The alarms should no longer be ignored: survey of the demand, capacity and provision of adult community eating disorder services in England and Scotland before COVID-19.

AIMS/METHOD: This national pre-pandemic survey compared demand and capacity of adult community eating disorder services (ACEDS) with NHS England (NHSE) commissioning guidance. RESULTS: Thirteen services in England and Scotland responded (covering 10.7 million population). Between 2016-2017 and 2019-2020 mean referral rates increased by 18.8%, from 378 to 449/million population. Only 3.7% of referrals were from child and adolescent eating disorder services (CEDS-CYP), but 46% of patients were aged 18-25 and 54% were aged >25. Most ACEDS had waiting lists and rationed access. Many could not provide full medical monitoring, adapt treatment for comorbidities, offer assertive outreach or provide seamless transitions. For patient volume, the ACEDS workforce budget was 15%, compared with the NHSE workforce calculator recommendations for CEDS-CYP. Parity required £7 million investment/million population for the ACEDS. CLINICAL IMPLICATIONS: This study highlights the severe pressure in ACEDS, which has increased since the COVID-19 pandemic. Substantial investment is required to ensure NHS ACEDS meet national guidance, offer evidence-based treatment, reduce risk and preventable deaths, and achieve parity with CEDS-CYP.

A UK nationwide study of adults admitted to hospital with diabetic ketoacidosis or hyperosmolar hyperglycaemic state and COVID-19.

AIMS: To investigate characteristics of people hospitalized with coronavirus-disease-2019 (COVID-19) and diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS), and to identify risk factors for mortality and intensive care admission. MATERIALS AND METHODS: Retrospective cohort study with anonymized data from the Association of British Clinical Diabetologists nationwide audit of hospital admissions with COVID-19 and diabetes, from start of pandemic to November 2021. The primary outcome was inpatient mortality. DKA and HHS were adjudicated against national criteria. Age-adjusted odds ratios were calculated using logistic regression. RESULTS: In total, 85 confirmed DKA cases, and 20 HHS, occurred among 4073 people (211 type 1 diabetes, 3748 type 2 diabetes, 114 unknown type) hospitalized with COVID-19. Mean (SD) age was 60 (18.2) years in DKA and 74 (11.8) years in HHS (p < .001). A higher proportion of patients with HHS than with DKA were of non-White ethnicity (71.4% vs 39.0% p = .038). Mortality in DKA was 36.8% (n = 57) and 3.8% (n = 26) in type 2 and type 1 diabetes respectively. Among people with type 2 diabetes and DKA, mortality was lower in insulin users compared with non-users [21.4% vs. 52.2%; age-adjusted odds ratio 0.13 (95% CI 0.03-0.60)]. Crude mortality was lower in DKA than HHS (25.9% vs. 65.0%, p = .001) and in statin users versus non-users (36.4% vs. 100%; p = .035) but these were not statistically significant after age adjustment. CONCLUSIONS: Hospitalization with COVID-19 and adjudicated DKA is four times more common than HHS but both associate with substantial mortality. There is a strong association of previous insulin therapy with survival in type 2 diabetes-associated DKA.

Psychological predictors of health anxiety and pain in ambulatory presentations in a hospital emergency department.

BACKGROUND: Health anxiety in attendees of out-patient medical clinics is well established; however, there has been a lack of research into health anxiety within emergency settings. AIMS: This study explored the prevalence of health anxiety in ambulatory presentations in a tertiary emergency department (ED) as well as the factors associated with pain and health anxiety in this setting. METHOD: A cross-sectional questionnaire design was used to gather data from adult ED ambulatory attendees across a 4-day sampling period to assess psychological and physical health variables. Number of attendances to ED over the previous 12 months was accessed through healthcare records. RESULTS: Of the final sample (n = 106), 77% were white British, 54% were male, and 14% presented with severe health anxiety as measured by the Short Health Anxiety Inventory (≥18). Participants with pre-existing health conditions had significantly higher levels of health anxiety (M = 12.36, SE = 1.59) compared with those without (M = 7.79, SE = 0.66). Stepwise multiple regression analyses identified anxiety sensitivity and pain catastrophizing as significant independent predictors of health anxiety, explaining 51% of the variance in health anxiety. Pain catastrophizing was also a significant independent predictor of pain level, accounting for 20% of the variance. CONCLUSION: This study provides insight into the prevalence of health anxiety in ED ambulatory presentations and key psychological predictors of health anxiety and pain. This has implications for treatment in an ED setting whereby patients may benefit from referral to medical psychology or mental health services.

Association Between SGLT2 Inhibitor Treatment and Diabetic Ketoacidosis and Mortality in People With Type 2 Diabetes Admitted to Hospital With COVID-19.

