Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin.

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.

Postoperative Analgesics Score as a Predictor of Chronic Postoperative Inguinal Pain After Inguinal Hernia Repair: Lessons Learned From a Retrospective Analysis.

BACKGROUND: Chronic postoperative inguinal pain (CPIP) is a common complication after inguinal hernia surgery and occurs in up to 10-14% of cases. CPIP has a significant impact on daily life, work ability and thus compromises quality of life. The aim of this retrospective study was an in-depth analysis of patients undergoing inguinal hernia repair to further refine the prediction of the onset of CPIP reliably. METHODS: A single center retrospective analysis of patients with who underwent open or minimally invasive inguinal hernia repair from 2016 to 2021 was carried out. Complication rates, detailed analysis of postoperative pain medication and quality of life using the EuraHS Quality of Life questionnaire were assessed. RESULTS: Out of 596 consecutive procedures, 344 patients were included in detailed analyses. While patient cohorts were different in terms of age and co-morbidities, and the prevalence of CPIP was 12.2% without differences between the surgical procedures (Lichtenstein: 12.8%; TEP 10.9%; TAPP 13.5%). Postoperative pain was evaluated using a newly developed analgesic score. Patients who developed CPIP later had a significant higher consumption of analgesics at discharge (p = 0.016). As additional risk factors for CPIP younger patient age and postoperative complications were identified. CONCLUSION: The prospective use of the analgesic score established here could be helpful to identify patients that are at risk to develop CPIP. These patients could benefit from a structured follow-up to allow early therapeutic intervention to prevent chronification and restore the quality of life.

Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Optimizing laparoscopic training efficacy by 'deconstruction into key steps': a randomized controlled trial with novice medical students.

BACKGROUND: Simulator training is an effective way of acquiring laparoscopic skills but there remains a need to optimize teaching methods to accelerate learning. We evaluated the effect of the mental exercise 'deconstruction into key steps' (DIKS) on the time required to acquire laparoscopic skills. METHODS: A randomized controlled trial with undergraduate medical students was implemented into a structured curricular laparoscopic training course. The intervention group (IG) was trained using the DIKS approach, while the control group (CG) underwent the standard course. Laparoscopic performance of all participants was video-recorded at baseline (t0), after the first session (t1) and after the second session (t2) nine days later. Two double-blinded raters assessed the videos. The Impact of potential covariates on performance (gender, age, prior laparoscopic experience, self-assessed motivation and self-assessed dexterity) was evaluated with a self-report questionnaire. RESULTS: Both the IG (n = 58) and the CG (n = 68) improved their performance after each training session (p < 0.001) but with notable differences between sessions. Whereas the CG significantly improved their performance from t0 -t1 (p < 0.05), DIKS shortened practical exercise time by 58% so that the IG outperformed the CG from t1 -t2, (p < 0.05). High self-assessed motivation and dexterity associated with significantly better performance (p < 0.05). Male participants demonstrated significantly higher overall performance (p < 0.05). CONCLUSION: Mental exercises like DIKS can improve laparoscopic performance and shorten practice times. Given the limited exposure of surgical residents to simulator training, implementation of mental exercises like DIKS is highly recommended. Gender, self-assessed dexterity, and motivation all appreciably influence performance in laparoscopic training.

Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease.

The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg-1 ) combined with nivolumab (3 mg kg-1 ), pathological responses were observed in 77% of patients, while only 20% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far. Linked Comment: Blankenstein and van Akkooi. Br J Dermatol 2020; 183:421-422.

Engineering the Mucus Barrier.

Mucus selectively controls the transport of molecules, particulate matter, and microorganisms to the underlying epithelial layer. It may be desirable to weaken the mucus barrier to enable effective delivery of drug carriers. Alternatively, the mucus barrier can be strengthened to prevent epithelial interaction with pathogenic microbes or other exogenous materials. The dynamic mucus layer can undergo changes in structure (e.g., pore size) and/or composition (e.g., protein concentrations, mucin glycosylation) in response to stimuli that occur naturally or are purposely administered, thus altering its barrier function. This review outlines mechanisms by which mucus provides a selective barrier and methods to engineer the mucus layer from the perspective of strengthening or weakening its barrier properties. In addition, we discuss strategic design of drug carriers and dosing formulation properties for efficient delivery across the mucus barrier.

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial.

BACKGROUND: The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS: We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS: We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION: Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Marinesco bodies and substantia nigra neuron density in Parkinson's disease.

AIM: Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. METHODS: Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. RESULTS: Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles. CONCLUSIONS: While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes.

