Anharmonic strong-coupling effects at the origin of the charge density wave in CsV3Sb5.

The formation of charge density waves is a long-standing open problem, particularly in dimensions higher than one. Various observations in the vanadium antimonides discovered recently further underpin this notion. Here, we study the Kagome metal CsV3Sb5 using polarized inelastic light scattering and density functional theory calculations. We observe a significant gap anisotropy with 2 Δ max / k B T CDW ≈ 20 , far beyond the prediction of mean-field theory. The analysis of the A1g and E2g phonons, including those emerging below TCDW, indicates strong phonon-phonon coupling, presumably mediated by a strong electron-phonon interaction. Similarly, the asymmetric Fano-type lineshape of the A1g amplitude mode suggests strong electron-phonon coupling below TCDW. The large electronic gap, the enhanced anharmonic phonon-phonon coupling, and the Fano shape of the amplitude mode combined are more supportive of a strong-coupling phonon-driven charge density wave transition than of a Fermi surface instability or an exotic mechanism in CsV3Sb5.

High affinity mAb infusion can enhance maximum affinity maturation during HIV Env immunization.

Antigen-specific antibody infusion is known to enhance or suppress germinal center (GC) responses depending on the affinity of the infusion. We hypothesized that infusing monoclonal antibodies (mAbs) of escalating affinity during an immunization regimen may progressively escalate selection pressure on competing B cells, increasing their affinity. To test this, we immunized mice with HIV envelope gp120 and infused CD4 binding-site (CD4bs)-specific mAbs. While mAb infusion reduced somatic hypermutation (SHM) and affinity in most CD4bs-specific B cells, a sub-population was identified with greater SHM and affinity than control. High-throughput sequencing of plasma cells revealed that CD4bs-specific plasma cells possessed elevated SHM after mAb infusion, with phylogenetic tree topology that suggested more rapid differentiation. We therefore conclude, in accordance with other studies, that high-affinity mAb infusion primarily suppresses recruitment of most competing B cells but can increase and expedite affinity maturation of certain epitope-specific B cells.

Barriers to early diagnosis and management of oral cancer in Latin America and the Caribbean.

OBJECTIVE: This study aimed to explore perceived barriers to early diagnosis and management of oral cancer, as well as potential pathways for improvement in Latin America and the Caribbean (LAC). METHODS: This cross-sectional study used a self-administered online questionnaire created via the Research Electronic Data Capture platform. The survey was distributed to health professionals trained in Oral Medicine, Oral Pathology, Oral and Maxillofacial Surgery, and Dentists with clinical and academic expertise in oral potentially malignant disorder (OPMD) and oral cancer. Data obtained were systematically organized and analyzed descriptively using Microsoft Excel. RESULTS: Twenty-three professionals from 21 LAC countries participated. Major barriers included the limited implementation of OPMD and oral cancer control plans (17.4%), low compulsory reporting for OPMD (8.7%) and oral cancer (34.8%), unclear referral pathways for OPMD (34.8%) and oral cancer (43.5%), and a shortage of trained professionals (8.7%). Participants endorsed the utility of online education (100%) and telemedicine (91.3%). CONCLUSION: The survey highlights major perceived barriers to early diagnosis and management of OPMD and oral cancer in LAC, as well as potential avenues for improvement.

Tibial fractures treated with mono-lateral fixation: Principles of design and application.

This paper presents the outcome of a data review of patients treated with the IOS external fixation system at the Royal Stoke University Hospital: a fixation designed to meet four requirements for external fixation proposed in this paper. Demographic data and outcome were collected and assessed. From 69 initial patients, 64 patients (55 males and 9 females) had an average age of 35.9 years. The mean time to union was 127 days. There were no incidences of malunion, or refracture post fixation removal attributable to the treatment method. In addition, in this cohort, there was no incidence of pin tract infection resulting in osteomyelitis. Of all the factors assessed the only factor to have any significant effect on healing was smoking: an average delay of 31 days. An examination of RUST (radiographic union score tibia) and modified RUST scores illustrated a potential false negative of up to 80%. Hence, this study cannot support the use of either scoring system to diagnose fracture healing. IOS external fixation was shown to be an effective method for the treatment of unstable tibial fractures. The reduction at fixation removal was shown to be very good. There was no incidence of osteomyelitis. It is, therefore, suggested that appropriately used external fixation is a viable alternative to intramedullary nailing if designed and surgically applied using four design principles outlined in this paper. Furthermore, it is proposed that external fixation be designed and applied to meet these four principles.

