aimed to assess caregiver burdens and factors associated with caregiver burden. METHOD: A cross-sectional study was conducted in 2019, using data from 1,241 informal caregivers (ICGs). Caregiver burden was scored from 0-32 using 8 questions from the Zarit Burden Interview (ZBI). Quantile regression analysis was used to identify factors associated with caregiver burden. RESULTS: The median score of the ZBI was 7.0 (Q1-Q3: 2.0-10.0), indicating that the burden among caregiver of persons with T2DM is not high. Quantile regression showed that the higher the monthly income, the lower the burden among caregivers (50% quantile and 75% quantile of burden: -0.004). Lower educational level (25%Q: 4.0, 50%Q; 3.0, 75%Q: 2.16), being a farmer (25%Q: 2.0) and providing care to other people besides the person with T2DM (25%Q: 2.0, 50%Q; 2.54, 75%Q: 1.66) were associated with higher burden on caregivers. CONCLUSION: The study found that caregivers facing additional life stressors, such as low income or other caregiving responsibilities, reported higher levels of burden. These findings could inform the development of interventions targeted at supporting informal caregivers in rural areas in low- and middle-income countries.

The pioneers of Vietnam's epidemiological transition: an ethnographic study of pregnant women's experiences of gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is an abnormal glucose metabolism diagnosed during pregnancy that can have serious adverse consequences for mother and child. GDM is an exceptional health condition, as its management serves not only as treatment but also as prevention, reducing the risk of future diabetes in mother and child. OBJECTIVES: This qualitative study aimed to explore how pregnant women experience and respond to GDM, focusing particularly on the role of the family environment in shaping women's experiences. METHODS: The research was carried out in Vietnam's Thái Bình province in April-May 2023. We conducted in-depth ethnographic interviews with 21 women with GDM, visiting them in their homes. Our theoretical starting point was phenomenological anthropology, and the data were analysed using a thematic analysis approach. RESULTS: At the centre of women's experiences was the contrast between GDM as a biomedical and a social condition. Whereas GDM was biomedically diagnosed and managed in the healthcare system, it was often deemed insignificant or non-existent by family members. This made GDM a biomedically present but socially absent health condition. This paradox posed challenges to women's GDM self-care, placing them in pioneering social positions. CONCLUSIONS: The biomedical presence yet social absence of GDM turned women into pioneers at biomedical, digital, epidemiological, and family frontiers. This article calls for appreciation of pregnant women's pioneering roles and for health systems action to involve women and families in the development of GDM policies and programmes at a time of sweeping global health changes.

Main findings: Vietnamese women's experiences of gestational diabetes were affected by social splits between clinic and home; between biomedical and family worlds.Added knowledge: Gestational diabetes places pregnant women in Northern Vietnam in pioneering roles on biomedical, digital, epidemiological, and family frontiers.Global health impact for policy and action: Pregnant women should be involved in the development of policies and programmes addressing gestational diabetes, with particular attention to the connections between clinical and family worlds.

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Background: Pharmacokinetic (PK)-guided dosing is used to individualize factor (F)VIII and FIX replacement therapy. Objectives: This study investigates the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B. Methods: In this multicenter, prospective cohort study, people of all ages with hemophilia received prophylactic treatment with factor concentrates based on individual PK parameters. During follow-up, at least 4 measured FVIII/FIX levels per patient were compared with corresponding predicted levels obtained by Bayesian forecasting. Predictive performance was defined as adequate when ≥80% of measured FVIII/FIX levels were within ±25% of prediction (relative error). Additionally, mean absolute error and mean error were calculated. In post hoc analyses, predictive performance was assessed allowing maximum absolute errors of 1 (trough), 5 (mid), and 15 (peak) IU/dL. Five-point scale questionnaires addressed feasibility of PK guidance. Results: We included 50 patients (median age, 19 years; range: 2-72 years). Median follow-up was 36 weeks. Seventy-one percent of levels (58% trough, 83% mid, and 80% peak) were within ±25% of prediction. Mean absolute errors were 0.8 (trough), 2.0 (mid), and 8.6 (peak) IU/dL. In post hoc analyses, 81% (trough), 96% (mid), and 82% (peak) of levels were within set limits. Patients reported low burden and high satisfaction. Conclusion: PK-guided dosing was reliable according to post hoc analyses, based on low absolute errors that were regarded as clinically irrelevant in most cases. The predefined predictive performance was achieved in mid and peak factor levels but not in trough factor levels due to measurement inaccuracy. PK guidance also seemed feasible.