OBJECTIVE: To determine the association between prescription of SGLT2 inhibitors (SGLT2is) and diabetic ketoacidosis (DKA) incidence or mortality in people with type 2 diabetes (T2D) hospitalized with COVID-19. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study based on secondary analysis of data from a large nationwide audit from a network of 40 centers in the U.K. with data collection up to December 2020. The study was originally designed to describe risk factors associated with adverse outcomes among people with diabetes who were admitted to hospital with COVID-19. The primary outcome for this analysis was DKA on or during hospital admission. The secondary outcome was mortality. Crude, age-sex adjusted, and multivariable logistic regression models were used to generate odds ratios (ORs) and 95% CIs for people prescribed SGLT2i compared with those not prescribed SGLT2i. RESULTS: The original national audit included 3,067 people with T2D who were admitted to hospital with COVID-19, of whom 230 (7.5%) were prescribed SGLT2is prior to hospital admission. The mean age of the overall cohort was 72 years, 62.3% were men, and 34.9% were prescribed insulin. Overall, 2.8% of the total population had DKA and 35.6% of people in the study died. The adjusted odds of DKA were not significantly different between those prescribed SGLT2is and those not (OR 0.56; 95% CI 0.16-1.97). The adjusted odds of mortality associated with SGLT2is were similar in the total study population (OR 1.13; 95% CI 0.78-1.63), in the subgroup prescribed insulin (OR 1.02; 95% CI 0.59-1.77), and in the subgroup that developed DKA (OR 0.21; 95% CI 0.01-8.76). CONCLUSIONS: We demonstrate a low risk of DKA and high mortality rate in people with T2D admitted to hospital with COVID-19 and limited power, but no evidence, of increased risk of DKA or in-hospital mortality associated with prescription of SGLT2is.

Association of statin and/or renin-angiotensin-aldosterone system modulating therapy with mortality in adults with diabetes admitted to hospital with COVID-19: A retrospective multicentre European study.

BACKGROUND & AIMS: To assess the impact of pre-admission renin-angiotensin-aldosterone system inhibitor (RAASi) and statin use on mortality following COVID-19 hospitalization in adults with pre-existing diabetes. METHODS: Retrospective cohort study of adults with diabetes admitted to ninety-nine participating hospitals in the United Kingdom, France and Spain during the first wave of the COVID-19 pandemic. Logistic regression models adjusted for demographic factors and comorbidity were used to describe associations with mortality in hospital or within 28 days of admission and individual or combined RAASi and statin therapy prescription followed by a country level meta-analysis. RESULTS: Complete data were available for 3474 (42.6%) individuals. Prescribing patterns varied by country: 25-50% neither RAASi nor statin therapy, 14-36% both RAASi and statin therapy, 9-24% RAASi therapy alone, 12-36% statin alone. Overall, 20-37% of patients died within 28 days. Meta-analysis found no evidence of an association between mortality and prescription of RAASi therapy (OR 1.09, CI 0.78-1.52 (I2 22.2%)), statin (OR 0.97, CI 0.59-1.61 (I2 72.9%)) or both (OR 1.14, CI 0.67-1.92 (I2 78.3%)) compared to those prescribed neither drug class. CONCLUSIONS: This large multicentre, multinational study found no evidence of an association between mortality from COVID-19 infection in people with diabetes and use of either RAASi, statin or combination therapy. This provides reassurance that clinicians should not change their RAASi and statin therapy prescribing practice in people with diabetes during the COVID-19 pandemic.

Bridging Allied Health Professional Roles to Improve Patient Outcomes in Rural and Remote Australia: A Descriptive Qualitative Study.

Purpose: Australia's rural and remote populations experience inequality of access to healthcare, with demand exceeding capacity for delivery of health services, often due to a maldistribution of the health workforce. A strategy which may overcome barriers to accessing adequate healthcare includes implementation of interdisciplinary collaborative teams, identified as a successful method of healthcare delivery. This study thus aimed to explore interdisciplinary allied health collaborative practice in a rural community. Methods: Role theory, as a philosophical perspective, was used to explore role perceptions and the potential for interdisciplinary collaboration between pharmacists and allied health professionals including dieticians/public health nutritionists, speech pathologists, occupational therapists, and physiotherapists, by conducting 29 interviews in a rural community. All interviews were transcribed verbatim, coded, and categorised into emerging themes. Results: Five constructs of role theory were used to describe the data: role identity, role overload, role sufficiency, role conflict, and role ambiguity. Participants identified as rural generalists and health promoters, who work within innovative and adaptive healthcare settings. Role overload was reported as considerable due to high demand for services and a lack of resources in rural and remote regions, resulting in poor role sufficiency. Overall, there was a low level of role conflict, and participants were highly in favor of interprofessional collaboration; however, uncertainty of the pharmacist's role (role ambiguity) was a major barrier identified. Health professionals with more years in practice provided few examples of how they would utilise a pharmacist in their practice, although these gave valuable insight into the potential integration of a pharmacist into an interdisciplinary health team, with allied health professionals. Conclusion: This study has applied role theory providing a greater understanding of the enablers and barriers of pharmacists working within interdisciplinary allied health teams and highlighting opportunities to bridge interprofessional roles to improve patient outcomes, especially in rural and remote communities.

