The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

What Do Program and Geographic Preference Signals Signal? A Survey of Diagnostic Radiology and Integrated Interventional Radiology Residency Applicants.

RATIONALE AND OBJECTIVES: As part of the 2022-2023 Diagnostic/Interventional Radiology residency application process, applicants could participate in the ERAS supplemental application, including sending up to six preference signals and three geographic signals. Our goal was to survey Diagnostic Radiology and Integrated Interventional Radiology applicants at two large academic institutions in different geographic locations regarding their perceived impact of program and geographic preference signaling on the application process. METHODS: An anonymous survey was sent to 282 applicants between two academic medical centers asking about their participation in program and geographic preference signaling as well as their perception on its impact on the application process. RESULTS: 105 applicants responded to the survey (37.2% [105/282]). Most applicants (26% [27/102]) received four interviews from signaled programs. When prompted to best describe their sentiments with respect to program signaling (one being most negative and five being most positive), the plurality of applicants reported a positive sentiment of four (36% [37/103]). Applicants that received four to six interviews from signaled programs were significantly more likely to feel positively towards program signaling than those that received one to three interviews (p = 0.01). Geography was the most important deciding factor on which programs to signal for applicants (57% [58/101]). DISCUSSION: Our survey results demonstrate that most applicants felt positively towards program signaling and it increased their odds of receiving interviews from preferred programs, which is consistent with the current literature. CONCLUSION: Program and geographic signaling are relatively new features of the ERAS residency application process and therefore, their effects on the match outcome are still in question. However, our study results indicate that they are perceived positively by most applicants and that they boost their chances in finding their ideal match.

Dorsal hippocampus to nucleus accumbens projections drive reinforcement via activation of accumbal dynorphin neurons.

The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli. Despite extensive research on dHPC→NAc direct projections, their sufficiency in driving reinforcement and reward-related behavior remains to be determined. Our study establishes that activating excitatory neurons in the dHPC is sufficient to induce reinforcing behaviors through its direct projections to the dorso-medial subregion of the NAc shell (dmNAcSh). Notably, dynorphin-containing neurons specifically contribute to dHPC-driven reinforcing behavior, even though both dmNAcSh dynorphin- and enkephalin-containing neurons are activated with dHPC stimulation. Our findings unveil a pathway governing reinforcement, advancing our understanding of the hippocampal circuity's role in reward-seeking behaviors.

Groundfish biodiversity change in northeastern Pacific waters under projected warming and deoxygenation.

In the coming decades, warming and deoxygenation of marine waters are anticipated to result in shifts in the distribution and abundance of fishes, with consequences for the diversity and composition of fish communities. Here, we combine fisheries-independent trawl survey data spanning the west coast of the USA and Canada with high-resolution regional ocean models to make projections of how 34 groundfish species will be impacted by changes in temperature and oxygen in British Columbia (BC) and Washington. In this region, species that are projected to decrease in occurrence are roughly balanced by those that are projected to increase, resulting in considerable compositional turnover. Many, but not all, species are projected to shift to deeper depths as conditions warm, but low oxygen will limit how deep they can go. Thus, biodiversity will likely decrease in the shallowest waters (less than 100 m), where warming will be greatest, increase at mid-depths (100-600 m) as shallow species shift deeper, and decrease at depths where oxygen is limited (greater than 600 m). These results highlight the critical importance of accounting for the joint role of temperature, oxygen and depth when projecting the impacts of climate change on marine biodiversity. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

Interprofessional Extracorporeal Membrane Oxygenation Cardiopulmonary Resuscitation Simulations Aimed at Decreasing Actual Cannulation Times: A Longitudinal Study.

