Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

Objective: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). Subjects and methods: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. Results: A genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. Conclusions: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded

The impact of training non-physician clinicians in Malawi on maternal and perinatal mortality : a cluster randomised controlled evaluation of the enhancing training and appropriate technologies for mothers and babies in Africa (ETATMBA) project

Background: Maternal mortality in much of sub-Saharan Africa is very high whereas there has been a steady decline in over the past 60 years in Europe. Perinatal mortality is 12 times higher than maternal mortality accounting for about 7 million neonatal deaths; many of these in sub-Saharan countries. Many of these deaths are preventable. Countries, like Malawi, do not have the resources nor highly trained medical specialists using complex technologies within their healthcare system. Much of the burden falls on healthcare staff other than doctors including non-physician clinicians (NPCs) such as clinical officers, midwives and community health-workers. The aim of this trial is to evaluate a project which is training NPCs as advanced leaders by providing them with skills and knowledge in advanced neonatal and obstetric care. Training that will hopefully be cascaded to their colleagues (other NPCs, midwives, nurses). Methods/design: This is a cluster randomised controlled trial with the unit of randomisation being the 14 districts of central and northern Malawi (one large district was divided into two giving an overall total of 15). Eight districts will be randomly allocated the intervention. Within these eight districts 50 NPCs will be selected and will be enrolled on the training programme (the intervention). Primary outcome will be maternal and perinatal (defined as until discharge from health facility) mortality. Data will be harvested from all facilities in both intervention and control districts for the lifetime of the project (3–4 years) and comparisons made. In addition a process evaluation using both quantitative and qualitative (e.g. interviews) will be undertaken to evaluate the intervention implementation. Discussion: Education and training of NPCs is a key to improving healthcare for mothers and babies in countries like Malawi. Some of the challenges faced are discussed as are the potential limitations. It is hoped that the findings from this trial will lead to a sustainable improvement in healthcare and workforce development and training. Trial registration: ISRCTN6329415

Fainting Fanconi syndrome clarified by proxy: a case report

BACKGROUND: Rare diseases may elude diagnosis due to unfamiliarity of the treating physicians with the specific disorder. Yet, advances in genetics have tremendously enhanced our ability to establish specific and sometimes surprising diagnoses. CASE PRESENTATION: We report a case of renal Fanconi syndrome associated with intermittent hypoglycemic episodes, the specific cause for which remained elusive for over 30 years, despite numerous investigations, including three kidney and one liver biopsy. The most recent kidney biopsy showed dysmorphic mitochondria, suggesting a mitochondrial disorder. When her son presented with hypoglycemia in the neonatal period, he underwent routine genetic testing for hyperinsulinemic hypoglycemia, which revealed a specific mutation in HNF4A. Subsequent testing of the mother confirmed the diagnosis also in her. CONCLUSION: Modern sequencing technologies that test multiple genes simultaneously enable specific diagnoses, even if the underlying disorder was not clinically suspected. The finding of mitochondrial dysmorphology provides a potential clue for the mechanism, by which the identified mutation causes renal Fanconi syndrome

The OPERA trial : a protocol for the process evaluation of a randomised trial of an exercise intervention for older people in residential and nursing accommodation

Background: The OPERA trial is large cluster randomised trial testing a physical activity intervention to address depression amongst people living in nursing and residential homes for older people. A process evaluation was commissioned alongside the trial and we report the protocol for this process evaluation. Challenges included the cognitive and physical ability of the participants, the need to respect the privacy of all home residents, including study non-participants, and the physical structure of the homes. Evaluation activity had to be organised around the structured timetable of homes, leaving limited opportunities for data collection. The aims of this process evaluation are to provide findings that will assist in the interpretation of the clinical trial results, and to inform potential implementation of the physical activity intervention on a wider scale. Methods/design: Quantitative data on recruitment of homes and individuals is being collected. For homes in the intervention arm, data on dose and fidelity of the intervention delivered; including individual rates of participation in exercise classes are collected. In the control homes, uptake and delivery of depression awareness training is monitored. These data will be combined with qualitative data from an in-depth study of a purposive sample of eight homes (six intervention and two control). Discussion: Although process evaluations are increasingly funded alongside trials, it is still rare to see the findings published, and even rarer to see the protocol for such an evaluation published. Process evaluations have the potential to assist in interpreting and understanding trial results as well as informing future roll-outs of interventions. If such evaluations are funded they should also be reported and reviewed in a similar way to the trial outcome evaluation

Neural correlates of emotion acceptance vs worry or suppression in generalized anxiety disorder

