IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.

Metabolic dysregulation is one of the most common causes of pediatric neurodegenerative disorders. However, how the disruption of ubiquitous and essential metabolic pathways predominantly affect neural tissue remains unclear. Here we use mouse models of a childhood neurodegenerative disorder caused by AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that mouse models of AMPD2 deficiency exhibit predominant degeneration of the hippocampal dentate gyrus, despite a general reduction of brain GTP levels. Neurodegeneration-resistant regions accumulate micron-sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis, while these filaments are barely detectable in the hippocampal dentate gyrus. Furthermore, we show that IMPDH2 filament disassembly reduces GTP levels and impairs growth of neural progenitor cells derived from individuals with human AMPD2 deficiency. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation, opening the possibility of exploring the induction of IMPDH2 assembly as a therapy for neurodegeneration.

Bones, groans and sending patients home: Perioperative opioid-related harm reduction strategy utilisation in a regional New South Wales (NSW) hospital.

OBJECTIVE: Perioperative initiation of opioids continues to be a major contributor to chronic use, misuse and diversion in regional areas. There is considerable effort to mitigate harm through avoiding excessive prescribing and reducing the risk of persistent postoperative opioid use. Improving perioperative documentation practices has been reported to ensure appropriate opioid initiation and de-escalation. It has not been established whether these strategies are utilised in regional hospitals. METHODS: A retrospective observational study of perioperative opioid prescribing and documentation practices in Goulburn Base Hospital, a regional centre in the Southern New South Wales (NSW) Local Health District. Data were collected from 110 records and validated for adult patients undergoing elective total knee replacement (TKR) or total hip replacement (THR) from 12 January 2020 to 13 January 2021. OUTCOME MEASURES: To observe perioperative opioid prescribing and utilisation of harm reduction strategies in a regional hospital. RESULTS: 65% of patients were opioid naïve (ON). Preoperative pain assessments and patient education were completed in 23% and 15% of records, respectively. Postoperative opioids were prescribed for 99% of patients, with 74% prescribed a slow-release (SR) formulation. 50% of patients were discharged with an SR prescription. Inadequate postoperative pain control was reported in 21% of patients. Of the 103 patients prescribed opioids on discharge, only 20% included a de-escalation plan and only 35% of discharge summaries included dose and quantity of opioids supplies. CONCLUSIONS: This study has identified underutilisation of perioperative harm reduction strategies despite the potential to improve appropriate initiation and de-escalation of opioids. These findings highlight opportunities for improvement in regional hospitals.

Preparing Students for Change: An Advisement Seminar Informed by Tolman and Kremling's Integrated Model of Student Resistance.

Graduate students entering entry-level occupational therapy programs are confronted by new ways of learning and interacting for which they may be ill-prepared. Confronted with the need to change their approach to learning, students may become frustrated and lose motivation, resulting in resistance. This article describes a pilot first term group advisement seminar, informed by Tolman and Kremling. Integrated Model of Student Resistance (IMSR), and designed to prepare students for these necessary changes. The article describes topics addressed, strategies implemented, and insights and reflections on the process and outcomes of participation in the seminar.

Coping with workplace minority stress: Associations between dyadic coping and anxiety among women in same-sex relationships.

Sexual minorities are exposed to stressors in the workplace (workplace minority stress), which can be detrimental for well-being (e.g., levels of anxiety). The present study examined whether a particular set of relationship processes, dyadic coping, served to moderate the association between workplace minority stress and symptoms of anxiety. Using a dyadic sample of 64 female same-sex couples, we found that partner problem-focused supportive dyadic coping (DC) and emotion-focused supportive DC (marginally) buffered, whereas partner delegated DC and negative DC did not moderate, the association between workplace minority stress and symptoms of anxiety. Implications for relationship researchers and mental health practitioners are discussed.

IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.

Metabolic dysregulation is one of the most common causes of pediatric neurodegenerative disorders. However, how the disruption of ubiquitous and essential metabolic pathways predominantly affect neural tissue remains unclear. Here we use mouse models of AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that AMPD deficiency in mice primarily leads to hippocampal dentate gyrus degeneration despite causing a generalized reduction of brain GTP levels. Remarkably, we found that neurodegeneration resistant regions accumulate micron sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis. In contrast, IMPDH2 filaments are barely detectable in the hippocampal dentate gyrus, which shows a progressive neuroinflammation and neurodegeneration. Furthermore, using a human AMPD2 deficient neural cell culture model, we show that blocking IMPDH2 polymerization with a dominant negative IMPDH2 variant, impairs AMPD2 deficient neural progenitor growth. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation in neurons with available GTP precursor molecules, providing resistance to neurodegeneration. Our findings open the possibility of exploring the involvement of IMPDH2 assembly as a therapeutic intervention for neurodegeneration.

Volunteer Service From American Physicians During the Vietnam War.

This article draws on resources from the American Medical Association Archives on the Volunteer Physicians for Vietnam Program (1966-1973) to consider benefits and costs of immersion opportunities in medical education. Selected images and reports illuminate how such programs can influence both physicians-in-training and the environments in which they are immersed.

Naming and the Public Health Roles of Physicians.

Resources from the American Medical Association (AMA) Archives facilitate historical consideration of how physicians' authority has been exercised in naming diseases, epidemics, and other health-related issues of national importance. Selected images emphasize physicians' roles in motivating public health initiatives through public service posters, advertisements, and minutes of the AMA House of Delegates meetings.

Impact of integrated cerebrovascular program on outcomes in patients with intracranial aneurysms.

BACKGROUND: Recent evidence indicates that multidisciplinary care improves patient outcomes in cerebrovascular (CV) disease. A multidisciplinary integrated CV program was recently instituted at a high-volume tertiary referral center, providing the opportunity to evaluate patient outcomes before and after its introduction. OBJECTIVE: To evaluate outcomes after treatment of patients with intracranial aneurysm in relation to the introduction of a CV program at our institution. METHODOLOGY: A retrospective chart review was performed on all new patient encounters for a 6-month period each before and immediately after the introduction of the CV program, as well as at a more recent 6-month period to evaluate long-term results. Data were collected on demographic variables, rupture status, medical comorbidities, hospital complications, in-hospital procedures, hospital course and modified Rankin score at discharge and follow up. RESULTS: The total number of patients treated increased from 55 in the 6-month period before the introduction of the CV program to 112 in the most recent time period (p<0.05). Both the surgical clipping and endovascular coiling procedures increased (p<0.05). A significant increase occurred in patients with multiple comorbidities (30.5% vs 34.7%, p=0.035). The mean length of stay decreased from 12.22 ± 13.26 days before the program to 9.23 ± 12.04 days in the most current data (p<0.05). CONCLUSIONS: Creation of an integrated CV program at a large-volume tertiary referral center resulted in better outcomes for an increased number of more medically complicated patients with intracranial aneurysms. This study provides preliminary data for developing an integrated model of multidisciplinary care for the management of CV disease.