Maximal Exercise Tolerance, Objective Trunk Strength, and Mobility Measurements in Axial Spondyloarthritis.

OBJECTIVE: Although exercise therapy is safe, effective, and recommended as a nonpharmacological treatment for axial spondyloarthritis (axSpA), there is a lack of guidelines regarding type and dosage. Insufficient knowledge about physical and physiological variables makes designing effective exercise programs challenging. Therefore, the goal of this study was to simultaneously assess trunk strength, spinal mobility, and the cardiorespiratory fitness of patients with axSpA. METHODS: In a cross-sectional study, 58 patients with axSpA (mean age 40.8 yrs, 50% male, mean symptom duration 10.3 yrs) performed maximal cervical and trunk mobility and isometric strength tests in all planes (using David Back Concept devices) and a maximal cardiopulmonary bicycle exercise test (n = 25). Mobility and strength data were compared to healthy reference data. Cut-off values for clinical cardiopulmonary exercise testing interpretation were used to judge normality. Patients were compared based on radiographic involvement and symptom duration. RESULTS: Both strength (P ≤ 0.02) and mobility (P ≤ 0.001) were significantly lower for the patients with axSpA compared to the reference. Strength deficits were comparable between the radiographic and nonradiographic groups (P > 0.05, except trunk extension [P = 0.03]), whereas mobility showed higher deficits in the radiographic group (cervical extension [P = 0.02] and rotation [P = 0.01], and trunk extension [P = 0.03] and rotation [P = 0.03]), regardless of symptom duration. Similarly, symptom duration positively affected oxygen pulse (P = 0.03), relative anaerobic threshold (P = 0.02), and aerobic capacity (P = 0.02). CONCLUSION: In patients with axSpA, strength is more affected than mobility when compared to healthy controls. Likewise, mainly the metabolic component of aerobic capacity is impaired, affecting cardiopulmonary fitness. These findings indicate that future personalized exercise programs in patients with axSpA should incorporate exercises for cardiopulmonary fitness next to strength and mobility training.

A new population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B.

AIMS: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data. METHODS: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling. RESULTS: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01). CONCLUSIONS: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.

Isolation, characterization, and fibroblast uptake of bacterial extracellular vesicles from Porphyromonas gingivalis strains.

Periodontitis is an inflammatory condition caused by bacteria and represents a serious health problem worldwide as the inflammation damages the supporting tissues of the teeth and may predispose to systemic diseases. Porphyromonas gingivalis is considered a keystone periodontal pathogen that releases bacterial extracellular vesicles (bEVs) containing virulence factors, such as gingipains, that may contribute to the pathogenesis of periodontitis. This study aimed to isolate and characterize bEVs from three strains of P. gingivalis, investigate putative bEV uptake into human oral fibroblasts, and determine the gingipain activity of the bEVs. bEVs from three bacterial strains, ATCC 33277, A7A1-28, and W83, were isolated through ultrafiltration and size-exclusion chromatography. Vesicle size distribution was measured by nano-tracking analysis (NTA). Transmission electron microscopy was used for bEV visualization. Flow cytometry was used to detect bEVs and gingipain activity was measured with an enzyme assay using a substrate specific for arg-gingipain. The uptake of bEVs into oral fibroblasts was visualized using confocal microscopy. NTA showed bEV concentrations from 108 to 1011 particles/mL and bEV diameters from 42 to 356 nm. TEM pictures demonstrated vesicle-like structures. bEV-gingipains were detected both by flow cytometry and enzyme assay. Fibroblasts incubated with bEVs labeled with fluorescent dye displayed intracellular localization consistent with bEV internalization. In conclusion, bEVs from P. gingivalis were successfully isolated and characterized, and their uptake into human oral fibroblasts was documented. The bEVs displayed active gingipains demonstrating their origin from P. gingivalis and the potential role of bEVs in periodontitis.