Recent emotion dysregulationmodels of generalized anxiety disorder (GAD) propose chronic worry in GAD functions as a maladaptive attempt to regulate anxiety related to uncertain or unpredictable outcomes. Emotion acceptance is an adaptive emotion regulation strategy increasingly incorporated into newer cognitive behavioral therapy (CBT) approaches to GAD to counter chronic worry. The current study explores themechanisms of emotion acceptance as an alternate emotion regulation strategy to worry or emotion suppression using functionalmagnetic resonance imaging. Twenty-one female participants diagnosed with GAD followed counterbalanced instructions to regulate responses to personally relevant worry statements by engaging in either emotion acceptance, worry or emotion suppression. Emotion acceptance resulted in lower ratings of distress than worry and was associated with increased dorsal anterior cingulate cortex (dACC) activation and increased ventrolateral prefrontal cortex (VLPFC)-amygdala functional connectivity. In contrast, worry showed significantly greater distress ratings than acceptance or suppression and was associated with increased precuneus, VLPFC, amygdala and hippocampal activation. Suppression did not significantly differ fromacceptance in distress ratings or amygdala recruitment, but resulted in significantly greater insula and VLPFC activation and decreased VLPFC-amygdala functional connectivity. Emotion acceptance closely aligned with activation and connectivity patterns reported in studies of contextual extinction learning and mindful awareness.National Institute of Mental Health (U.S.) (Grant F31 MH084422

Falha de resposta à glibenclamida em criança brasileira com diabetes melito neonatal permanente e síndrome DEND devido a mutação C166Y no gene KCNJ11 (Kir6.2)

Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (PNDM) and several cases have been successfully treated with oral sulfonylureas. We report on the attempted transfer of insulin therapy to glibenclamide in a 4-year old child with PNDM and DEND syndrome, bearing a C166Y mutation in KCNJ11. An inpatient transition from subcutaneous NPH insulin (0.2 units/kg/d) to oral glibenclamide (1 mg/kg/d and 1.5 mg/kg/d) was performed. Glucose and C-peptide responses stimulated by oral glucose tolerance test (OGTT), hemoglobin A1c levels, the 8-point self-measured blood glucose (SMBG) profile and the frequency of hypoglycemia episodes were analyzed, before and during treatment with glibenclamide. Neither diabetes control nor neurological improvements were observed. We concluded that C166Y mutation was associated with a form of PNDM insensitive to glibenclamide.As mutações ativadoras, heterozigóticas do gene KCNJ11 (Kir6.2) são a causa mais freqüente de diabetes melito neonatal permanente (DMNP) e a terapêutica oral com sulfoniluréias tem sido bem sucedida em muitos destes casos. Relatamos o processo de substituição da insulinoterapia convencional para o tratamento oral com glibenclamida em uma paciente de 4 anos, portadora de DMNP e síndrome DEND devido a uma mutação C166Y no gene KCNJ11. A insulina NPH (0,2 U/kg/dia) foi substituída pela glibenclamida (1 mg/kg/dia e 1,5 mg/kg/dia) durante internação hospitalar. As respostas de glicose e peptídeo-C no teste de tolerância oral à glicose (OGTT), os níveis de hemoglobina glicada, o perfil de glicemias capilares de 8 pontos e a freqüência de hipoglicemias foram comparados antes e durante o tratamento com glibenclamida. Não houve melhora no controle glicêmico, nem no quadro neurológico. Concluímos que a mutação C166Y associa-se a uma forma de DMNP insensível à glibenclamida

Whole home exercise intervention for depression in older care home residents (the OPERA study) : a process evaluation

Background: The ‘Older People’s Exercise intervention in Residential and nursing Accommodation’ (OPERA) cluster randomised trial evaluated the impact of training for care home staff together with twice-weekly, physiotherapist-led exercise classes on depressive symptoms in care home residents, but found no effect. We report a process evaluation exploring potential explanations for the lack of effect. Methods: The OPERA trial included over 1,000 residents in 78 care homes in the UK. We used a mixed methods approach including quantitative data collected from all homes. In eight case study homes, we carried out repeated periods of observation and interviews with residents, care staff and managers. At the end of the intervention, we held focus groups with OPERA research staff. We reported our first findings before the trial outcome was known. Results: Homes showed large variations in activity at baseline and throughout the trial. Overall attendance rate at the group exercise sessions was low (50%). We considered two issues that might explain the negative outcome: whether the intervention changed the culture of the homes, and whether the residents engaged with the intervention. We found low levels of staff training, few home champions for the intervention and a culture that prioritised protecting residents from harm over encouraging activity. The trial team delivered 3,191 exercise groups but only 36% of participants attended at least 1 group per week and depressed residents attended significantly fewer groups than those who were not depressed. Residents were very frail and therefore most groups only included seated exercises. Conclusions: The intervention did not change the culture of the homes and, in the case study homes, activity levels did not change outside the exercise groups. Residents did not engage in the exercise groups at a sufficient level, and this was particularly true for those with depressive symptoms at baseline. The physical and mental frailty of care home residents may make it impossible to deliver a sufficiently intense exercise intervention to impact on depressive symptoms