"It's Been Ugly": A Large-Scale Qualitative Study into the Difficulties Frontline Doctors Faced across Two Waves of the COVID-19 Pandemic.

This study aimed to gain an uncensored insight into the most difficult aspects of working as a frontline doctor across successive COVID-19 pandemic waves. Data collected by the parent study (CERA) was analysed using conventional content analysis. Participants comprised frontline doctors who worked in emergency, anaesthetic, and intensive care medicine in the UK and Ireland during the COVID-19 pandemic (n = 1379). All seniority levels were represented, 42.8% of the sample were male, and 69.2% were white. Four themes were identified with nine respective categories (in parentheses): (1) I'm not a COVID hero, I'm COVID cannon fodder (exposed and unprotected, "a kick in the teeth"); (2) the relentlessness and pervasiveness of COVID ("no respite", "shifting sands"); (3) the ugly truths of the frontline ("inhumane" care, complex team dynamics); (4) an overwhelmed system exacerbated by COVID (overstretched and under-resourced, constant changes and uncertainty, the added hinderance of infection control measures). Findings reflect the multifaceted challenges faced after successive pandemic waves; basic wellbeing needs continue to be neglected and the emotional impact is further pronounced. Steps are necessary to mitigate the repeated trauma exposure of frontline doctors as COVID-19 becomes endemic and health services attempt to recover with inevitable long-term sequelae.

Anxiety, confidence and self-concept in adults with and without developmental coordination disorder.

BACKGROUND: Previous research suggests that adults with Developmental Coordination Disorder (DCD) report lower general wellbeing and higher general anxiety levels than typically developing (TD) adults. AIMS: To examine and explore relationships between anxiety and confidence (self-efficacy and resilience) generally and in a movement-specific context, along with self-concept among adults with DCD and TD adults. METHODS: 74 adults with diagnosed DCD, 26 adults with suspected DCD and 79 TD adults (18-60 years) completed an online questionnaire composed of a mixture of existent psychometric measures and novel scales. RESULTS: General and movement-specific anxiety, self-efficacy and general resilience were all poorer in adults with diagnosed and suspected DCD compared to TD adults. Higher resilience was related to higher self-efficacy and lower anxiety in adults with DCD. Individuals with suspected DCD for whom motor skills difficulties were an important aspect of their self-concept had lower movement-specific self-efficacy. CONCLUSIONS: Interventions to improve the psychosocial wellbeing of adults with DCD should include a focus on lowering anxiety and building self-efficacy and resilience, with particular attention to movement-related domains. IMPLICATIONS: This would facilitate the effective development of strategies to manage motor skills difficulties and their impact on everyday life for adults with DCD.

Vessel diameter and close surveillance helps predict early patency in native arteriovenous fistulas.

INTRODUCTION: Arteriovenous fistulas are the preferred method of vascular access for haemodialysis. Data suggests patency rates can be low and may be related to vessel diameters prior to creation. We use specific size criteria for fistula selection. We aimed to establish patency rates in relation to vessel size and whether other factors affect fistula patency. METHODS: Consecutive patients undergoing radiocephalic (RCF) or brachiocephalic (BCF) creation between 2016 and 2018 were analysed. Preoperative arterial and venous diameters were collected. Six-week and six-month primary and secondary patency rates were analysed to establish any impact of vessel size on patency and re-intervention rates between groups. A univariate analysis was performed. RESULTS: Ninety four RCFs and 101 BCFs were created. Median artery and vein size for RCF were 2.7 and 3.0 mm respectively. For BCF, they were 4.6 and 4.3 mm respectively. At 6-weeks, overall satisfactory patency for RCF and BCF combined was 91.8%. 89.7% demonstrated primary patency; 2.1% secondary patency. At 6-months, overall patency was 78.7%; 58.5% demonstrated primary patency, 20.2% secondary patency. A univariate analysis, for both groups, revealed vein size was a significant predictor of overall satisfactory patency at 6-weeks, with larger veins more likely to remain patent (p = 0.025 RCF, p = 0.007 BCF). However, artery size was not predictive (p = 0.1 RCF, p = 0.5 BCF). At 6-months, neither artery nor vein diameter were predictive in either group. When comparing size of vessel based on fistula type, vessels used to create RCFs were smaller than those for BCFs (p < 0.001). RCFs were more likely to receive endovascular intervention or occlude when compared to BCFs (p = 0.014). DISCUSSION: Excellent patency and maturation rates can be achieved using fairly strict vessel size criteria. Vein size might be the more important predictor of early success. RCFs can be challenging due to smaller vessels, but maturation rates can be optimised by close surveillance and aggressive re-intervention.