BACKGROUND: Since 2013, the cardiac intensive care unit (CICU) at Children's National has conducted annual extracorporeal membrane oxygenation cardiopulmonary resuscitation (ECPR) simulations that focus on team dynamics, room setup, and high-quality CPR. In 2019 and 2020, the simulations were expanded to include the surgical and extracorporeal membrane oxygenation (ECMO) teams in an effort to better understand and improve this process. METHODS: During a 4-week period in 2019, 7 peripheral ECPR simulations were conducted, and through a 3-week period in 2020, 7 central ECPR simulations were conducted. Participants in each session included: 8 to 10 CICU nurses, 1 CICU attending, 1 to 2 ICU or cardiology fellows, 1 cardiovascular surgery fellow or attending, and 1 ECMO specialist. For each session, the scenario continued until the simulated patient was on full cardiopulmonary bypass. An ECMO trainer was used for peripheral simulations and a 3-dimensionally-printed heart was used for central cannulations. An ECMO checklist was used to objectively determine when the patient and room were fully prepared for surgical intervention, and simulated cannulation times were recorded for both groups. A retrospective chart review was conducted to compare actual cannulation times before and after the intervention period, and video was used to review the events and assist in dividing them into medical versus surgical phases. Control charts were used to trend the total ECPR times before and after the intervention period, and mean and P values were calculated for both ECPR times and for all other categorical data. RESULTS: Mean peripheral ECPR times decreased significantly from 71.7 to 45.1 minutes ( P = 0.036) after the intervention period, and this was reflected by a centerline shift. Although we could not describe a similar decrease in central ECPR times because there were only 6 postintervention events, the times for each of these events were shorter than the historical mean of 37.8 minutes. There was a trend in improved survival, which did not meet significance both among patients undergoing peripheral ECPR (15.4% ± 10% to 43.8% ± 12.4%, P = 0.10) and central ECPR (36.4% ± 8.4% to 50% ± 25%, P = 0.60). The percentage of time dedicated to the medical phases of the actual versus simulated procedures was very consistent among both peripheral (33.0% vs. 31.9%) and central (39.6% vs. 39.8%) cannulations. CONCLUSIONS: We observed a significant decrease in peripheral cannulation times at our institution after conducting interprofessional ECPR simulations taken to the establishment of full cardiopulmonary bypass. The use of an ECMO trainer and a 3-dimensionally-printed heart allowed for both the medical and surgical phases of the procedure to be studied in detail, providing opportunities to streamline and improve this complex process. Larger multisite studies will be needed in the future to assess the effect of efforts like these on patient survival.

Lateral septum DREADD activation alters male prairie vole prosocial and antisocial behaviors, not partner preferences.

Although much has been written on the topic of social behavior, many terms referring to different aspects of social behavior have become inappropriately conflated and the specific mechanisms governing them remains unclear. It is therefore critical that we disentangle the prosocial and antisocial elements associated with different forms of social behavior to fully understand the social brain. The lateral septum (LS) mediates social behaviors, emotional processes, and stress responses necessary for individuals to navigate day-to-day social interactions. The LS is particularly important in general and selective prosocial behavior (monogamy) but its role in how these two behavioral domains intersect is unclear. Here, we investigate the effects of chemogenetic-mediated LS activation on social responses in male prairie voles when they are 1) sex-naïve and generally affiliative and 2) after they become pair-bonded and display selective aggression. Amplifying neural activity in the LS augments same-sex social approach behaviors. Despite partner preference formation remaining unaltered, LS activation in pair-bonded males leads to reduced selective aggression while increasing social affiliative behaviors. These results suggest that LS activation alters behavior within certain social contexts, by increasing sex-naïve affiliative behaviors and reducing pair bonding-induced selective aggression with same-sex conspecifics, but not altering bonding with opposite-sex individuals.

A Pilot Study Assessing Retinal Blood Flow Dysregulation in Glaucoma Using Erythrocyte Mediated Velocimetry.