Optimization of home treatment in haemophilia: effects of transmural support by a haemophilia nurse on adherence and quality of life.

BACKGROUND: Transmural support by a haemophilia nurse may improve treatment and may empower parents and patients. AIM: To measure the effect of structured home visits by a haemophilia nurse in (parents of) patient on aspects of prophylactic home treatment. METHODS: A multicentre intervention study in two paediatric haemophilia treatment centres was performed. Primary outcome measures were: adherence to prescribed treatment, health-related quality of life and behavioural scores. Secondary outcome measures were: total clotting factor consumption, self-efficacy and number of joint bleeds. RESULTS: Over a period of 22 months (median, IQR 21-23), four to seven home visits in 46 patients (mean age 9.4 ± 4.2 years) were made. No difference in adherence to prescribed treatment was seen after the home visits when compared to baseline measurements. Both the Child Health Questionnaire (CHQ) scales on 'Role functioning - Emotional/Behavioural' (P = 0.02, d = 0.53) and 'Parental Time Impact' (P = 0.04, d = 0.33) were reduced after intervention. The disease-specific Haemo-QoL questionnaire showed improvement in domains: 'Family' (P = 0.04, d = -0.14), 'Friends' (P = 0.03, d = -0.29) and 'Perceived support' (P = 0.03, d = -0.37). Significant improvement was observed with regard to domain 'Communication' of the VERITAS-Pro scale (P = 0.03, d = -0.28). CONCLUSIONS: After a period of transmural care by a haemophilia nurse, significant but small positive effects were demonstrated with regard to communication and increase of perceived support between parents and haemophilia treatment centre. No improvement was observed in other outcome measures.

Facilitating the implementation of pharmacokinetic-guided dosing of prophylaxis in haemophilia care by discrete choice experiment.

INTRODUCTION: Patients', parents' and providers' preferences with regard to medical innovations may have a major impact on their implementation. AIM: To evaluate barriers and facilitators for individualized pharmacokinetic (PK)-guided dosing of prophylaxis in haemophilia patients, parents of young patients, and treating professionals by discrete choice experiment (DCE) questionnaire. PATIENTS/METHODS: The study population consisted of patients with haemophilia currently or previously on prophylactic treatment with factor concentrate (n = 114), parents of patients aged 12-18 years (n = 19) and haemophilia professionals (n = 91). DCE data analysis was performed, taking preference heterogeneity into account. RESULTS: Overall, patients and parents, and especially professionals were inclined to opt for PK-guided dosing of prophylaxis. In addition, if bleeding was consequently reduced, more frequent infusions were acceptable. However, daily dosing remained an important barrier for all involved. 'Reduction of costs for society' was a facilitator for implementation in all groups. CONCLUSIONS: To achieve implementation of individualized PK-guided dosing of prophylaxis in haemophilia, reduction of bleeding risk and reduction of costs for society should be actively discussed as they are motivating for implementation; daily dosing is still reported to be a barrier for all groups. The knowledge of these preferences will enlarge support for this innovation, and aid in the drafting of implementable guidelines and information brochures for patients, parents and professionals.

A randomized controlled trial of in-patient treatment for anorexia nervosa in medically unstable adolescents.

BACKGROUND: Anorexia nervosa (AN) is a serious disorder incurring high costs due to hospitalization. International treatments vary, with prolonged hospitalizations in Europe and shorter hospitalizations in the USA. Uncontrolled studies suggest that longer initial hospitalizations that normalize weight produce better outcomes and fewer admissions than shorter hospitalizations with lower discharge weights. This study aimed to compare the effectiveness of hospitalization for weight restoration (WR) to medical stabilization (MS) in adolescent AN. METHOD: We performed a randomized controlled trial (RCT) with 82 adolescents, aged 12-18 years, with a DSM-IV diagnosis of AN and medical instability, admitted to two pediatric units in Australia. Participants were randomized to shorter hospitalization for MS or longer hospitalization for WR to 90% expected body weight (EBW) for gender, age and height, both followed by 20 sessions of out-patient, manualized family-based treatment (FBT). RESULTS: The primary outcome was the number of hospital days, following initial admission, at the 12-month follow-up. Secondary outcomes were the total number of hospital days used up to 12 months and full remission, defined as healthy weight (>95% EBW) and a global Eating Disorder Examination (EDE) score within 1 standard deviation (s.d.) of published means. There was no significant difference between groups in hospital days following initial admission. There were significantly more total hospital days used and post-protocol FBT sessions in the WR group. There were no moderators of primary outcome but participants with higher eating psychopathology and compulsive features reported better clinical outcomes in the MS group. CONCLUSIONS: Outcomes are similar with hospitalizations for MS or WR when combined with FBT. Cost savings would result from combining shorter hospitalization with FBT.