The COVID-19 Clinician Cohort (CoCCo) Study: Empirically Grounded Recommendations for Forward-Facing Psychological Care of Frontline Doctors.

This study aimed to develop empirically grounded recommendations and a coherent model of psychological care derived from the experiences and psychological care needs of COVID-19 frontline doctors, using semi-structured interviews and thematic analysis. Participants were UK frontline doctors specialising in Emergency Medicine, Anaesthetics, or Intensive Care (n = 31) purposively sampled for maximum variation on gender, specialty, ethnicity, and trauma-related distress; most worked in ICU during the pandemic (71%). Four themes were derived: (1) 'coping strategies', participants used many, including exercise, mindfulness, and "wait until it gets really bad"; (2) 'sources of support', participants valued embedded psychological support, digital services, and informal conversations with colleagues or family, though there was little opportunity; (3) 'organisational influences on wellbeing', participants reported a love-hate relationship for concepts like 'wellbeing', seen as important but insulting when basic workplace needs were unmet; (4) 'improving engagement with support', analysis suggests we must reduce physical and psychological barriers to access and encourage leaders to model psychologically supportive behaviours. Doctors' frontline COVID-19 working experiences shine a 'spotlight' on pre-existing problems such as lack of physical resources and access to psychological care. Empirically grounded recommendations and a model of incremental psychological care are presented for use in clinical services.

A UK nationwide study of people with type 1 diabetes admitted to hospital with COVID-19 infection.

AIMS/HYPOTHESIS: The aim of this work was to describe the clinical characteristics of adults with type 1 diabetes admitted to hospital and the risk factors associated with severe coronavirus disease-2019 (COVID-19) in the UK. METHODS: A retrospective cohort study was performed using data collected through a nationwide audit of people admitted to hospital with diabetes and COVID-19, conducted by the Association of British Clinical Diabetologists from March to October 2020. Prespecified demographic, clinical, medication and laboratory data were collected from the electronic and paper medical record systems of the participating hospitals by local clinicians. The primary outcome of the study, severe COVID-19, was defined as death in hospital and/or admission to the adult intensive care unit (AICU). Logistic regression models were used to generate age-adjusted ORs. RESULTS: Forty UK centres submitted data. The final dataset included 196 adults who were admitted to hospital and had both type 1 diabetes and COVID-19 on admission (male sex 55%, white 70%, with mean [SD] age 62 [19] years, BMI 28.3 [7.3] kg/m2 and last recorded HbA1c 76 [31] mmol/mol [9.1 (5.0)%]). The prevalence of pre-existing microvascular disease and macrovascular disease was 56% and 39%, respectively. The prevalence of diabetic ketoacidosis on admission was 29%. A total of 68 patients (35%) died or were admitted to AICU. The proportions of people that died were 7%, 38% and 38% of those aged <55, 55-74 and ≥75 years, respectively. BMI, serum creatinine levels and having one or more microvascular complications were positively associated with the primary outcome after adjusting for age. CONCLUSIONS/INTERPRETATION: In people with type 1 diabetes and COVID-19 who were admitted to hospital in the UK, higher BMI, poorer renal function and presence of microvascular complications were associated with greater risk of death and/or admission to AICU. Risk of severe COVID-19 is reassuringly very low in people with type 1 diabetes who are under 55 years of age without microvascular or macrovascular disease. IN PEOPLE WITH TYPE 1 DIABETES AND COVID-19 ADMITTED TO HOSPITAL IN THE UK, BMI AND ONE OR MORE MICROVASCULAR COMPLICATIONS HAD A POSITIVE ASSOCIATION AND LOW SERUM CREATINE LEVELS HAD A NEGATIVE ASSOCIATION WITH DEATH/ADMISSION TO INTENSIVE CARE UNIT AFTER ADJUSTING FOR AGE.

Cannabis and Cigarette Use Before and After Living Kidney Donation.