Perineural injections of incobotulinumtoxin-A for diabetic neuropathic pain of the lower extremities: protocol for a phase II, single-centre, double-blind, randomised, placebo-controlled trial (the PINBOT study).

INTRODUCTION: Diabetic neuropathic pain (DNP) is a debilitating complication affecting 15-20% of people with diabetes and is a predictor of depression, poor sleep and decreased quality of life. Current pharmacological treatments are often insufficient and have significant side-effects. Subcutaneous or intradermal botulinumtoxin-A (BonT-A) is an effective and safe treatment for neuropathic pain but is limited by the need to cover the entire affected area with injections. For large cutaneous areas, infiltration of the sensory nerve supply with BonT-A could provide similar effects, with a single injection. We aim to investigate the safety, efficacy, and effects on quality of life, physical activity, depressive symptoms and activities of daily living of perineural injections of BonT-A in patients with DNP of both lower extremities. METHODS: This study is a double-blind, randomised, placebo-controlled clinical trial. 80 participants with moderate to severe DNP of both legs will be randomised 1:1 to receive injections of either 100 units incobotulinumtoxin-A or a saline placebo around each distal sciatic nerve for two cycles of 12 weeks. Average daily pain scores will be recorded once a day from 1 week prior to the first treatment and through the entire study period. Primary outcomes are differences between groups in daily and weekly mean pain scores. Secondary outcomes are levels of physical activity, depression scores, health-related quality of life, activities of daily living, sensory profiles and motor function, recorded at baseline, 4, 12, 16 and 24 weeks. The use of rescue medication and adverse events will be recorded throughout the study period. ETHICS AND DISSEMINATION: The study is approved by the Danish Committee on Health Research Ethics and the Danish Medicines Agency. EU-Clinical Trial Information System (EU: 2022-500727-68-01), clinicaltrials.gov (ID: NCT05623111). Results will be published in peer-reviewed journals in open-access formats and data made available in anonymised form. TRIAL REGISTRATION NUMBER: NCT05623111.

Effect of Standardized Reminder Calls on Trauma Patient No-Show Rate.

BACKGROUND: Most patients who sustain a traumatic injury require outpatient follow-up. A common barrier to outpatient postadmission care is patient failure to follow-up. One of the most significant factors resulting in failure to follow-up is age more than 35 years. Recent work has shown that follow-up telephone calls reduce readmission rates. Our aim was to decrease no-show appointments by 10% in 12 months. STUDY DESIGN: The electronic medical records at our level I and II trauma centers were queried for all outpatient appointments for trauma between July 1, 2020, and June 9, 2021, and whether the patient attended their follow-up appointment. Patients with visits scheduled after August 1, 2021, received 24- and 48-hour previsit reminder calls. Patients with visits scheduled between July 1, 2020, and August 1, 2021, did not receive previsit calls. Both groups were compared using multivariable direct logistic regression models. RESULTS: A total of 1,822 follow-up opportunities were included in the study. During the pre-implementation phase, there was a no-show rate of 30.9% (329 of 1,064 visits). Postintervention, a 12.2% reduction in overall no-show rate occurred. A statistically significant 11.2% decrease (p < 0.001) was seen in elderly patients. Multivariate analysis showed standardized calls resulted in significantly decreased odds of failing to keep an appointment (adjusted odds ratio = 0.610, p < 0.001). CONCLUSIONS: Reminder calls led to a 12.2% reduction in no-show rate and were an independent predictor of a patient's likelihood of attending their appointment. Other predictors of attendance included insurance status and abdominal injury.

The role of lung ultrasound for detecting atelectasis, consolidation, and/or pneumonia in the adult cardiac surgery population: A scoping review of the literature.