Purpose: The purpose of this study was to compare autoregulation of retinal arteriolar and venular blood flow in patients with glaucoma, glaucoma suspect participants, and control participants using erythrocyte mediated velocimetry. Methods: This prospective cohort pilot study included 7 eyes of 5 participants with glaucoma, 15 eyes of 8 glaucoma suspect participants, and 11 eyes of 6 control participants. Mean erythrocyte velocity in retinal arterioles and venules was measured using erythrocyte mediated velocimetry at room air and after oxygen supplementation. Change in erythrocyte velocity was compared among all groups using generalized estimating equations. Results: In total, 64 vessels (18 with glaucoma, 31 that were glaucoma suspect, and 15 controls) of 33 eyes of 19 participants were analyzed. There was no significant difference in baseline velocities in arterioles or venules among the three groups. With induction of hyperoxia, mean arterial erythrocyte velocity decreased in glaucoma (-7.2 ± 13.7%), which differed from controls and glaucoma suspects where erythrocyte velocity increased with hyperoxia by 4.6 ± 13.3% (P = 0.002) and 7.2 ± 21.7% (P = 0.03), respectively. A higher baseline arteriolar velocity (ß = -3.9% per mm/s, P = 0.002), glaucoma diagnosis (ß = -21.1%, P = 0.03), and White race (ß = -20.0%, P = 0.01) were associated with decreased velocity in response to arterial hyperoxia. Conclusions: Hyperoxia increased erythrocyte velocity in control and glaucoma suspect participants, but decreased erythrocyte velocity in glaucoma participants, possibly due to impaired autoregulation. Baseline velocity, glaucoma diagnosis, and White race were associated with a decrease in velocity with induction of hyperoxia. Translational Relevance: The European Medicines Agency (EMA) permits precision measurements of blood flow which may aid in the development of biomarkers of glaucoma-related dysregulation of blood flow.

Synergistic consequences of early-life social isolation and chronic stress impact coping and neural mechanisms underlying male prairie vole susceptibility and resilience.

Chronic stress can be challenging, lead to maladaptive coping strategies, and cause negative mental and physical health outcomes. Early-life adversity exposes developing young to physical or psychological experiences that risks surpassing their capacity to effectively cope, thereby impacting their lifetime physical and mental wellbeing. Sensitivity to stressful events, like social isolation, has the potential to magnify stress-coping. Chronic stress through social defeat is an established paradigm that models adverse early-life experiences and can trigger enduring alterations in behavioral and neural phenotypes. To assess the degree to which stress resilience and sensitivity stemming from early-life chronic stress impact sociability, we exposed male prairie voles to chronic social defeat stress (CSDS) during adolescence. We simultaneously exposed subjects to either social isolation (CSDS+Isol) or group housing (CSDS+Soc) during this crucial time of development. On PND41, all subjects underwent a social approach test to examine the immediate impact of isolation, CSDS, or their combined effects on sociability. Unlike the CSDS+Isol group which primarily displayed social avoidance, the CSDS+Soc group was split by individuals exhibiting susceptible or resilient stress phenotypes. Notably, the Control+Soc and CSDS+Soc animals and their cage-mates significantly gained body weight between PND31 and PND40, whereas the Control+Isol and CSDS+Isol animals did not. These results suggest that the effects of early-life stress may be mitigated by having access to social support. Vasopressin, oxytocin, and opioids and their receptors (avpr1a, oxtr, oprk1, oprm1, and oprd1) are known to modulate social and stress-coping behaviors in the lateral septum (LS). Therefore, we did an mRNA expression analysis with RT-qPCR of the avpr1a, oxtr, oprk1, oprm1, and oprd1 genes to show that isolation and CSDS, or their collective influence, can potentially differentially bias sensitivity of the LS to early-life stressors. Collectively, our study supports the impact and dimensionality of early-life adversity because the type (isolation vs. CSDS), duration (acute vs. chronic), and combination (isolation + CSDS) of stressors can dynamically alter behavioral and neural outcomes.

Prostate cancer grade downgrading at time of prostatectomy provides risk-stratification insight into future tumor behavior after prostatectomy.