Reliability and validity of a novel haemophilia-specific self-efficacy scale.

Higher self-efficacy in chronic disease patients is associated with higher development of self-management skills and increased quality-of-life. Quantification and monitoring of self-efficacy is therefore of importance. Self-efficacy in haemophilia patients has received little attention due to lack of standardized scales. To validate the novel Haemophilia-specific Self-Efficacy Scale (HSES) in haemophilia patients on prophylactic home treatment, haemophilia patients aged 1-18 years on prophylactic treatment ≥1 year were included from three Dutch Haemophilia Treatment Centres. The HSES consists of 12 items, relating to perceptions of the ability to function on a day-to-day basis with regard to patient's disease. Retest was performed in a subsample. Validity was proven by the General Self-Efficacy Scale and by the health-related quality-of-life assessment tool Haemo-QoL. Data were analysed from 53 children (response 75%), with a mean age of 9.8 years (SD 4.0). Mean total scale score of HSES was 55.5 (SD 4.7; range 38-60), with a ceiling effect of 17%. The HSES showed adequate internal consistency (Cronbach's alpha 0.72) and good test-retest reliability (Intra-Class-Correlation coefficient 0.75; P < 0.01; n = 37). The convergent validity was adequate as haemophilia-specific self-efficacy correlated significantly with general self-efficacy (r = 0.38; P < 0.01). High HSES scores correlated significantly with quality-of-life as measured by the Haemo-QoL (r = -0.42; P ≤ 0.01). The novel HSES is a reliable and valid tool to assess self-efficacy in paediatric haemophilia patients on prophylactic home treatment. High self-efficacy correlated with higher quality-of-life, further underlining the importance to standardly assess, monitor and improve self-efficacy.

Adherence to treatment in a Western European paediatric population with haemophilia: reliability and validity of the VERITAS-Pro scale.

Treatment adherence in haemophilia is strongly associated with quality of life and the cost-benefit of treatment. Therefore, it is important to quantify and monitor it. This study aimed to validate a translation of the VERITAS-Pro cross-culturally and analyse treatment adherence in a Dutch population of paediatric haemophilia patients. Children aged 1-18 years with haemophilia were included from three Haemophilia Treatment Centres, on prophylactic clotting factor replacement therapy for more than 1 year. Parents and adolescents were analysed separately. The adherence scale for prophylactic therapy (VERITAS-Pro) was translated according to international guidelines. This instrument contains a total of six subscales ('Time', 'Dose', 'Plan', 'Remember', 'Skip' and 'Communicate') each with four items. Lower scores reflect higher adherence. Overall response rate was 85%, leading to a study population of 60 children. Mean age was 10 years (SD 4.1). Internal consistency reliability: Mean Cronbach's alphas were adequate (>0.70) for total score and the subscales 'Skip' and 'Communicate'. Item-own subscale correlations were stronger than most item-other subscale correlations. Convergent validity: Total scores were higher for non-adherent participants compared with adherent participants according to patient infusion logs (n = 48; P < 0.05). Test-retest correlations: Significant for all scales except 'Dose' (n = 58; P < 0.01). This study demonstrates applicability of VERITAS-Pro outside the United States, as total score and most subscales effectively quantified treatment adherence in a Dutch paediatric population on prophylactic therapy. Non-adherent respondents' total scores were significantly higher, demonstrating the ability of VERITAS-Pro to identify non-adherent individuals.

Chronic postsurgical pain (CPSP): an underestimated problem after incisional hernia treatment.