OBJECTIVES: Postoperative pulmonary complications (PPCs) frequently occur after cardiac surgery and may lead to adverse patient outcomes. Traditional diagnostic tools such as auscultation or chest x-ray have inferior diagnostic accuracy compared to the gold standard (chest computed tomography). Lung ultrasound (LUS) is an emerging area of research combating these issues. However, no review has employed a formal search strategy to examine the role of LUS in identifying the specific PPCs of atelectasis, consolidation, and/or pneumonia or investigated the ability of LUS to predict these complications in this cohort. The objective of this study was to collate and present evidence for the use of LUS in the adult cardiac surgery population to specifically identify atelectasis, consolidation, and/or pneumonia. REVIEW METHOD USED: A scoping review of the literature was completed using predefined search terms across six databases which identified 1432 articles. One additional article was included from reviewing reference lists. Six articles met the inclusion criteria, providing sufficient data for the final analysis. DATA SOURCES: Six databases were searched: MEDLINE, Embase, CINAHL, Scopus, CENTRAL, and PEDro. This review was not registered. REVIEW METHODS: The review followed the PRISMA Extension for Scoping Reviews. RESULTS: Several LUS methodologies were reported across studies. Overall, LUS outperformed all other included bedside diagnostic tools, with superior diagnostic accuracy in identifying atelectasis, consolidation, and/or pneumonia. Incidences of PPCs tended to increase with each subsequent timepoint after surgery and were better identified with LUS than all other assessments. A change in diagnosis occurred at a rate of 67% with the inclusion of LUS and transthoracic echocardiography in one study. Pre-established assessment scores were improved by substituting chest x-rays with LUS scans. CONCLUSION: The results of this scoping review support the use of LUS as a diagnostic tool after cardiac surgery; however, they also highlighted a lack of consistent methodologies used. Future research is required to determine the optimal methodology for LUS in diagnosing PPCs in this cohort and to determine whether LUS possesses the ability to predict these complications and guide proactive respiratory supports after extubation.

Emergency Department and Inpatient Utilization Reductions and Cost Savings Associated With Trauma Center Mental Health Intervention: Results From a 5-year Longitudinal Randomized Clinical Trial Analysis.

OBJECTIVE: To identify and refer patients at high risk for the psychological sequelae of traumatic injury, the American College of Surgeons Committee on Trauma now requires that trauma centers have in-place protocols. No investigations have documented reductions in utilization and associated potential cost savings associated with trauma center mental health interventions. BACKGROUND: The investigation was a randomized clinical trial analysis that incorporated novel 5-year emergency department (ED)/inpatient health service utilization follow-up data. METHODS: Patients were randomized to a mental health intervention, targeting the psychological sequelae of traumatic injury (n = 85) versus enhanced usual care control (n = 86) conditions. The intervention included case management that coordinated trauma center-to-community care linkages, psychotropic medication consultation, and psychotherapy elements. Mixed model regression was used to assess intervention and control group utilization differences over time. An economic analysis was also conducted. RESULTS: Over the course of the 5-year intervention, patients demonstrated significant reductions in ED/inpatient utilization when compared with control patients [ F (19,3210) = 2.23, P = 0.009]. Intervention utilization reductions were greatest at 3 to 6 months (intervention 15.5% vs control 26.7%, relative risk = 0.58, 95% CI: 0.34, 1.00) and 12 to 15 months (intervention 16.5% vs control 30.6%, relative risk = 0.54, 95% CI: 0.32, 0.91) postinjury time points. The economic analysis suggested potential intervention cost savings. CONCLUSIONS: Mental health intervention is associated with significant reductions in ED and inpatient utilization, as well as potential cost savings. These findings could be productively integrated into future American College of Surgeons Committee on Trauma policy discussions.

Measuring lipoprotein(a) for cardiovascular disease prevention - in whom and when?

PURPOSE OF REVIEW: The aim of this study is to summarize major cardiovascular guideline recommendations on lipoprotein(a) and highlighting recent findings that emphasize how measuring lipoprotein(a) once in all adults is meaningful regardless of age, sex, comorbidities, or ethnicity. RECENT FINDINGS: Many international guidelines now recommend once in a lifetime measurement of lipoprotein(a) in all adult individuals to facilitate accurate risk prediction. Lipoprotein(a)-lowering therapy to reduce cardiovascular disease is on the horizon, with results from the first phase 3 trial expected in 2025. SUMMARY: Elevated lipoprotein(a) is an independent causal risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis and measuring lipoprotein(a) once in all individuals regardless of age, sex, comorbidities, or ethnicity is meaningful to aid in risk stratification.