Cytokine Levels in Saliva Are Associated with Salivary Gland Fibrosis and Hyposalivation in Mice after Fractionated Radiotherapy of the Head and Neck.

Cytokines are mediators of inflammation that could lead to fibrosis. The aim was to monitor cytokine levels in saliva and serum after locally fractionated radiotherapy of the head and neck in mice and investigate associations with salivary gland fibrosis and hyposalivation. C57BL/6 mice were randomized to sham or X-ray irradiation of 66 Gy in 10 fractions over 5 days. Blood and saliva were collected on days -7, 5, 35, 80, and 105 following cytokine analysis. The harvested submandibular salivary gland was assessed for the presence of fibrosis. Decision tree regression analysis was used to investigate whether cytokine levels could predict late endpoints in terms of hyposalivation or fibrosis. Significant formation of fibrosis in gland tissue and reduced saliva production was found after irradiation. The pro-inflammatory cytokines IL-1α, TNF, TIMP1, G-CSF, KC, and MIP-1α showed increased levels in saliva in irradiated mice and a strong correlation with late endpoints. The decision tree analysis largely separated controls from irradiated animals, with IL-1α being the strongest predictor. Pro-inflammatory cytokines in saliva, but not in serum, were associated with late endpoints. This indicates that cytokine expression in saliva is a good biomarker for local salivary gland damage with IL-1α as the strongest single predictor.

The road to implementation of pharmacokinetic-guided dosing of factor replacement therapy in hemophilia and allied bleeding disorders. Identifying knowledge gaps by mapping barriers and facilitators.

Clinical guidelines and expert groups recommend the use of pharmacokinetic (PK)-guided dosing of factor replacement therapy for the treatment of bleeding disorders, especially for patients with hemophilia. Although PK-guided dosing is increasingly applied, it is generally not considered standard clinical practice. The aim of this scoping review is to map barriers and facilitators for the implementation of PK-guided dosing in clinical practice and to identify knowledge gaps. A literature search was performed and 110 articles were included that describe PK-guided dosing in patients with bleeding disorders, mostly hemophilia A. We defined two overarching themes, efficacy and feasibility, and discuss five topics within each theme. For each topic, barriers, facilitators and knowledge gaps were described. Although consensus was found with regard to some topics, contradicting reports were found for others, especially with respect to the efficacy of PK-guided dosing. These contradictions highlight the need for future research to elucidate current ambiguities.

Nursing Roles in Cancer Rehabilitation: An Integrative Review.

BACKGROUND: Because of cancer survivors' increased need for help and support, cancer rehabilitation should be an essential part of cancer treatment, where focusing on patients' individual needs is essential. OBJECTIVE: To provide an overview of existing evidence about nurses' roles and participation in cancer rehabilitation, based on both nurses' and patients' perspectives. METHODS: A systematic search was conducted in PubMed, CINAHL, EMBASE and Cochrane databases for studies published from January 2001-January 2022. Whittemore and Knafl's methodology for data extraction and synthesis was used, and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were followed. The review was registered in PROSPERO (CRD42021223683). RESULTS: Ten qualitative studies and 7 quantitative studies were included, encompassing 306 patients and 1847 clinicians (1164 nurses). Three nursing roles emerged: (1) relationship-forming, in which nurses described ongoing involvement in patients' rehabilitation and patients described nurses as trusted partners; (2) coordinating, in which nurses described a lack of time and resources and a focus on medical treatment, and patients described nurses as expert coordinators; and (3) follow-up, in which patients described nurses as good communicators and trusted partners in their follow-up, and nurses described their natural interest in patients' rehabilitation outcomes during follow-up. CONCLUSIONS: Patients were comfortable with nurses as trusted partners during cancer rehabilitation. Significant barriers such as lack of time, resources, and education about rehabilitation may negatively influence rehabilitation planning, implementation, and monitoring. IMPLICATIONS FOR PRACTICE: Clinicians can use the findings to improve cancer rehabilitation with the nurse as a central provider and conduct further research on the coordinating and follow-up roles.