BACKGROUND: Chronic postsurgical pain (CPSP) is a potential long-term problem following open incisional hernia repair which may affect the quality of life of patients despite successful anatomical repair of the hernia. The aim of this manuscript was to identify the incidence and outcome of patients following open incisional hernia repair in respect of risk factors to develop CPSP. METHODS: A single-center retrospective analysis of patients who underwent open incisional hernia repair between 2015 and 2021 was performed. Pre-existing conditions (e.g., diabetes mellitus and malignancy), hernia complexity, postoperative complications, and postoperative pain medication were analyzed using the local database. Quality of life and CPSP were assessed using the EuraHS Quality of Life (QoL) questionnaire. RESULTS: A total of 182 cases were retrospectively included in a detailed analysis based on the complete EuraHS (QoL) questionnaire. During the average follow-up period of 46 months, this long-term follow-up revealed a 54.4% incidence of CPSP and including a rate of 14.8% for severe CPSP (sCPSP) after open incisional hernia surgery. The complexity of the hernia and the demographic variables were not different between the group with and without CPSP. Patients with CPSP reported significantly reduced QoL. The analgesics score which includes the need of pain medication in the initial days after surgery was significantly higher in patients with CPSP than in those without (no CPSP: 2.86 vs. CPSP: 3.35; p = 0.047). CONCLUSION: The presence of CPSP after open incisional hernia repair represents a frequent and underestimated long-term problem which has been not been recognized to this extent before. CPSP impairs QoL in these patients. Patients at risk to develop CPSP can be identified in the perioperative setting by the need of high doses of pain medication using the analgesics score. Possibly timely adjustment of pain medication, even in the domestic setting, could alleviate the chronicity or severity of CPSP.

Efficacy and safety of bexagliflozin compared with dapagliflozin as an adjunct to metformin in Chinese patients with type 2 diabetes mellitus: A 24-week, randomized, double-blind, active-controlled, phase 3 trial.

BACKGROUND: Bexagliflozin and dapagliflozin are sodium-glucose cotransporter-2 (SGLT2) inhibitors. No direct comparison of SGLT2 inhibitors in a randomized controlled trial has been reported to date. METHODS: This was a multicenter, randomized, double-blind, active-controlled trial comparing bexagliflozin to dapagliflozin for the treatment of type 2 diabetes mellitus in adults with disease inadequately controlled by metformin. Subjects (n = 406) were randomized to receive bexagliflozin (20 mg) or dapagliflozin (10 mg) plus metformin. The primary endpoint was noninferiority of bexagliflozin to dapagliflozin for the change in glycated hemoglobin (HbA1c) from baseline to week 24. Secondary endpoints included intergroup differences in fasting plasma glucose (FPG), 2-h-postprandial glucose (PPG), body weight, and systolic blood pressure (SBP) from baseline to week 24. The trial also evaluated the safety profiles. RESULTS: The model-adjusted mean change from baseline to week 24 HbA1c was -1.08% for bexagliflozin and -1.10% for dapagliflozin. The intergroup difference of 0.03% (95% confidence interval [CI] -0.14% to 0.19%) was below the prespecified margin of 0.4%, confirming the noninferiority of bexagliflozin. The changes from baseline in FPG, PPG, body weight, and SBP were -1.95 mmol/L, -3.24 mmol/L, -2.52 kg, and -6.4 mm Hg in the bexagliflozin arm and -1.87 mmol/L, -3.07 mmol/L, -2.22 kg, and -6.3 mm Hg in the dapagliflozin arm. Adverse events were experienced in 62.6% and 65.0% and serious adverse events affected 4.4% and 3.5% of subjects in the bexagliflozin and dapagliflozin arm, respectively. CONCLUSIONS: Bexagliflozin showed nearly identical effects and a similar safety profile to dapagliflozin when used in Chinese patients on metformin.

Aorto-mesenteric and renal allograft transplant: a novel treatment for midaortic syndrome.

Midaortic syndrome (MAS) is a rare condition characterized by stenosis of the aorta and often involving renal and visceral arteries. Current therapies include medical management of associated hypertension, and interventional procedures such as angioplasty or surgical bypass. We report a 2-year-old female with severe MAS who was initially treated with angioplasty and stents in both her aorta and superior mesenteric artery (SMA). Due to the presence of long segment stenoses, her renal arteries were not amenable to surgical reconstruction and she rapidly progressed to Stage V chronic kidney disease. The patient underwent bilateral nephrectomy and renal transplantation using a donor thoracoabdominal aorta allograft to provide inflow for the kidney as well as to bypass the nearly occluded aorta. The donor SMA was used to bypass the native SMA stenosis. Postoperatively, the patient had normalization of four limb blood pressures. She weaned from five anti-hypertensive agents to monotherapy with excellent renal function. This is the first reported case of thoracoabdominal aortic bypass using allograft aorta to address MAS. This approach allowed for successful kidney transplantation with revascularization of the mesenteric, and distal aortic circulation using allograft conduit that will grow with the child, obviating the need for repeated interventional or surgical procedures.

The group medical appointment (GMA) in haemophilia and von Willebrand's disease: a new development in outpatient paediatric care.