Lipoprotein(a) and Risks of Peripheral Artery Disease, Abdominal Aortic Aneurysm, and Major Adverse Limb Events.

BACKGROUND: Lp(a) (lipoprotein[a])-lowering therapy to reduce cardiovascular disease is under investigation in phase 3 clinical trials. High Lp(a) may be implicated in peripheral artery disease (PAD), abdominal aortic aneurysms (AAAs), and major adverse limb events (MALE). OBJECTIVES: The authors investigated the association of high Lp(a) levels and corresponding LPA genotypes with risk of PAD, AAA, and MALE. METHODS: The authors included 108,146 individuals from the Copenhagen General Population Study. During follow-up, 2,450 developed PAD, and 1,251 AAAs. Risk of MALE was assessed in individuals with PAD at baseline and replicated in the Copenhagen City Heart Study. RESULTS: Higher Lp(a) was associated with a stepwise increase in risk of PAD and AAA (P for trend <0.001). For individuals with Lp(a) levels ≥99th (≥143 mg/dL, ≥307 nmol/L) vs <50th percentile (≤9 mg/dL, ≤17 nmol/L), multivariable-adjusted HRs were 2.99 (95% CI: 2.09-4.30) for PAD and 2.22 (95% CI: 1.21-4.07) for AAA. For individuals with PAD, the corresponding incidence rate ratio for MALE was 3.04 (95% CI: 1.55-5.98). Per 50 mg/dL (105 nmol/L) genetically higher Lp(a) risk ratios were 1.39 (95% CI: 1.24-1.56) for PAD and 1.21 (95% CI: 1.01-1.44) for AAA, consistent with observational risk ratios of 1.33 (95% CI: 1.24-1.43) and 1.27 (95% CI: 1.15-1.41), respectively. In women smokers aged 70 to 79 years with Lp(a) <50th and ≥99th percentile, absolute 10-year risks of PAD were 8% and 21%, and equivalent risks in men 11% and 29%, respectively. For AAA, corresponding risks were 2% and 4% in women, and 5% and 12% in men. CONCLUSIONS: High Lp(a) levels increased risk of PAD, AAA, and MALE by 2- to 3-fold in the general population, opening opportunities for prevention given future Lp(a)-lowering therapies.

Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer's and Parkinson's diseases.

BACKGROUND: A number of peptide incretin receptor agonists (IRAs) show promise as therapeutics for Alzheimer's disease (AD) and Parkinson's disease (PD). Transport across the blood-brain barrier (BBB) is one way for IRAs to act directly within the brain. To determine which IRAs are high priority candidates for treating these disorders, we have studied their brain uptake pharmacokinetics. METHODS: We quantitatively measure the ability of four IRAs to cross the BBB. We injected adult male CD-1 mice intravenously with 125I- or 14C-labeled albiglutide, dulaglutide, DA5-CH, or tirzepatide and used multiple-time regression analyses to measure brain kinetics up to 1 hour. For those IRAs failing to enter the brain 1 h after intravenous injection, we also investigated their ability to enter over a longer time frame (i.e., 6 h). RESULTS: Albiglutide and dulaglutide had the fastest brain uptake rates within 1 hour. DA5-CH appears to enter the brain rapidly, reaching equilibrium quickly. Tirzepatide does not appear to cross the BBB within 1 h after iv injection but like albumin, did so slowly over 6 h, presumably via the extracellular pathways. CONCLUSIONS: We find that IRAs can cross the BBB by two separate processes; one that is fast and one that is slow. Three of the four IRAs investigated here have fast rates of transport and should be taken into consideration for testing as AD and PD therapeutics as they would have the ability to act quickly and directly on the brain as a whole.

No difference in patient reported outcome and inflammatory response after coated and uncoated total knee arthroplasty - a randomized controlled study.

