Distinct changes to hippocampal and medial entorhinal circuits emerge across the progression of cognitive deficits in epilepsy.

Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneous in vivo electrophysiology in hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within MEC and between HPC-MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.

Development of a novel and more holistic approach for assessing impact in health and medical research: the Research Impact Assessment Framework.

Considered investment in health and medical research (HMR) is critical for fostering a healthcare system that is sustainable, effective, responsive, and innovative. While several tools exist to measure the impact of research, few assess the research environment that nurtures and supports impactful research and the strategic alignment of research with societal needs. This perspective article discusses the limitations of existing assessment tools and presents a novel Research Impact Assessment Framework designed to enable more strategic and targeted investment towards HMR, having the potential for significant public benefit.

Characteristics of patients diagnosed with pancreatic cancer who access palliative care: An observational study.

PURPOSE: Despite the benefits of palliative care (PC) in pancreatic cancer, little is known about patients who access PC. This observational study examines the characteristics of patients with pancreatic cancer at their first episode of PC. METHODS: First-time, specialist PC episodes captured through the Palliative Care Outcomes Collaboration (PCOC), in Victoria, Australia between 2014 and 2020, for pancreatic cancer, were identified. Multivariable logistic regression analyses examined the impact of patient- and service-level characteristics on symptom burden (measured through patient-reported outcome measures and clinician-rated scores) at first PC episode. RESULTS: Of 2890 eligible episodes, 45% began when the patient was deteriorating and 32% ended in death. High fatigue and appetite-related distress were most common. Generally, increasing age, higher performance status and more recent year of diagnosis predicted lower symptom burden. No significant differences were noted between symptom burden of regional/remote versus major city dwellers; however, only 11% of episodes recorded the patient as a regional/remote resident. A greater proportion of first episodes for non-English-speaking patients began when the patient was unstable, deteriorating or terminal, ended in death and were more likely to be associated with high family/carer problems. Community PC setting predicted high symptom burden, with the exception of pain. CONCLUSION: A large proportion of first-time specialist PC episodes in pancreatic cancer begin at a deteriorating phase and end in death, suggesting late access to PC. Timely referrals to community-based specialist PC, access in regional/remote areas, as well as development of culturally diverse support systems require further investigation.

Systematic review of the predictors of health service use in pancreatic cancer.

INTRODUCTION: Pancreatic cancer (PC) has a dismal prognosis, with identified disparities in survival outcomes based on demographic characteristics. These disparities may be ameliorated by equitable access to treatments and health services. This systematic review identifies patient and service-level characteristics associated with PC health service utilisation (HSU). METHODS: Medline, Embase, CINAHL, PsycINFO and Scopus were systematically searched between 1st January, 2010 and 17 May, 2021 for population-based, PC studies which conducted univariable and/or multivariable regression analyses to identify patient and/or service-level characteristics associated with use of a treatment or health service. Direction of effect sizes were reported in an aggregate manner. RESULTS: Sixty-two eligible studies were identified. Most (48/62) explored the predictors of surgery (n=25) and chemotherapy (n=23), and in populations predominantly based in the United States of America (n=50). Decreased HSU was observed among people belonging to older age groups, non-Caucasian ethnicities, lower socioeconomic status (SES) and lower education status. Non-metropolitan location of residence predicted decreased use of certain treatments, and was associated with reduced hospitalisations. People with comorbidities were less likely to use treatments and services, including specialist consultations and palliative care but were more likely to be hospitalised. A more recent year of diagnosis/year of death was generally associated with increased HSU. Academically affiliated and high-volume centres predicted increased treatment use and hospital readmissions. CONCLUSION: Findings of this review may assist identification of vulnerable patient groups experiencing disparities in accessing and using treatments and therapies.

A qualitative investigation of the supportive care experiences of people living with pancreatic and oesophagogastric cancer.