BACKGROUND: Prostate biopsy (Bx) sampling-based diagnosis of prostate cancer (PCa) has well-described inaccuracy when compared against whole gland analysis upon prostatectomy. Although upgrading of PCa Grade Group (GG) is often described, the occurrence and prognostic implications of downgrading PCa GG at the time of radical prostatectomy (RP) is less understood. Our objective was to evaluate whether downgrading PCa GG at the time of RP was associated with future tumor behavior. METHODS: The SEER database was searched from 2010 to 2017 and patients were included if they were assigned pathological grades on both Bx and RP specimen. Patients were stratified into Bx GG > RP GG and Bx GG ≤ RP GG groups, and tumor behavior after treatment was examined. Cox regression was used for the survival analysis. RESULTS: Here, 99,835 patients were included in this study. A total of 18,516 (18.5%) patients encountered downgrading from Bx GG to RP GG. A downgrading of 1 grade occurred in 13,969 (75.4%) of these patients and of 2 or more grades occurred in 4547 (24.6%) patients. A history of higher Bx GG compared with RP GG increased the risk of cancer-specific mortality (CSM) for each given RP GG controlling for age, race, preop prostate-specific antigen level, percentage of positive biopsy cores, and pathologic TNM stages. Specifically, a history of high Bx GG conferred a 45% increased risk of CSM for any given RP GG (hazard ratio = 1.45 95% confidence interval = 1.16-1.82, p < 0.001). CONCLUSION: A history of higher Bx GG, and hence downgrading at the time of RP, demonstrates some value as a risk-stratification tool for future cancer outcomes after prostatectomy.

Identifying Patient-Centered Research Priorities in Overactive Bladder by Crowdsourcing and Targeted Recruitment.

INTRODUCTION: Patient perspectives in quality-of-life improvement are critical to measuring treatment outcomes. We aimed to identify patient priorities for overactive bladder (OAB) research. METHODS: Participants were recruited utilizing the Amazon Mechanical Turk database, an online marketplace where individuals receive payment for completing tasks. Those who scored 4 or higher on the OAB-V3, a simple 3-question screening survey, were requested to complete an "OAB-q and Prioritization Survey," which identified preferences for future OAB research priorities, demographic and clinical data, and symptom severity via the OAB-q. Participants must have correctly answered an attention-confirming question to have their responses included in the final analysis. RESULTS: Of 555 responders, 352 screened positive on the OAB-V3 and 232 completed the followup survey and met study criteria. The top 3 research preferences were: discovering the etiology of OAB (31%); individualized treatment based on age, race, gender and comorbidities (19%); and identifying the fastest OAB treatments (15%). Participants who selected etiology of OAB in the top 3 research priorities (56%) were older (38.7±2.1 vs 33.9±1.5 years, p=0.05) and had significantly lower mean health-related quality of life scores than those who did not (25.1±2.5 vs 35.5±3.9, p=0.02). CONCLUSIONS: Using Amazon Mechanical Turk, we present the first report of OAB research priorities identified by patients experiencing OAB symptoms. Crowdsourcing offers a timely and cost-effective manner to learn directly from people with OAB symptoms. Few participants sought treatment for OAB despite having bothersome symptoms.

Sociodemographic Factors Associated with Types of Projects Implemented by Volunteer Lay Health Educators in Their Congregations.

This study focused on the association between type of community health interventions and lay health educator variables. Lay health educators are volunteers from local faith communities who complete a healthcare training program, taught by physicians in-training. Lay health educators are instructed to implement health-related initiatives in their respective communities after graduation. Of the 72 graduates since 2011, we surveyed 55 lay health educators to gain insight into their involvement with their congregation and the type of health projects they have implemented. We dichotomized the health projects into "raising awareness" and "teaching new health skills." Using adjusted logistic regression models, variables associated with implementing health projects aimed at teaching health skills included length of time as a member of their congregation, current employment, and age. These results may help future programs prepare lay health community educators for the type of health interventions they intend to implement in their respective communities.

Reversing behavioural abnormalities in mice exposed to maternal inflammation.

Viral infection during pregnancy is correlated with increased frequency of neurodevelopmental disorders, and this is studied in mice prenatally subjected to maternal immune activation (MIA). We previously showed that maternal T helper 17 cells promote the development of cortical and behavioural abnormalities in MIA-affected offspring. Here we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ). Moreover, activation of pyramidal neurons in this cortical region was sufficient to induce MIA-associated behavioural phenotypes in wild-type animals, whereas reduction in neural activity rescued the behavioural abnormalities in MIA-affected offspring. Sociability and repetitive behavioural phenotypes could be selectively modulated according to the efferent targets of S1DZ. Our work identifies a cortical region primarily, if not exclusively, centred on the S1DZ as the major node of a neural network that mediates behavioural abnormalities observed in offspring exposed to maternal inflammation.