BACKGROUND: Allergies against implant materials are still not fully understood. Despite controversies about its relevance, some patients need treatment with hypoallergenic implants. This study compared coated and standard total knee arthroplasty (TKA) regarding inflammatory response and patient-reported outcome measures (PROMs). METHODS: 76 patients without self-reported allergies against implant materials were included in a RCT and received a coated or standard TKA of the same cemented posterior-stabilized knee system. 73 patients completed the 3-year follow-up. Two patients died and there was one revision surgery. Serum levels of cytokines with a possible role in implant allergy were measured in patient`s serum (IL-1beta, IL-5, IL-6, IL-8, IL-10, IFN γ, TNF α) prior to, one and three years after surgery. Furthermore, PROMs including knee function (Oxford Knee Score, Knee Society Score) and health-related quality of life (QoL, EuroQuol questionnaire) were assessed. Additionally, 8 patients with patch-test proven skin allergy against implant materials who received the coated implant were assessed similarly and compared to a matched-pair group receiving the same implant. RESULTS: There were no differences in function and QoL between the assessed groups at any follow-up. The majority of patients demonstrated no elevation of the measured blood cytokines. Cytokine patterns showed no differences between study groups at any follow-up. The allergy patients demonstrated slower functional improvement and minor differences in cytokine pattern. Yet these results were not significant. There were no differences in the matched-pair analysis. CONCLUSION: We observed no relevant increase in serum cytokine levels in any group. The inflammatory response measured seems limited, even in allergy patients. Furthermore, there were no differences between coated and standard TKA in non-allergy patients in the 3-year Follow-Up period. TRIAL REGISTRATION: The study protocol was registered in the US National Institutes of Health's database ( http://www. CLINICALTRIALS: gov ) registry under NCT03424174 on 03/17/2016.

Decline in HbA1c during the first year of elexacaftor/tezacaftor/ivacaftor treatment in the Danish cystic fibrosis cohort: Short title: Decline in HbA1c after elexacaftor/tezacaftor/ivacaftor treatment.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved the clinical status of individuals with cystic fibrosis (CF), however, whether ETI impacts glucose tolerance remains unknown. We aimed to study the change in glycated hemoglobin (HbA1c) and CF related diabetes (CFRD) status after initiation of ETI. METHODS: We included individuals ≥12 years treated with ETI in Denmark in a longitudinal observational study. HbA1c was measured at baseline, 3, 6, 9 and 12 months after treatment initiation. Change in HbA1c was assessed in mixed models adjusted for age, sex, glucose tolerance and prior CFTR modulator treatment. In a sub-population with CFRD, we assessed the change in insulin usage, hypoglycemic events and the 30-day continuous glucose monitoring (CGM) parameters (i.e., average blood glucose, time below (≤3.9 mM) and above (>10.0 mM) normal range, and the variation in glucose) after 12 months of treatment. RESULTS: Among 321 individuals with CF, HbA1c declined by 2.1 mmol/mol [95 % confidence interval (CI): -2.6; -1.5 mmol/mol] after 3 months and by 2.3 mmol/mol [95 %CI: -2.8; -1.9 mmol/mol] after 12 months of ETI treatment. The decline was independent of glucose tolerance status at baseline. In 26 individuals with CFRD at baseline, the mean decline in HbA1c was 3.6 mmol/mol [95 %CI: -6.9; -0.4 mmol/mol] after 12 months, but we did not observe any change in insulin usage, weekly number of hypoglycemic events or CGM parameters. CONCLUSION: In the Danish CF cohort, HbA1c declined over 12 months of ETI treatment, however, among a subset with CFRD, we observed no change in insulin usage and CGM glucose levels.

Evolutionary history of Castanea sativa in the Caucasus driven by Middle and Late Pleistocene paleoenvironmental changes.