Limited sampling strategies for individualized BAX 855 prophylaxis in severe hemophilia A: in silico evaluation.

OBJECTIVE: Limited sampling strategies (LSS) lower the burden of pharmacokinetic (PK)-guided dosing, but an extensive evaluation of LSS for BAX 855 (Adynovi) is currently lacking. This study aimed to develop a LSS for BAX 855 and combine this with a LSS of a standard half-life (SHL) factor VIII (FVIII) concentrate in a clinical setting. METHODS: Individual PK parameters of BAX 855 were estimated for 10 000 virtual patients with severe hemophilia A using Monte Carlo simulations. Several LSS consisting of 2-6 samples were examined based on patient burden, bias and accuracy of clearance, elimination half-life, volume of distribution and trough levels at 72 h (C72). Analyses were performed separately for adults and children <12 years. RESULTS: The preferred LSS for BAX 855 consisted of three sampling points at 15-30 min, 48 h and 72 h for both adults (mean accuracy C72: 14.0% vs. 10.8% using six samples) and children (mean accuracy C72: 14.9% vs. 11.4% using six samples). The best strategy with two samples (peak, 48 h) resulted in an adequate, but lower accuracy than strategies with ≥3 samples (mean accuracy C72: 22.3%). The optimal combination of the LSS of SHL FVIII and BAX 855 led to six samples during four clinical visits. CONCLUSION: This in silico study has identified that two to three samples are necessary to estimate the individual PK of BAX-855 adequately. These samples can be collected in one or two clinical visits. When combining PK profiling of SHL FVIII and BAX 855, six samples during four clinical visits are needed.

Cognitive function in individuals with and without painful and painless diabetic polyneuropathy-A cross-sectional study in type 1 diabetes.

INTRODUCTION: Previous studies suggest that cognitive impairment is more prevalent in individuals with painful and painless diabetic peripheral neuropathy (DPN). However, the current evidence is not well described. This study investigated cognitive function in adults with type 1 diabetes mellitus (T1DM) and the association to painful/painless DPN and clinical parameters. METHODS: This cross-sectional, observational, case-control study included 58 participants with T1DM, sub-grouped into 20 participants with T1DM and painful DPN, 19 participants with T1DM and painless DPN, 19 participants with T1DM without DPN, and 20 healthy controls were included. The groups were matched for sex and age. The participants performed Addenbrooke's examination III (ACE-III), which assesses attention, memory, verbal fluency, language and visuospatial skills. Working memory was evaluated using an N-back task. Cognitive scores were compared between the groups and correlated to age, diabetes duration, HbA1c and nerve conduction measurements. RESULTS: Compared to healthy controls, T1DM participants showed lower total ACE-III (p = .028), memory (p = .013) and language scores (p = .028), together with longer reaction times in the N-back task (p = .041). Subgroup analyses demonstrated lower memory scores in those with painless DPN compared with healthy controls (p = .013). No differences were observed between the three T1DM subgroups. Cognitive scores and clinical parameters were not associated. CONCLUSIONS: This study supports the notion of cognitive alterations in T1DM and indicates that cognitive function is altered in T1DM regardless of underlying neuropathic complications. The memory domain appears altered in T1DM, particularly in those with painless DPN. Further studies are needed to verify the findings.

The spectrum and frequency of histopathological diagnosis of oral diseases in Oslo: Implications to oral pathology syllabus.

