Aims/hypothesis
The finding that patients with diabetes due to potassium channel mutations can transfer from insulin to sulfonylureas has revolutionised the management of patients with permanent ...neonatal diabetes. The extent to which the in vitro characteristics of the mutation can predict a successful transfer is not known. Our aim was to identify factors associated with successful transfer from insulin to sulfonylureas in patients with permanent neonatal diabetes due to mutations in
KCNJ11
(which encodes the inwardly rectifying potassium channel Kir6.2).
Methods
We retrospectively analysed clinical data on 127 patients with neonatal diabetes due to
KCNJ11
mutations who attempted to transfer to sulfonylureas. We considered transfer successful when patients completely discontinued insulin whilst on sulfonylureas. All unsuccessful transfers received ≥0.8 mg kg
−1
day
−1
glibenclamide (or the equivalent) for >4 weeks. The in vitro response of mutant Kir6.2/SUR1 channels to tolbutamide was assessed in
Xenopus
oocytes. For some specific mutations, not all individuals carrying the mutation were able to transfer successfully; we therefore investigated which clinical features could predict a successful transfer.
Results
In all, 112 out of 127 (88%) patients successfully transferred to sulfonylureas from insulin with an improvement in HbA
1c
from 8.2% (66 mmol/mol) on insulin, to 5.9% (41 mmol/mol) on sulphonylureas (
p
= 0.001). The in vitro response of the mutation to tolbutamide determined the likelihood of transfer: the extent of tolbutamide block was <63% for the p.C166Y, p.I296L, p.L164P or p.T293N mutations, and no patients with these mutations successfully transferred. However, most individuals with mutations for which tolbutamide block was >73% did transfer successfully. The few patients with these mutations who could not transfer had a longer duration of diabetes than those who transferred successfully (18.2 vs 3.4 years,
p
= 0.032). There was no difference in pre-transfer HbA
1c
(
p
= 0.87), weight-for-age
z
scores (SD score;
p
= 0.12) or sex (
p
= 0.17).
Conclusions/interpretation
Transfer from insulin is successful for most
KCNJ11
patients and is best predicted by the in vitro response of the specific mutation and the duration of diabetes. Knowledge of the specific mutation and of diabetes duration can help predict whether successful transfer to sulfonylureas is likely. This result supports the early genetic testing and early treatment of patients with neonatal diabetes aged under 6 months.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Supreme Court case of Montgomery vs Lanarkshire Health Board in 2015 was a landmark case for consent practice in the UK which shifted focus from a traditional paternalistic model of consent ...towards a more patient-centered approach. Widely recognised as the most significant legal judgment on informed consent in the last 30 years, the case was predicted to have a major impact on the everyday practice of surgeons working in the UK National Health Service (NHS). Two years after the legal definition of informed consent was redefined, we carried out an audit of surgical consent practice across the UK to establish the impact of the Montgomery ruling on clinical practice.
Data was collected by distribution of an electronic questionnaire to NHS doctors working in surgical specialities with a total of 550 respondents.
81% of surgical doctors were aware of the recent change in consent law, yet only 35% reported a noticeable change in the local consent process. Important barriers to modernisation included limited consent training, a lack of protected time for discussions with patients and minimal uptake of technology to aid decision-making/documentation.
On the basis of these findings, we identify a need to develop strategies to improve the consent process across the NHS and limit the predicted rise in litigation claims.
•The case of Montgomery vs Lanarkshire Health Board in 2015 revolutionised UK informed consent law.•We investigated the impact of the ruling on surgical consent practice using an online questionnaire.•65% of surgical doctors reported no noticeable change in the local consent process.•Key barriers to change included a lack of consent training, limited time availability and low uptake of technology to facilitate the consent process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction: The COVID-19 pandemic has resulted in a significant number of changes to elective and emergency neurosurgical practice.
Materials and Methods: This paper reports the results of an ...online survey of Society of British Neurological Surgeons (SBNS) members undertaken between 10th and 24th of June 2020 regarding changes in consent practice in response to COVID-19, as well as the physical challenges experienced while operating under higher levels of personal protective equipment (PPE).
Results: Despite the real and substantial risks associated with COVID-19, 23% of surgeons reported they were not made any changes to their usual consent process, and 54% of surgeons indicated that they made reference to COVID-19-associated risks in their written consent documentation. 93% of neurosurgeons reported physical difficulties operating using PPE; 62% reported visors/goggles fogging up, 55% experienced 'overheating', 62% reported fatigue, and 82% of surgeons reported difficulty communicating with the theatre staff.
Conclusions: This survey highlights discrepancies in the consent practice between neurosurgeons which needs to be addressed at both local and national levels. The PPE being used in neurosurgical operations is not designed for use with specialist equipment (82% of respondents reported having to remove PPE to use the microscope) and the reported physical difficulties using PPE intraoperatively could significantly impact on both neurosurgeon performance and patient outcomes. This requires urgent attention by NHS procurement and management and should be urgently escalated to trust occupational health authorities as a workplace safety concern.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Around 50% of patients undergoing frontal lobe surgery for focal drug-resistant epilepsy become seizure free post-operatively; however, only about 30% of patients remain seizure free in the ...long-term. Early seizure recurrence is likely to be caused by partial resection of the epileptogenic lesion, whilst delayed seizure recurrence can occur even if the epileptogenic lesion has been completely excised. This suggests a coexistent epileptogenic network facilitating ictogenesis in close or distant dormant epileptic foci. As thalamic and striatal dysregulation can support epileptogenesis and disconnection of cortico-thalamostriatal pathways through hemispherotomy or neuromodulation can improve seizure outcome regardless of focality, we hypothesize that projections from the striatum and the thalamus to the cortex may contribute to this common epileptogenic network.