Due to global climate cooling and aridification since the Paleogene, members of the Neogene flora were extirpated from the Northern Hemisphere or were confined to a few refugial areas. For some species, the final reduction/extinction came in the Pleistocene, but some others have survived climatic transformations up to the present. This has occurred in Castanea sativa, a species of high commercial value in Europe and a significant component of the Caucasian forests' biodiversity. In contrast to the European range, neither the historical biogeography nor the population genetic structure of the species in its isolated Caucasian range has been clarified. Here, based on a survey of 21 natural populations from the Caucasus and a single one from Europe, we provide a likely biogeographic reconstruction and genetic diversity details. By applying Bayesian inference, species distribution modelling and fossil pollen data, we estimated (i) the time of the Caucasian-European divergence during the Middle Pleistocene, (ii) the time of divergence among Caucasian lineages and (iii) outlined the glacial refugia for species. The climate changes related to the Early-Middle Pleistocene Transition are proposed as the major drivers of the intraspecific divergence and European-Caucasian disjunction for the species, while the impact of the last glacial cycle was of marginal importance.

Cardiac arrhythmia and hypoglycaemia in patients receiving haemodialysis with and without diabetes (the CADDY study): protocol for a Danish multicentre cohort study.

INTRODUCTION: Patients receiving haemodialysis are at increased risk of arrhythmias and sudden cardiac death, but data on arrhythmia burden and the pathophysiology remain limited. Among potential risk factors, hypoglycaemia is proposed as a possible trigger of lethal arrhythmias. The development of implantable loop recorders (ILR) and continuous glucose monitoring (CGM) enables long-term continuous ECG and glycaemic monitoring. The current article presents the protocol of a study aiming to increase the understanding of arrhythmias and risk factors in patients receiving haemodialysis. The findings will provide a detailed exploration of the burden and nature of arrhythmias in these patients including the potential association between hypoglycaemia and arrhythmias. METHODS AND ANALYSIS: The study is an investigator-initiated, prospective, multicentre cohort study recruiting 70 patients receiving haemodialysis: 35 with diabetes and 35 without diabetes. Participants are monitored with ILRs and CGM for 18 months follow-up. Data collection further includes a monthly collection of predialysis blood samples and dialysis parameters. The primary outcome is the presence of clinically significant arrhythmias defined as a composite of bradycardia, ventricular tachycardia, or ventricular fibrillation. Secondary outcomes include the characterisation of clinically significant arrhythmias and other arrhythmias, glycaemic characteristics, and mortality. The data analyses include an assessment of the association between arrhythmias and hypoglycaemia and hyperglycaemia, baseline clinical variables, and parameters related to kidney failure and the haemodialysis procedure. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the Capital Region of Denmark (H-20069767). The findings will be presented at national and international congresses as well as in international peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT04841304.

Clinicopathologic Profile and Psychosocial Experiences of Nigerian Breast Cancer Survivors.

PURPOSE: Breast cancer survivors are a distinct category of patients with unique characteristics and needs. The population of survivors is expected to increase, given the rising incidence of breast cancer in Nigeria, and the improvements in breast cancer outcomes. This study evaluated the clinicopathologic characteristics and the psychosocial experiences of a cohort of Nigerian breast cancer survivors. METHODS: From an institutional breast cancer database, patients managed between January 2010 and December 2016 were evaluated. Clinicopathologic characteristics, treatment details, and survival estimates were assessed. These were compared with nonsurvivors managed during the same period. Survivors were defined as those who have been alive for at least 5 years from the date of presentation. Qualitatively, a purposive sample of 20 survivors was evaluated using one-on-one in-depth interviews to assess their experiences and coping mechanisms after treatment. RESULTS: Of the 355 patients in the database during the study period, there were 163 survivors (45.9%), while 192 (54.1%) died. Age, stage at presentation, tumor size, and receipt of multiple treatment modalities were significantly associated with survival. Five themes were identified in qualitative analysis: initial reaction to the diagnosis, experiences during treatment, social support, coping strategies, and advocacy. Strong family support and spirituality were prominent coping strategies identified in this cohort. CONCLUSION: Despite obvious infrastructural and manpower limitations, Nigerian patients who present early and receive multimodal therapy and different breast cancer treatments have better odds of survival. Survivors have some unmet psychosocial and physical needs requiring intervention.

Characterization of impaired beta and alpha cell function in response to an oral glucose challenge in cystic fibrosis: a cross-sectional study.

Aims: The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment. Methods: Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI). Results: Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia. Conclusions: The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response.