INTRODUCTION: To assure knowledge and skills in diagnostic work of oral diseases a continuously updated curriculum is essential. The first aim of the present study was to evaluate the spectrum and frequency of oral histopathological diagnoses signed out by oral pathologists at the Department of Pathology, Oslo University Hospital (OUS), Norway during a two-year period. The second aim was to compare the spectrum of histopathological diagnoses with the content of the current syllabus in oral pathology at the Faculty of Dentistry, University of Oslo (UiO). MATERIALS AND METHODS: In this retrospective cross-sectional study, all histological diagnosis signed out during 2015 and 2016 were included. All histopathological reports were analysed with regard to clinical information and histopathological diagnosis. The spectrum of histopathological diagnoses was compared to the diagnoses presented in lectures and courses for dental and dental hygienist students at UiO. RESULTS: Three thousand four hundred and two histopathological reports (47% males and 53% females) were included. The diagnoses were categorised into eight disease groups and the three most frequent disease groups were cysts, benign tumours/reactive lesions, and white, red, ulcerative and vesiculobullous lesions. The lateral periodontal cyst was more frequent than expected. CONCLUSIONS: We conclude that a minor revision of the syllabus is needed, although the most frequent oral conditions presented in this study are well covered in the oral pathology teaching in Oslo. A more clinical related teaching approach should be considered by categorising oral diseases according to, for example location and age groups.

Alterations in Functional Connectivity of Thalamus and Primary Somatosensory Cortex in Painful and Painless Diabetic Peripheral Neuropathy.

OBJECTIVE: In this study we aimed to investigate the functional connectivity of brain regions involved in sensory processing in diabetes with and without painful and painless diabetic peripheral neuropathy (DPN) and the association with peripheral nerve function and pain intensity. RESEARCH DESIGN AND METHODS: In this cross-sectional study we used resting-state functional MRI (fMRI) to investigate functional brain connectivity of 19 individuals with type 1 diabetes and painful DPN, 19 with type 1 diabetes and painless DPN, 18 with type 1 diabetes without DPN, and 20 healthy control subjects. Seed-based connectivity analyses were performed for thalamus, postcentral gyrus, and insula, and the connectivity z scores were correlated with peripheral nerve function measurements and pain scores. RESULTS: Overall, compared with those with painful DPN and healthy control subjects, subjects with type 1 diabetes without DPN showed hyperconnectivity between thalamus and motor areas and between postcentral gyrus and motor areas (all P ≤ 0.029). Poorer peripheral nerve functions and higher pain scores were associated with lower connectivity of the thalamus and postcentral gyrus (all P ≤ 0.043). No connectivity differences were found in insula (all P ≥ 0.071). CONCLUSIONS: Higher functional connectivity of thalamus and postcentral gyrus appeared only in diabetes without neuropathic complications. Thalamic/postcentral gyral connectivity measures demonstrated an association with peripheral nerve functions. Based on thalamic connectivity, it was possible to group the phenotypes of type 1 diabetes with painful/painless DPN and type 1 diabetes without DPN. The results of the current study support that fMRI can be used for phenotyping, and with validation, it may contribute to early detection and prevention of neuropathic complications.

Gray Matter Brain Alterations in Type 1 Diabetes - Findings Based on Detailed Phenotyping of Neuropathy Status.

AIMS: This study investigated brain structure in patients of type 1 diabetes with diabetic peripheral neuropathy (DPN) and type 1 diabetes with neuropathic pain and the associations to clinical, peripheral, and cognitive measurements. METHODS: Sixty individuals with type 1 diabetes and 20 healthy controls were included in the study. Nineteen individuals with type 1 diabetes and neuropathic pain, 19 with type 1 diabetes and DPN, 18 with type 1 diabetes without DPN, and 20 healthy controls were included in the brain analyses. We utilized structural brain magnetic resonance imaging to investigate total and regional gray matter volume. RESULTS: Significant lower gray matter volume was found in type 1 diabetes with neuropathic pain and in type 1 diabetes without DPN compared to healthy controls (p=0.024 and p=0.019, respectively). Lower insula volume was observed in all three diabetes groups (all p≤0.050). Thalamus and hippocampus volume was lower in type 1 diabetes with neuropathic pain, cerebellum volume was lower in type 1 diabetes with DPN, and somatosensory cortex volume was lower in type 1 diabetes without DPN (all p≤0.018). Attenuated memory was associated with lower gray matter volume in type 1 diabetes with DPN. No associations were found between gray matter volume and clinical/peripheral measurements. CONCLUSION: We demonstrated lower gray matter volume in individuals with type 1 diabetes regardless of the presence of DPN and neuropathic pain. Hence, central gray matter alteration was not associated with peripheral alterations.