BACKGROUND: It is unclear whether kidney donation leads to lifestyle changes in terms of cannabis and cigarette use. OBJECTIVE: To describe cigarette and cannabis use before and after kidney donation and to determine their associations with lifestyle and clinical factors. DESIGN: Retrospective cohort study. SETTING: The Living Kidney Donor program in the Champlain Local Health Integration Network at The Ottawa Hospital in Ottawa, Canada. PATIENTS: The study included 178 living kidney donors who donated between January 2009 and December 2018. MEASUREMENTS: Donors were screened for cannabis and cigarette use by telephone interview. Their clinical characteristics and changes in kidney function before and after donation were recorded. METHODS: Cannabis and cigarette use before and after kidney donation were compared using chi-square test. Risk factors associated with their use was examined by univariate and multivariate logistic regression. Wilcoxon rank sum test was used to examine the association of cannabis and Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) estimated glomerular filtration rate (eGFR) at donation and at last follow-up. T-test was used to examine the association of cigarette smoking and CKD-EPI eGFR at donation and at last follow-up. RESULTS: Among 305 donors, 262 met inclusion criteria and 178 participated (mean of 4.7 ± 2.9 years from kidney donation). Cannabis and cigarette use were reported by 5% (9 of 178) and 13% (23 of 178) at donation. After donation, 8% (14 of 178) and 5% (9 of 178) started cannabis and cigarettes, respectively; 74% (17 of 23) of smokers remained smokers after donation and 88% (53 of 60) who quit smoking before donation did not restart after donation. In multivariate analysis, non-married/common-in-law status was associated with cannabis use (odds ratio, 2.73; 95% confidence interval, 1.05-7.11; P = .04). There was no difference in eGFR pre- or post-donation among cannabis or cigarette users. LIMITATIONS: The single-center study design limits generalizability. Social desirability bias may have affected survey responses and cigarette smoking was not quantified. CONCLUSIONS: Cannabis and cigarette use was uncommon in the studied population and was not associated with remaining kidney function. Cannabis use increased post-donation. Most smokers remained smokers after donation and most donors who quit smoking before donation did not restart after donation. This warrants education and support for potential donors who smoke, to quit smoking prior to donation to reduce risks of cardiovascular and end-stage kidney disease. TRIAL REGISTRATION: Not applicable as this is not a clinical trial.

CONTEXTE: On ignore si la perspective de faire don d'un rein conduit les donneurs potentiels à changer leurs habitudes de vie en matière de tabagisme et de consommation de cannabis. OBJECTIFS: Examiner la prévalence du tabagisme et de la consommation de cannabis avant et après le don d'un rein, puis déterminer leur association avec le mode de vie et les facteurs cliniques. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Le program de don de rein vivant du Réseau local d'intégration des services de santé de Champlain de l'hôpital d'Ottawa (Canada). SUJETS: L'étude a inclus 178 individus ayant fait don d'un rein entre janvier 2009 et décembre 2018. MESURES: Les donneurs ont été questionnés par téléphone sur leur consommation de cigarettes et de cannabis. Les caractéristiques cliniques et les changements dans la fonction rénale ont été enregistrés pré- et post-don. MÉTHODOLOGIE: Le test du Chi2 a été employé pour comparer la consommation de cigarettes et de cannabis pré- et post-don, tandis que les facteurs de risque associés à leur utilization ont été examinés par régression logistique univariée et multivariée. L'association entre la consommation de cannabis/le tabagisme et le CKD-EPI eGFR (débit de filtration glomérulaire estimé [DFGe] par l'équation de la Chronic Kidney Disease Epidemiology [CKD-EPI] Collaboration) a été examinée au moment du don et lors du dernier suivi par le test Wilcoxon (cannabis) ou le test t (tabagisme), selon le cas. RÉSULTATS: Des 305 donneurs admissibles, 262 répondaient aux critères d'inclusion et 178 ont participé à l'étude (moyenne: 4,7 ± 2,9 ans depuis le don). Au moment du don, 5 % (9/178) des donneurs consommaient du cannabis et 13 % (23/178) fumaient la cigarette. Après le don, 8 % (14/178) des donneurs ont commencé à consommer du cannabis et 5 % (9/178) à fumer la cigarette. La majorité des donneurs qui fumaient avant le don ont continué après le don (74 % [17/23]). La grande majorité des donneurs qui avaient cessé de fumer avant le don n'ont pas repris après (88 % [53/60]). Dans l'analyze multivariée, le fait de ne pas être marié ou conjoint de fait a été associé à la consommation de cannabis (rapport de cotes: 2,73; IC à 95 %: 1,05-7,11; p=0,04). Aucune différence n'a été observée dans les taux de filtration glomérulaire estimé pré- et post-don chez les fumeurs et les consommateurs de cannabis. LIMITES: L'étude est monocentrique, ce qui limite la généralisabilité des résultats. Un biais de désirabilité sociale pourrait avoir influé sur les réponses à l'enquête. Le tabagisme n'a pas été quantifié. CONCLUSION: Le tabagisme et la consommation de cannabis étaient peu courants dans la population étudiée; ces habitudes de vie n'ont pas été associées à la fonction rénale résiduelle. La consommation de cannabis a augmenté après le don. La plupart des fumeurs le sont demeurés après le don et la majorité des donneurs qui avaient cessé de fumer avant le don n'ont pas repris après. Ces résultats justifient de sensibiliser les donneurs potentiels à l'importance de cesser de fumer avant le don, et de les appuyer dans cette démarche, afin de réduire les risques de maladies cardiovasculaires et d'insuffisance rénale terminale.