BACKGROUND: Pancreatic and oesophagogastric (OG) cancers have a dismal prognosis and high symptom burden, with supportive care forming an integral component of the care provided to patients. This study aimed to explore the supportive care experiences of patients and caregivers living with pancreatic and OG cancers in order to identify perceived opportunities for improvement. METHODS: Semi-structured individual interviews were conducted with people living with pancreatic and OG cancers, and their caregivers, across Victoria, Australia during 2020. Interviews were thematically analysed to identify common themes. RESULTS: Forty-one participants were interviewed, including 30 patients and 11 caregivers. Three overarching themes, each with multiple sub-themes, were identified: (i) inadequate support for symptoms and issues across the cancer journey (ii) caregiver's desire for greater support, and (iii) a multidisciplinary care team is the hallmark of a positive supportive care experience. Generally, those who had access to a cancer care coordinator and/or a palliative care team recounted more positive supportive care experiences. CONCLUSION: Unmet needs are prevalent across the pancreatic and OG cancer journey, with supportive care provided to varying levels of satisfaction. Greater awareness of and access to high-quality multidisciplinary support services is greatly desired by both patients with pancreatic and OG cancer and their caregivers.

Implementing innovative evidence-based perinatal mental health screening for women of refugee background.

PROBLEM: National guidelines recommend repeated screening for depression and anxiety for all women in the perinatal period. Routine screening in pregnancy is limited due to service, community and individual barriers. BACKGROUND: Perinatal depression and perinatal anxiety affect up to 20% of all women. Women of refugee background are at even greater risk for perinatal mental health conditions due to refugee experiences and resettlement stressors. AIM: To evaluate the acceptability and feasibility of a perinatal mental health screening program for women of refugee background from the perspective of health professionals. METHODS: A mixed methods design guided by the Normalization Process Theory was used. Data were collected at a dedicated refugee antenatal clinic in the south-eastern suburbs of Melbourne, Australia. An online survey (n=38), focus groups (n=2; 13 participants) and semi-structured interviews (n=8; 11 participants) with health professionals were conducted. FINDINGS: Under the four constructs of the Normalization Process Theory, health professionals reported improvements in identifying and referring women with mental health issues, more open and in-depth conversations with women about mental health and valued using an evidenced-based measure. Key issues included professional development, language barriers and time constraints. DISCUSSION: Implementing a perinatal mental health screening program has been positively received. Strategies for sustainability include professional development and the addition of audio versions of the measures. CONCLUSION: This perinatal mental health screening program is acceptable and a feasible option for health professionals. Health professionals value providing more holistic care and have more open discussion with women about mental health.

Development and evaluation of an early menopause question prompt list.

OBJECTIVE: A question prompt list (QPL)-a structured list of questions-assists women in acquiring relevant information and facilitates communication with healthcare providers (HPs). This study aims to co-develop an early menopause (EM) QPL and assess its acceptability and feasibility. METHODS: This three-phase study consisted of a survey to inform QPL development, interviews to explore acceptability, and clinical pilot-testing to assess feasibility. Participants included: 263 survey respondents with EM, 18 women interviewed, and 11 women and 6 HPs in pilot-testing. Main outcome measures were: survey-perceptions regarding communication with HPs, likeliness to use a QPL and QPL topics; interviews-QPL user-friendliness and acceptability; pilot study-women's QPL use, perceived helpfulness and future use, and HPs' perceived acceptability. Data analysis included descriptive statistics, logistic regression, and thematic analysis. RESULTS: Women's perceived communication difficulties most commonly related to sexual function (50.6%), vaginal/urinary symptoms (43%), and psychological effects (41.1%). Most women (67.3%) indicated they were very likely to use an EM QPL. EM symptoms, effects, and management were considered very important/essential QPL topics (>80%). Interviewed women perceived the QPL as comprehensive, user-friendly, informative, and empowering. Most pilot study women asked 1 to 2 questions (73%), perceived the QPL as helpful (100%), and would use it again (81.8%). HPs reported that the QPL helped patients to ask questions and initiate discussion about important and sensitive issues. CONCLUSIONS: Women with EM have unmet information and communication needs, and are supportive of a comprehensive EM QPL. The EM QPL was perceived as an acceptable and feasible resource for women to use during medical consultations. : Video Summary:http://links.lww.com/MENO/A484.