Does difference between label and actual potency of factor VIII concentrate affect pharmacokinetic-guided dosing of replacement therapy in haemophilia A?

BACKGROUND: To account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK-guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance. AIM: Explore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens. METHODS: We analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI-CLOT randomized controlled trial. Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration-time curves were constructed by nonlinear mixed-effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen. RESULTS: In 45/50 included patients, actual potency was higher than its label potency. The median potency difference was 6.0% (range -9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentration-time curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose. CONCLUSION: It is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK-guided dosing, trough levels may deviate ±20% from calculations based on label dose.

Everyday disease diplomacy: an ethnographic study of diabetes self-care in Vietnam.

BACKGROUND: Understanding people's subjective experiences of everyday lives with chronic health conditions such as diabetes is important for appropriate healthcare provisioning and successful self-care. This study explored how individuals with type 2 diabetes in northern Vietnam handle the everyday life work that their disease entails. METHODS: Detailed ethnographic data from 27 extended case studies conducted in northern Vietnam's Thái Bình province in 2018-2020 were analyzed. RESULTS: The research showed that living with type 2 diabetes in this rural area of Vietnam involves comprehensive everyday life work. This work often includes efforts to downplay the significance of the disease in the attempt to stay mentally balanced and ensure social integration in family and community. Individuals with diabetes balance between disease attentiveness, keeping the disease in focus, and disease discretion, keeping the disease out of focus, mentally and socially. To capture this socio-emotional balancing act, we propose the term "everyday disease diplomacy." We show how people's efforts to exercise careful everyday disease diplomacy poses challenges to disease management. CONCLUSIONS: In northern Vietnam, type 2 diabetes demands daily labour, as people strive to enact appropriate self-care while also seeking to maintain stable social connections to family and community. Health care interventions aiming to enhance diabetes care should therefore combine efforts to improve people's technical diabetes self-care skills with attention to the lived significance of stable family and community belonging.

The prognostic role of combining Krüppel-like factor 4 score and grade of inflammation in a Norwegian cohort of oral tongue squamous cell carcinomas.

Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor involved in inflammation, cancer development, and progression. However, the relationship between KLF4, inflammation, and prognosis in oral cancer is not fully understood. KLF4 expression levels were examined in a multicenter cohort of 128 oral squamous cell carcinoma (OSCC) specimens from the tongue (OTSCC) using immunohistochemistry. In two external KLF4 mRNA datasets (The Cancer Genome Atlas/The Genotype-Tissue Expression Portal), lower KLF4 mRNA expression was found in OSCC and head and neck squamous cell carcinomas (HNSCC) than in control oral epithelium. These data indicate that down-regulation of KLF4 mRNA is linked to OSCC/HNSCC progression. Using Cox-multivariate analysis, a significantly favorable 5-year disease-specific survival rate was observed for a subgroup of patients with a combination of high levels of KLF4 expression and inflammation. OSCC cell lines exposed to IFN-γ showed a significant upregulation of nuclear KLF4 expression, indicating a link between inflammation and KLF4 expression in OSCC. Overall, the current data suggest a functional link between KLF4 and inflammation. The combination of high KLF4 nuclear expression and marked/moderate stromal inflammation might be useful as a favorable prognostic marker for a subgroup of OTSCC patients.

Design of a Prospective Study on Pharmacokinetic-Guided Dosing of Prophylactic Factor Replacement in Hemophilia A and B (OPTI-CLOT TARGET Study).