To step or to spring: the influence of state anxiety on perceptual judgements and executed action.

Emotional state, in particular anxiety, has been shown to constrain perceptual judgement of action capabilities. However, whether anxiety also constrains actual behaviour is unknown. The current study, therefore, aimed to determine whether state anxiety constrained firstly perceptual judgements of action capabilities and secondly actual behaviour. To do this, we asked participants to make perceptual judgements and perform action behaviours in relation to crossing ground-based apertures representing puddles. State anxiety was measured in 30 participants using the State-Trait Anxiety Inventory. The critical ratio of aperture size relative to leg length at which participants' behaviour choice would switch between a step and a spring was calculated. In a perceptual judgement task, participants judged the ratio at which they would choose to switch. In a subsequent executed action task, the ratio at which they actually switched was measured. Perceptual critical ratio could be predicted via state anxiety and age, while action critical ratio was not predicted by either. Therefore, this study has demonstrated that state anxiety and age both constrain perceptual judgement of action capabilities, as shown in previous studies. However, this does not seem to result in a change in emergent behaviour. This highlights the importance of measuring emergent behaviour rather than inferring it from perceptual judgements even when they are couched in terms of action.

Sialyltransferase inhibition leads to inhibition of tumor cell interactions with E-selectin, VCAM1, and MADCAM1, and improves survival in a human multiple myeloma mouse model.

Aberrant glycosylation resulting from altered expression of sialyltransferases, such as ST3 ß-galactoside α2-3-sialyltransferase 6, plays an important role in disease progression in multiple myeloma (MM). Hypersialylation can lead to increased immune evasion, drug resistance, tumor invasiveness, and disseminated disease. In this study, we explore the in vitro and in vivo effects of global sialyltransferase inhibition on myeloma cells using the pan-sialyltransferase inhibitor 3Fax-Neu5Ac delivered as a per-acetylated methyl ester pro-drug. Specifically, we show in vivo that 3Fax-Neu5Ac improves survival by enhancing bortezomib sensitivity in an aggressive mouse model of MM. However, 3Fax-Neu5Ac treatment of MM cells in vitro did not reverse bortezomib resistance conferred by bone marrow (BM) stromal cells. Instead, 3Fax-Neu5Ac significantly reduced interactions of myeloma cells with E-selectin, MADCAM1 and VCAM1, suggesting that reduced sialylation impairs extravasation and retention of myeloma cells in the BM. Finally, we showed that 3Fax-Neu5Ac alters the post-translational modification of the α4 integrin, which may explain the reduced affinity of α4ß1/α4ß7 integrins for their counter-receptors. We propose that inhibiting sialylation may represent a valuable strategy to restrict myeloma cells from entering the protective BM microenvironment, a niche in which they are normally protected from chemotherapeutic agents such as bortezomib. Thus, our work demonstrates that targeting sialylation to increase the ratio of circulating to BM-resident MM cells represents a new avenue that could increase the efficacy of other anti-myeloma therapies and holds great promise for future clinical applications.

Safety and Efficacy of Tinzaparin Anticoagulation during Nocturnal Hemodialysis.

BACKGROUND: The safety and efficacy of low-molecular-weight heparin in the prevention of extracorporeal dialysis circuit clotting among in-center extended duration nocturnal hemodialysis (INHD) patients are unknown. The aim of this study was to determine the safety and efficacy of 2 doses of tinzaparin, among INHD patients receiving 6-8 h hemodialysis, 3 times per week. METHODS: We conducted a retrospective cohort study to examine antifactor Xa levels at time 0, 2 h, 4 h mid-hemodialysis (mid-HD), 6 h, and at end of each INHD session for 4 weeks and to determine extracorporeal dialysis circuit clotting and bleeding events after switching from unfractionated heparin to tinzaparin, using a standard protocol of tinzaparin delivery at the initiation and midpoint of HD. RESULTS: All 16 patients in The Ottawa Hospital INHD program were converted to tinzaparin and followed for 177 INHD sessions. Mean antifactor Xa level at 2 h of HD was 0.41 ± 0.21 (SD) IU/mL, at 4 h (mid-HD) 0.19 ± 0.17 IU/mL, at 6 h 0.44 ± 0.21 IU/mL, and at dialysis end 0.26 ± 0.14 IU/mL. Antifactor Xa levels were undetectable at the start of INHD, suggesting no tinzaparin accumulation. Five patients required an increase in tinzaparin due to extracorporeal dialysis circuit clotting. There were no bleeding events. One patient required a switch to fondaparinux due to an adverse reaction. CONCLUSION: Tinzaparin was safe and efficacious for most INHD patients without accumulation or bleeding. The conversion from unfractionated heparin to tinzaparin required an increased tinzaparin dose for 31% of INHD patients.