The Group Medical Appointment (GMA) is a novel consultation form in which patients undergo individual consultations in each other's presence. To compare participants' experiences with GMA and Individual Medical Appointments (IMA), the usual standard of care, our team recently implemented the GMA for children aged 0-18 years with haemophilia or von Willebrand's disease. Participants' experiences with GMA were measured using a standardized QUOTE-questionnaire. Of 100 addressed families, 53 participated in GMA. Of these 53 families, 38 parents (72%) and 14 adolescents (82%) filled in the questionnaire about the GMA. Patients not on prophylaxis were defined as less experienced and patients on prophylaxis, as experienced. Although parents were satisfied with both GMA and IMA (median score 8.0 vs. 9.0 of 10), a significant difference was demonstrated between less experienced and experienced parents. After GMA, less experienced parents were significantly more satisfied (median score 8.0 vs. 5.0; P-value 0.006), felt more social support (82% vs. 30%; P-value 0.005) and reported additional learning effects with regard to disease and treatment (64% vs. 0%; P-value <0.001) than experienced parents. None of the less experienced parents reported privacy problems during GMA compared with 40% of experienced parents. In adolescents an identical trend was reported. Sixty-six per cent of parents would join a GMA in the future and 87% would recommend a GMA to others. The GMA is a valuable addition in haemophilia and von Willebrand care, especially for less experienced patients. It leads to improved satisfaction, social support and improved information.

Factors influencing the fascial closure rate after open abdomen treatment: Results from the European Hernia Society (EuraHS) Registry : Surgical technique matters.

PURPOSE: Definitive fascial closure is an essential treatment objective after open abdomen treatment and mitigates morbidity and mortality. There is a paucity of evidence on factors that promote or prevent definitive fascial closure. METHODS: A multi-center multivariable analysis of data from the Open Abdomen Route of the European Hernia Society included all cases between 1 May 2015 and 31 December 2019. Different treatment elements, i.e. the use of a visceral protective layer, negative-pressure wound therapy and dynamic closure techniques, as well as patient characteristics were included in the multivariable analysis. The study was registered in the International Clinical Trials Registry Platform via the German Registry for Clinical Trials (DRK00021719). RESULTS: Data were included from 630 patients from eleven surgical departments in six European countries. Indications for OAT were peritonitis (46%), abdominal compartment syndrome (20.5%), burst abdomen (11.3%), abdominal trauma (9%), and other conditions (13.2%). The overall definitive fascial closure rate was 57.5% in the intention-to-treat analysis and 71% in the per-protocol analysis. The multivariable analysis showed a positive correlation of negative-pressure wound therapy (odds ratio: 2.496, p < 0.001) and dynamic closure techniques (odds ratio: 2.687, p < 0.001) with fascial closure and a negative correlation of intra-abdominal contamination (odds ratio: 0.630, p = 0.029) and the number of surgical procedures before OAT (odds ratio: 0.740, p = 0.005) with DFC. CONCLUSION: The clinical course and prognosis of open abdomen treatment can significantly be improved by the use of treatment elements such as negative-pressure wound therapy and dynamic closure techniques, which are associated with definitive fascial closure.

Rat islet cell aggregates are superior to islets for transplantation in microcapsules.

AIMS/HYPOTHESIS: Islet transplantation is a promising treatment for type 1 diabetes but is hampered by a shortage of donor human tissue and early failure. Research on islet cell transplantation includes finding new sources of cells and immunoisolation to protect from immune assault and tumourigenic potential. Small islet cell aggregates were studied to determine if their survival and function were superior to intact islets within microcapsules because of reduced oxygen transport limitation and inflammatory mediators. METHODS: Islet cell aggregates were generated by dispersing rat islets into single cells and allowing them to re-aggregate in culture. Rat islets and islet cell aggregates were encapsulated in barium alginate capsules and studied when cultured in low (0.5% or 2%) or normal (20%) oxygen, or transplanted into mice. RESULTS: Encapsulated islet cell aggregates were able to survive and function better than intact islets in terms of oxygen-consumption rate, nuclei counts, insulin-to-DNA ratio and glucose-stimulated insulin secretion. They also had reduced expression of pro-inflammatory genes. Islet cell aggregates showed reduced tissue necrosis in an immunodeficient transplant model and a much greater proportion of diabetic xenogeneic transplant recipients receiving islet cell aggregates (tissue volume of only 85 islet equivalents) had reversal of hyperglycaemia than recipients receiving intact islets. CONCLUSIONS/INTERPRETATION: These aggregates were superior to intact islets in terms of survival and function in low-oxygen culture and during transplantation and are likely to provide more efficient utilisation of islet tissue, a finding of importance for the future of cell therapy for diabetes.