In resource-rich countries, almost all severe hemophilia patients receive prophylactic replacement therapy with factor concentrates to prevent spontaneous bleeding in joints and muscles to decrease the development of arthropathy and risk of long-term disability. Pharmacokinetic (PK)-guided dosing can be applied to individualize factor replacement therapy, as interindividual differences in PK parameters influence factor VIII (FVIII) and FIX activity levels. PK-guided dosing may therefore lead to more optimal safeguarding of FVIII/FIX levels during prophylaxis and on demand treatment. The OPTI-CLOT TARGET study is a multicenter, nonrandomized, prospective cohort study that aims to investigate the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia-A and -B patients in daily clinical practice. At least 50 patients of all ages on prophylactic treatment using standard half-life (SHL) and extended half-life (EHL) factor concentrates will be included during 9 months and will receive PK-guided treatment. As primary endpoint, a minimum of four FVIII/FIX levels will be compared with FVIII/FIX levels as predicted by Bayesian forecasting. Secondary endpoints are the association of FVIII and FIX levels with bleeding episodes and physical activity, expectations and experiences, economic analyses, and optimization of population PK models. This study will lead to more insight in the reliability and feasibility of PK-guided dosing in hemophilia patients. Moreover, it will contribute to personalization of treatment by greater knowledge of dosing regimens needed to prevent and treat bleeding in the individual patient and provide evidence to more clearly associate factor activity levels with bleeding risk.

Existential vulnerability: an ethnographic study of everyday lives with diabetes in Vietnam.

This article asks: how can the concept of existential vulnerability help us to comprehend the human impact of chronic disease? Across the globe, the prevalence of chronic health conditions is rising dramatically, with wide-ranging consequences for human lives. Taking type II diabetes in northern Vietnam as its ethnographic case, this study explores how chronic health conditions are woven into everyday lives, altering subjectivities and social relations. Applying the notion of existential vulnerability as its analytical prism, the article explores three different dimensions of vulnerability: physical, emotional, and social. The analysis highlights the importance of a focus on social connectedness for comprehending the everyday impact of chronic disease and for the development of health care interventions in this domain.

Reduced Thalamic Volume and Metabolites in Type 1 Diabetes with Polyneuropathy.

OBJECTIVE: Thalamus is essential in processing of sensory information. This study explored the associations between thalamic volume and intra-thalamic metabolites and associations to clinical and experimental characteristics of sensory function in adults with diabetic polyneuropathy. METHODS: 48 adults with type 1 diabetes and confirmed distal symmetric peripheral neuropathy (DPSN) and 28 healthy controls participated in a cross-sectional study and underwent a brain magnetic resonance imaging scan. Estimates for thalamic volume were extracted using voxel-based morphometry and intra-thalamic N-acetylaspartate/creatine (NAA/cre) levels were assessed by magnetic resonance spectroscopy. Associations between thalamic volume and clinical measures, quantitative sensory testing and neuropathic phenotype were explored. RESULTS: In diabetes, reduced gray matter volume was identified including bilateral thalamus (all p≤0.001) in comparison to healthy participants. Thalamic volume estimates were positively associated to intra-thalamic NAA/cre (r=0.4; p=0.006), however not to diabetes duration (p=0.5), severity of DSPN (p=0.7), or presence of pain (p=0.3). Individuals with the lowest thalamic volume had greatest loss of protective sensation (light touch using von Frey-like filaments, p=0.037) and highest pain tolerance to electric stimulation (tetanic stimulation, p=0.008) compared to individuals with the highest thalamic volume. CONCLUSIONS: In this cohort with type 1 diabetes and severe DSPN, thalamic atrophy was present and associated with reduced NAA/cre, indicating thalamic structural loss and dysfunction. Thalamic atrophy was associated to reduced sensory function involving large fiber neuropathy and sensation to tetanic stimulation that may reflect synaptic transmission. This may ultimately contribute to the current understanding of the pathophysiology behind the perception changes evident in DSPN.