Can training non-physician clinicians/associate clinicians (NPCs/ACs) in emergency obstetric, neonatal care and clinical leadership make a difference to practice and help towards reductions in maternal and neonatal mortality in rural Tanzania? The ETATMBA project

Objectives During late 2010, 36 trainees including 19 assistant medical officers (AMOs) 1 senior clinical officer (CO) and 16 nurse midwives/nurses were recruited from districts across rural Tanzania and invited to join the Enhancing Human Resources and Use of Appropriate Technologies for Maternal and Perinatal Survival in the sub-Saharan Africa (ETATMBA) training programme. The ETATMBA project was training associate clinicians (ACs) as advanced clinical leaders in emergency obstetric care. The trainees returned to health facilities across the country with the hope of being able to apply their new skills and knowledge. The main aim of this study was to explore the impact of the ETATMBA training on health outcomes including maternal and neonatal morbidity and mortality in their facilities. Secondly, to explore the challenges faced in working in these health facilities. Design The study is a pre-examination/postexamination of maternal and neonatal health indicators and a survey of health facilities in rural Tanzania. The facilities surveyed were those in which ETATMBA trainees were placed post-training. The maternal and neonatal indicators were collected for 2011 and 2013 and the survey of the facilities was in early 2014. Results 16 of 17 facilities were surveyed. Maternal deaths show a non-significant downward trend over the 2 years (282–232 cases/100 000 live births). There were no significant differences in maternal, neonatal and birth complication variables across the time-points. The survey of facilities revealed shortages in key areas and some are a serious concern. Conclusions This study represents a snapshot of rural health facilities providing maternal and neonatal care in Tanzania. Enhancing knowledge, practical skills, and clinical leadership of ACs may have a positive impact on health outcomes. However, any impact may be confounded by the significant challenges in delivering a service in terms of resources. Thus, training may be beneficial, but it requires an infrastructure that supports it

A qualitative process evaluation of training for non-physician clinicians/associate clinicians (NPCs/ACs) in emergency maternal, neonatal care and clinical leadership, impact on clinical services improvements in rural Tanzania: the ETATMBA project: Table 1

Objectives The Enhancing Human Resources and Use of Appropriate Training for Maternal and Perinatal Survival in sub-Saharan Africa (ETATMBA) project is training non-physician clinicians as advanced clinical leaders in emergency maternal and newborn care in Tanzania and Malawi. The main aims of this process evaluation were to explore the implementation of the programme of training in Tanzania, how it was received, how or if the training has been implemented into practice and the challenges faced along the way. Design Qualitative interviews with trainees, trainers, district officers and others exploring the application of the training into practice. Participants During late 2010 and 2011, 36 trainees including 19 assistant medical officers one senior clinical officer and 16 nurse midwives/nurses (anaesthesia) were recruited from districts across rural Tanzania and invited to join the ETATMBA training programme. Results Trainees (n=36) completed the training returning to 17 facilities, two left and one died shortly after training. Of the remaining trainees, 27 were interviewed at their health facility. Training was well received and knowledge and skills were increased. There were a number of challenges faced by trainees, not least that their new skills could not be practised because the facilities they returned to were not upgraded. Nonetheless, there is evidence that the training is having an effect locally on health outcomes, like maternal and neonatal mortality, and the trainees are sharing their new knowledge and skills with others. Conclusions The outcome of this evaluation is encouraging but highlights that there are many ongoing challenges relating to infrastructure (including appropriate facilities, electricity and water) and the availability of basic supplies and drugs. This cadre of workers is a dedicated and valuable resource that can make a difference, which with better support could make a greater contribution to healthcare in the country

Development of Instrument to Assess Influence of Extension Conference on Intended Outcomes

The Annual Conference for Mississippi State University Extension is the sole event at which the majority of Extension personnel gather for networking, organizational updates, recognition of efforts, and professional development. Extension leaders plan this conference with intended outcomes but without ever evaluating those outcomes beyond attendee satisfaction. We developed an evaluation instrument to determine how certain conference events influence participants’ critical psychological states and ultimately, their perceived motivation, professional enrichment, opportunities for networking, professional accountability, and organizational awareness. Rather than simply assessing attendee satisfaction, this instrument may help inform planning for successive Extension conferences and other professional development events