To this end, we retrospectively reviewed a series of 47 consecutive individuals who underwent surgery for drug-resistant frontal lobe epilepsy. We performed voxel-based and tractography disconnectome analyses to investigate shared patterns of disconnection associated with long-term seizure freedom. Seizure freedom after 3 and 5 years was independently associated with disconnection of the anterior thalamic radiation and anterior cortico-striatal projections. This was also confirmed in a subgroup of 29 patients with complete resections, suggesting these pathways may play a critical role in supporting the development of novel epileptic networks.
Our study indicates that network dysfunction in frontal lobe epilepsy may extend beyond the resection and putative epileptogenic zone. This may be critical in the pathogenesis of delayed seizure recurrence as thalamic and striatal networks may promote epileptogenesis and disconnection may underpin long-term seizure freedom.
About 50% of patients undergoing frontal lobe surgery for focal drug-resistant epilepsy become seizure-free post-operatively, but only about 30% remain seizure-free in the long-term. By retrospectively reviewing a series of operated individuals, Giampiccolo et al. show that cortico-thalamostriatal disconnection is linked to long-term seizure freedom.
See Inati and Zaghloul (https://doi.org/10.1093/brain/awad141) for a scientific commentary on this article.
KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with ...excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.
In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.
90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer for HbA1c, year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol 55·2–77·1) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol 35·5–47·5; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol 41·0–56·3; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years IQR 9·2–10·9). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years IQR 10·5–24·0 vs 4·1 years 1·3–10·2; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients.
High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years.
Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.
Anteromesial temporal lobe resection is the most common surgical technique used to treat drug-resistant mesial temporal lobe epilepsy, particularly when secondary to hippocampal sclerosis. Structural ...and functional imaging data suggest the importance of sparing the posterior hippocampus for minimising language and memory deficits. Recent work has challenged the view that maximal posterior hippocampal resection improves seizure outcome. This study was designed to assess whether resection of posterior hippocampal atrophy was associated with improved seizure outcome.
Retrospective analysis of a prospective database of all anteromesial temporal lobe resections performed in individuals with hippocampal sclerosis at our epilepsy surgery centre, 2013–2021. Pre- and post-operative MRI were reviewed by 2 neurosurgical fellows to assess whether the atrophic segment, displayed by automated hippocampal morphometry, was resected, and ILAE seizure outcomes were collected at 1 year and last clinical follow-up. Data analysis used univariate and binary logistic regression.
Sixty consecutive eligible patients were identified of whom 70% were seizure free (ILAE Class 1 & 2) at one year. There was no statistically significant difference in seizure freedom outcomes in patients who had complete resection of atrophic posterior hippocampus or not (Fisher’s Exact test statistic 0.69, not significant at p < .05) both at one year, and at last clinical follow-up. In the multivariate analysis only a history of status epilepticus (OR=0.2, 95%CI:0.042–0.955, p = .04) at one year, and pre-operative psychiatric disorder (OR=0.145, 95%CI:0.036–0.588, p = .007) at last clinical follow-up, were associated with a reduced chance of seizure freedom.
Our data suggest that seizure freedom is not associated with whether or not posterior hippocampal atrophy is resected. This challenges the traditional surgical dogma of maximal posterior hippocampal resection in anteromesial temporal lobe resections and is a step further optimising this surgical procedure to maximise seizure freedom and minimise associated language and memory deficits.
•Temporal lobe resection is the commonest form of epilepsy surgery.•Surgical dogma is that we have to maximally resect the hippocampus to stop seizures.•We show that taking out the back of the hippocampus isn’t needed when it is scarred.•This may help prevent damage to language and memory after surgery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous ...studies suggested that people with
PNDM require lower sulfonylurea doses and have milder neurological features than those with
PNDM. However, these studies were short-term and included combinations of
-PNDM and
-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated
-PNDM.
We studied all 24 individuals with
PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods.
Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 range 4.1-13.2 years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA
7.2% vs. 5.7%,
= 0.0004) and remained excellent long-term (1-year vs. 10-year HbA
5.7% vs. 6.5%,
= 0.04),
= 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide,
= 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%).
Sulfonylurea treatment of
-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.
Abstract Poor weekend handover has been implicated as one of the causes of observed higher mortality rates at weekends in UK hospitals. In a large teaching hospital we, a group of junior doctors, set ...about improving the quality and effectiveness of weekend handover. We used the Model for Improvement to implement a weekend handover sticker through an iterative process using multiple Plan/Do/Study/Act (PDSA) cycles. Over the 16 week study period the number of completed weekend tasks increased by 30% and the number of patients with a documented weekend handover increased by nearly 50%. Junior doctors are well positioned to notice the quality and safety shortcomings within hospitals, and by using effective improvement methods they can improve these systems at little or no cost.
Purpose This perspective article responds to the emergence of artificial intelligence (AI) as a significant opportunity for growth among family businesses, highlighting the need for future research ...to attain a clear picture of the next generation of family business successors. Design/methodology/approach This is a literature review of current technology adoption within family businesses. The authors offer some research insight to spur critical thinking and discourse around the impact of AI on family business successors. Findings Family businesses are initially skeptical of AI technology. However, its use and adoption are crucial for the survival of the family business. To leverage this technology, the authors need to investigate the role of the family business successors as “Gen AI.” Originality/value It is challenging but necessary to develop policies and educational support for successors to ensure the survival of family businesses worldwide. The authors propose four key areas of future research.
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