Co-creating active communities: processes and outcomes of linking public rehabilitation programs with civic engagement for active living in a Danish municipality.

BACKGROUND: Increased levels of physical activity are associated with beneficial health effects for people with type 2 diabetes, cardiovascular disease and/or severe obesity; however, transforming knowledge about these effects into action is challenging. The aim of this paper is to explore lessons learnt from a co-creation process in a partnership project involving local stakeholders, including citizens, and researchers. The purpose of the process was to link a public health care institution with civil society organisations in the local community to make it possible for citizens to continue to be physically active after ending their public rehabilitation. Secondarily, this paper aims to develop a conceptual model of the above process. METHODS: The study constitutes the first part of Project Active Communities and was based on a partnership between three research institutions and a Danish rural municipality, involving municipal and civil society stakeholders and citizens with type 2 diabetes, cardiovascular disease and/or severe obesity in co-creation of concrete interventions for implementation. The co-creation process was divided into two tracks, one involving citizens (two workshops) and one involving municipal and civil society stakeholders (two workshops). The two tracks were concluded with a final workshop involving all stakeholders, including local politicians. Data sources are focus groups and bilateral meetings, workshop observations, and questionnaires. RESULTS: Lessons learnt include the importance of having a flexible timeframe for the co-creation process; giving room for disagreements and matching of mutual expectations between stakeholders; the value of a coordinator in the municipality to achieve acceptance of the project; and the significance of engaging local politicians in the co-creation process to accommodate internal political agendas. We have developed a conceptual model for a co-creation process, where we outline and explain three distinct phases: stakeholder identification and description, co-creation, and prototyping. The model can be adapted and applied to other sectors and settings. CONCLUSIONS: This study documents lessons learnt in a co-creation process aiming to link a public health care institution with civil society organisations in the local community. Further, this study has specified productive co-creative processes and documented the various phases in a conceptual model.

It is well known that physical activity has health benefits for people with chronic diseases. In this study, our aim was to explore lessons learnt from a co-creation process and develop a model for others to apply. The study was based on a partnership between three research institutions and a Danish rural municipality, involving municipal and civil society stakeholders and citizens with type 2 diabetes, cardiovascular disease and/or severe obesity. During the study, the above-mentioned stakeholders were invited to five workshops, where interventions for linking a public health care institution and civil society organisations were co-created. The five co-creation workshops led to the identification of four interventions, linking public health care institutions and civil society organisations. Lessons learnt from this project, which can be used by others who wish to design and conduct a co-creative process with diverse stakeholders, include: the importance of having a flexible timeframe for the co-creation process, as delays can easily occur in the unpredictable process of co-creation giving room for disagreements and matching of mutual expectations between stakeholders, as a common understanding of each stakeholder's motives is important for the success of the project the importance and value of a coordinator in the municipality to achieve acceptance of the project the significance of engaging local politicians in the co-creation process to take internal political agendas into consideration. We conclude by identifying three phases­a stakeholder, a co-creation, and a prototyping phase­in a model for co-creation that may be adapted and used by others.

Ligand-independent signaling and migration of breast cancer cells expressing membrane androgen receptor, ZIP9 (SLC39A9).

Zinc transporter ZIP9 is also a membrane androgen receptor that mediates androgen-dependent zinc and G-protein signaling to modulate tumorigenic responses in cancer cells. It is unclear whether unliganded ZIP9 causes similar responses. ZIP9 overexpression in MDA-MB-231 breast cancer cells (ZIP9 cells) increased zinc levels and cell migration/invasion which was mimicked with a zinc ionophore and attenuated with a zinc chelator, suggesting these tumorigenic responses are zinc-dependent. Expression of migration markers MYL9 and CYR61 was elevated in ZIP9 cells and further increased together with cell migration by forskolin treatment and blocked with H-89, indicating they are mediated through an AC/PKA pathway. Knockdown of ZIP9 expression in MDA-MB-468 cells decreased cell migration/invasion, migration markers and zinc levels, confirming similar roles of unliganded ZIP9 in another breast cancer cell line. Testosterone treatment further increased migration, biomarker expression and zinc in ZIP9 cells, suggesting it may act through similar pathways to induce tumorigenic responses.