Preconception Health Attitudes and Behaviours of Women: A Qualitative Investigation.

The preconception period is a critical window in which maternal health can profoundly affect both individual and intergenerational health. Despite its importance, little information about women's preconception health attitudes, behaviours and information preferences exists, yet these details are vital to inform targeted health communication. Semi-structured interviews were conducted to explore women's attitudes to preconception health (areas of importance, support sources, enablers and barriers), behaviours (information seeking and health actions taken) and information preferences. Interviews were transcribed, coded and thematically analysed. Fifteen women participated (n = 7 preconception, n = 7 pregnant and n = 1 postpartum). Women perceived optimising lifestyle behaviours including a healthy diet, regular physical activity, reducing alcohol intake and pre-pregnancy vitamin supplementation as important preconception health actions to adopt. Few women acknowledged the importance of formal preconception health checks and screening with health professionals. Barriers to achieving health behaviour change included anxiety, stress and challenges obtaining reputable information. Participants reported a lack of preconception information about supplementation requirements, safe foods and exercise recommendations. Information preferences included the internet or their general practitioner. Whilst women predominantly prioritised optimising diet and physical activity prior to pregnancy, there appeared to be limited awareness of preconception health checks and screening, highlighting a need for broader awareness of overall preconception health and wellbeing.

Identifying and addressing osteoporosis knowledge gaps in women with premature ovarian insufficiency and early menopause: A mixed-methods study.

OBJECTIVE: Osteoporosis associated with premature ovarian insufficiency (POI) and early menopause (EM) is a major concern for women. We aimed to (a) identify information and knowledge gaps and behaviours regarding bone health in women with POI/EM and (b) co-design an osteoporosis fact sheet. DESIGN: Mixed-methods study: survey of women and online resource appraisals to develop and refine, using semi-structured interviews, an osteoporosis fact sheet. PATIENTS: Women with POI/EM (menopause before ages 40 and 45 years respectively). MEASUREMENTS: Demographics, comorbidities, information needs, calcium intake, exercise, osteoporosis knowledge (OKAT), beliefs and self-efficacy, DISCERN appraisal (validated scales). ANALYSIS: descriptive statistics, logistic regression and thematic analysis of interviews. RESULTS: Median age of survey respondents (n = 316) was 54(IQR47-63) years, median age of menopause was 40(IQR38-43) years, and osteoporosis diagnosis was reported in 19%. Most reported inadequate dietary calcium intake (99%) and exercise (65%). Median OKAT score 8 [IQR6-10]/19 indicated knowledge gaps regarding risk factors and treatment options. Adjusting for age and education, OKAT predicted calcium intake (OR 1.126 [CI 1.035-1.225]; P = 0.006) and screening (OR 1.186 [CI 1.077-1.305]; P = 0.001); beliefs predicted screening (OR 1.027 [CI 1.004-1.050]; P = 0.019); and self-efficacy predicted calcium intake (OR1.040 (CI 1.013-1.069); P = 0.003] and exercise (OR 1.117 [CI 1.077-1.160]; P < 0.001). Current online resources have deficiencies. Five themes identified from two interview rounds (n = 10/ round) were as follows: content, emotional response, design, perceived usefulness and clinical considerations. The final fact sheet was considered acceptable and useful in addressing knowledge gaps, promoting information-seeking, impacting behaviours and facilitating healthcare discussions. CONCLUSION: A co-designed fact sheet is acceptable and addresses identified osteoporosis knowledge gaps in women with POI/EM.