Outcomes of percutaneous pedicle screw fixation for spinal trauma and tumours.

We investigated the clinical and radiological results of percutaneous pedicle screw fixation in the management of spinal trauma and metastatic tumours. A retrospective analysis was performed on a series of 14 patients who were operated on from March 2009 to November 2011 by a single surgeon (RJM). Following a radiological review (CT scan/MRI), six patients underwent short segment fixation, while the remaining underwent long segment fixation. All patients had routine follow-ups at 4, 6, 12months, and annually thereafter. Clinical examinations were conducted preoperatively and postoperatively, and the length of operation, blood loss, and postoperative pain relief were recorded. There was a single patient with an incision site complication. The mean blood loss was 269mL. All of the parameters demonstrated no significant differences between the trauma and the tumour groups (p=0.10). The neurological power scores improved for all patients, with the largest increase being from a score of 2 to 4. At follow-up, the majority of patients had returned to their previous activities and had reduced pain scores. One patient suffered high pain levels from other medical conditions that were not related to the operation. Minimally invasive pedicle screw fixation is a suitable option for patients with spinal tumours and fractures, with acceptable safety and efficacy in this small retrospective patient series. We have seen favourable results in our patients, who have experienced an increased quality of life following their surgery.

Neural Stem Cells Rescue Cognitive and Motor Dysfunction in a Transgenic Model of Dementia with Lewy Bodies through a BDNF-Dependent Mechanism.

Accumulation of α-synuclein (α-syn) into insoluble aggregates occurs in several related disorders collectively referred to as synucleinopathies. To date, studies have used neural stem cells (NSCs) to examine questions about α-syn propagation, but have overlooked the therapeutic potential of NSC transplantation to modulate cognition in disorders such as dementia with Lewy bodies or Parkinson's disease dementia. Here, we show that striatal transplantation of NSCs into aged α-syn transgenic mice significantly improves performance in multiple cognitive and motor domains. This recovery is associated with NSC expression of brain-derived neurotrophic factor (BDNF), which restores depleted levels and modulates dopaminergic and glutamatergic systems. Most importantly, transplantation of BDNF-depleted NSCs fails to improve behavior, whereas AAV-mediated BDNF delivery mimics the benefits of NSC transplantation, supporting a critical role for this neurotrophin in functional improvement. Thus, NSC transplantation could offer a promising approach to treat the understudied yet devastating cognitive components of many synucleinopathies.

Decreased adrenomedullary function in infants with classical congenital adrenal hyperplasia.

CONTEXT: Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency can cause life-threatening adrenal crises as well as severe hypoglycemia, especially in very young children. Studies of CAH patients 4 years old or older have found abnormal morphology and function of the adrenal medulla and lower levels of epinephrine and glucose in response to stress than in controls. However, it is unknown whether such adrenomedullary abnormalities develop in utero and/or exist during the clinically high-risk period of infancy and early childhood. OBJECTIVE: The objective of the study was to characterize adrenomedullary function in infants with CAH by comparing their catecholamine levels with controls. Design/Settings: This was a prospective cross-sectional study in a pediatric tertiary care center. MAIN OUTCOME MEASURES: Plasma epinephrine and norepinephrine levels were measured by HPLC. RESULTS: Infants with CAH (n = 9, aged 9.6 ± 11.4 d) had significantly lower epinephrine levels than controls [n = 12, aged 7.2 ± 3.2 d: median 84 [(25th; 75th) 51; 87] vs 114.5 (86; 175.8) pg/mL, respectively (P = .02)]. Norepinephrine to epinephrine ratios were also significantly higher in CAH patients than controls (P = .01). The control infants had primary hypothyroidism, but pre- and posttreatment analyses revealed no confounding effects on catecholamine levels. CONCLUSIONS: This study demonstrates for the first time that infants with classical CAH due to 21-hydroxylase deficiency have significantly lower plasma epinephrine levels than controls, indicating that impaired adrenomedullary function may occur during fetal development and be present from birth. A longitudinal study of adrenomedullary function in CAH patients from infancy through early childhood is warranted.