Development of medical-grade, discrete, multi-walled carbon nanotubes as drug delivery molecules to enhance the treatment of hematological malignancies.

Carbon nanotubes (CNTs) hold great potential as drug delivery transporters given their large drug-binding surface area. Herein, we designed novel, multi-walled, discrete CNTs (dMWCNTs), PEGylated dMWCNTs (PEG-dMWCNTs), and bone-targeting (BT), alendronate-conjugated PEG-dMWCNTs (BT-PEG-dMWCNTs). Using zeta potential, thermogravimetric analysis, TEM, SEM, and FTIR, dMWCNTs were characterized as individual, uniform, and stable. Drug binding and release assays validated dMWCNTs as effective doxorubicin (DOX) transporters. The mass ratio of DOX loading onto dMWCNTs was 35% wt/wt with a ~95% wt/wt efficiency. DOX release was ~51% w/w after 48 hours. Neoplastic transformation, chromosomal aberration, and cytotoxicity assays, confirmed biocompatibility for all dMWCNTs. PEG-dMWCNTs were well tolerated and modulated drug pharmacokinetics in mice. In mice with Burkitt's lymphoma, DOX-loaded PEG-dMWCNTs and BT-PEG-dMWCNTs reduced tumor burden and increased survival similarly to free drug. Importantly, DOX toxicity was abrogated when DOX was loaded onto PEG-dMWCNTs or BT-PEG-dMWCNTs. Overall, PEG-dMWCNTs and BT-PEG-dMWCNTs represent a promising new nanocarrier platform.

Saline versus albumin fluid for extracorporeal removal with slow low-efficiency dialysis (SAFER-SLED): study protocol for a pilot trial.

BACKGROUND: Critically ill patients frequently develop acute kidney injury that necessitates renal replacement therapy (RRT). At some centers, critically ill patients who are hemodynamically unstable and require RRT are treated with slow low-efficiency dialysis (SLED). Unfortunately, hypotension is a frequent complication that occurs during SLED treatments and may limit the recovery of kidney function. Hypotension may also limit the amount of fluid that can be removed by ultrafiltration with SLED. Fluid overload can be exacerbated as a consequence, and fluid overload is associated with increased mortality.Occasionally, intravenous albumin fluid is given to prevent or treat low blood pressure during SLED. The intent of doing so is to increase the colloid oncotic pressure in the circulation to draw in extravascular fluid, increase the blood pressure, and enable more aggressive fluid removal with ultrafiltration. Nonetheless, there is little evidence to support this practice and theoretical reasons why it may not be especially effective at augmenting fluid removal in critically ill patients. At the same time, albumin fluid is expensive.As such, we present a protocol for a study to assess the feasibility of a randomized controlled trial evaluating the use of albumin fluid versus saline in critically ill patients receiving SLED. METHODS: This study is a single-center, double-blind, and randomized controlled pilot trial with two parallel arms. It involves randomly assigning patients receiving SLED treatment in the ICU to receive either albumin (25%) boluses or normal saline fluid boluses (placebo) to prevent and treat low blood pressure. DISCUSSION: The results of this pilot trial will help with planning a larger trial comparing the efficacy of the interventions in achieving fluid removal in critically ill patients with AKI on SLED. They will establish whether enough participants would participate in a larger study and accept the study procedures. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov Identifier NCT03665311, registered on September 11, 2018.

Changes in Body Weight Before and After Kidney Donation.