Histone deacetylase inhibitors restore normal hippocampal synaptic plasticity and seizure threshold in a mouse model of Tuberous Sclerosis Complex.

Abnormal synaptic plasticity has been implicated in several neurological disorders including epilepsy, dementia and Autism Spectrum Disorder (ASD). Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder that manifests with seizures, autism, and cognitive deficits. The abnormal intracellular signaling underlying TSC has been the focus of many studies. However, nothing is known about the role of histone modifications in contributing to the neurological manifestations in TSC. Dynamic regulation of chromatin structure via post translational modification of histone tails has been implicated in learning, memory and synaptic plasticity. Histone acetylation and associated gene activation plays a key role in plasticity and so we asked whether histone acetylation might be dysregulated in TSC. In this study, we report a general reduction in hippocampal histone H3 acetylation levels in a mouse model of TSC2. Pharmacological inhibition of Histone Deacetylase (HDAC) activity restores histone H3 acetylation levels and ameliorates the aberrant plasticity in TSC2+/- mice. We describe a novel seizure phenotype in TSC2+/- mice that is also normalized with HDAC inhibitors (HDACis). The results from this study suggest an unanticipated role for chromatin modification in TSC and may inform novel therapeutic strategies for TSC patients.

Development of a question prompt list for women with polycystic ovary syndrome.

OBJECTIVE: To develop a question prompt list (QPL) for women with polycystic ovary syndrome (PCOS) and explore its acceptability and feasibility. DESIGN: Nationwide online survey, interviews, and clinical pilot test. SETTING: Australia. PATIENT(S): Two-hundred and forty-nine women online, 18 women in interviews, and 20 women in clinics. INTERVENTION(S): A QPL for PCOS. MAIN OUTCOME MEASURE(S): From survey, women's likeliness to use a QPL and priority topics; from interview, QPL user-friendliness and associated feelings; from pilot, women's QPL use, perceived helpfulness, and intended future use. RESULT(S): Evidence-based guidelines and multidisciplinary experts informed the QPL development. Of 249 survey respondents, 66.7% to 68.7% reported difficulty communicating with health care providers about mood, weight management, and how PCOS affects daily life, and 85.8% indicated they were very likely to use a PCOS QPL. Women were interviewed to explore acceptability; the semistructured interviews (n = 18) revealed that the devised QPL was easy to understand, user-friendly, and encouraged information seeking and targeted question asking. The refined QPL was pilot-tested in a clinic setting to explore feasibility between 2016 and 2017: 60.0% of women asked 1 to 2 questions from the QPL, 20.0% asked several questions, and 10.0% reported the QPL helped them generate their own questions. Women agreed the QPL was helpful (95.0%) and that they would use the QPL again (90.0%). CONCLUSION(S): The PCOS QPL is acceptable and feasible, and may assist women in information seeking and targeted question asking.

Recent gene therapy advancements for neurological diseases.

The past few years have seen rapid advancements in vector-mediated gene transfer to the nervous system and modest successes in human gene therapy trials. The purpose of this review is to describe commonly-used viral gene transfer vectors and recent advancements towards producing meaningful gene-based treatments for central nervous system (CNS) disorders. Gene therapy trials for Canavan disease, Batten disease, adrenoleukodystrophy, and Parkinson's disease are discussed to illustrate the current state of clinical gene transfer to the CNS. Preclinical studies are under way for a number of diseases, primarily lysosomal storage disorders, using a newer generation of vectors and delivery strategies. Relevant studies in animal models are highlighted for Mucopolysaccharidosis IIIB and Krabbe disease to provide a prelude for what can be expected in the coming years for human gene transfer trials, using recent advancements in gene transfer technology. In conclusion, recent improvements in CNS gene transfer technology are expected to significantly increase the degree of disease rescue in future CNS-directed clinical trials, exceeding the modest clinical successes that have been observed so far.