BACKGROUND: Living kidney donors remain at low risk of end-stage kidney disease (ESKD), but the risk for obese and overweight donors is increased. The Kidney Disease Improving Global Outcomes (KDIGO) clinical guideline recommends that overweight and obese patients pursue weight loss before donation and maintain a healthy post-donation weight. OBJECTIVE: To determine the trajectory of weight changes before and after living kidney donation. DESIGN: Retrospective cohort study. SETTING: The Living Kidney Donor program in the Champlain Local Health Integration Network at The Ottawa Hospital in Ottawa, Canada. PATIENTS: The study included 151 living kidney donors who donated between January 2009 and December 2017. MEASUREMENTS: Date of kidney donation, relationship to the transplant recipient, and cause of ESKD in the transplant recipient were documented. Demographic data, markers of glycemic control, and weights at the time of clinic visits were recorded. METHODS: The analysis included use of paired Student's t tests to compare mean differences in weight at kidney donation relative to the time of initial assessment and at last follow-up. RESULTS: The median (interquartile range [IQR]) follow-up was 392 (362, 1096) days post-donation. Among donors with normal body mass index (BMI; 18.5-24.9 kg/m2), weight loss occurred before donation (62.8 ± 3.1 kg to 61.5 kg ± 2.9 kg; mean difference 1.1 ± 2.7 kg, P < .01) and did not change significantly post-donation. Among overweight/obese donors (BMI ≥25 kg/m2), weight did not change significantly pre-donation, but increased significantly post-donation (86.0 ± 2.1 kg to 88.8 ± 2.7 kg; mean difference 2.3 ± 0.9 kg, P < .0001). LIMITATIONS: The single-center design of the study limits generalizability. CONCLUSIONS: Donors with normal BMI experienced significant weight loss before donation and maintained healthy body weight post-donation. Conversely, donors with BMI ≥25 kg/m2 at donation experienced significant weight gain over 1-year post-donation. Our findings suggest the need for enhanced weight control efforts among obese and overweight kidney donors to reduce the risk of ESKD.

CONTEXTE: Le risque d'insuffisance rénale terminale (IRT) demeure faible chez les donneurs vivants d'un rein, mais ce risque augmente si le donneur est obèse ou en surcharge pondérale. Les lignes directrices cliniques du KDIGO recommandent que ces derniers perdent du poids avant l'intervention et qu'ils maintiennent un poids santé par la suite. OBJECTIF: Suivre les variations du poids avant et après un don vivant de rein. TYPE D'ÉTUDE: Une étude de cohorte rétrospective. CADRE: Le programme de don vivant de rein du Réseau local d'intégration des services de santé de Champlain de l'hôpital d'Ottawa (Canada). SUJETS: L'étude a inclus 151 individus ayant fait don d'un rein entre janvier 2009 et décembre 2017. MESURES: On a recensé la date du don, le lien entre le donneur et le receveur, et la cause de l'IRT chez le receveur. On a également colligé les données démographiques, les marqueurs de contrôle glycémique et le poids des sujets lors des consultations en clinique. MÉTHODOLOGIE: Des tests de Student pour échantillons appariés ont été utilisés pour comparer les différences moyennes du poids au moment du don par rapport au poids initial et au poids mesuré lors de la dernière consultation. RÉSULTATS: Le suivi médian (EIQ) post-don s'est fait sur 392 (362, 1 096) jours. Les donneurs dont l'indice de masse corporelle était normal (IMC: 18,5 à 24,9 kg/m2) avaient perdu du poids avant le don (62,8 ± 3,1 kg à 61,5 kg ± 2,9 kg; différence moyenne: 1,1 ± 2,7 kg; p < 0,01) et l'avaient maintenu après. Le poids des donneurs obèses ou en embonpoint (IMC ≥ 25 kg/m2) était demeuré stable avant le don, mais avait nettement augmenté après (86,0 ± 2,1 kg à 88,8 ± 2,7 kg; différence moyenne: 2,3 ± 0,9 kg; p < 0,0001). LIMITE: L'étude était monocentrique, ce qui limite la généralisation des résultats. CONCLUSION: Les donneurs dont l'IMC était normal au moment du don ont connu une perte de poids significative avant l'intervention qui s'est maintenue post-don. À l'inverse, les donneurs avec un IMC d'au moins 25 kg/m2 au moment du don ont connu un gain pondéral important dans l'année suivant l'intervention. Ces résultats suggèrent que pour réduire les risques d'IRT, il est nécessaire de redoubler d'efforts pour contrôler le poids des donneurs de rein obèses ou en embonpoint.

Characterization of Adults With Type 1 Diabetes Not Attending Self-Management Education Courses: The Barriers to Uptake of Type 1 Diabetes Education (BUD1E) Study.

People with type 1 diabetes mellitus (T1DM) are offered attendance at diabetes self-management education courses to provide them with skills for self-management of flexible insulin dose adjustment. Attendance is poor, even when courses are evidence-based and nationally available. To understand barriers to attendance, we sought common characteristics of nonattenders from adults with T1DM living in south London. Twenty-five in person semistructured interviews were carried out until thematic saturation occurred. Thematic framework analysis identified six themes: psychological capability, numerical capability, internal/external judgment, confidence in self, thirst for knowledge, and barriers to attendance. Characterization of response profiles according to the themes identified four different typologies. These identified typologies and themes for barriers to attending diabetes self-management courses suggest strategies to improve attendance and extend the benefit of such courses more widely.