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Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo, the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter-dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health.

BACKGROUND: Disorders of the Gut-Brain Interaction (DGBIs) account for 50% of pediatric gastrointestinal (GI) consultations. Children with DGBIs have worse quality of life (QoL) than those with organic GI disorders such as inflammatory bowel disease and gastroesophageal reflux disease. Pediatric DGBIs patients, especially those with chronic abdominal pain (AP), have impaired QoL and increased psychological distress in the form of anxiety and depression. Percutaneous Electrical Nerve Field Stimulation (PENFS) therapy has been shown to be effective in improving symptoms and functioning in children with DGBIs. The treatments impact on these patients QoL is unknown. METHODS: This prospective study evaluated changes in QoL, gastrointestinal symptoms, functional disability, somatization, global health, anxiety, and depression in patients aged 11-18 years who received PENFS therapy (IB-stim, NeurAxis, Versailles, IN) for treatment of pain related DGBIs, once a week for four consecutive weeks. RESULTS: This study included 31 patients with an average age of 15.7 years (SD = 2); 80.6% were female. After PENFS therapy, patients reported significant reductions in abdominal pain, nausea severity, functional disability, somatization, and anxiety from baseline to week 4 (p

There has been considerable focus on investigating age-related memory changes in cognitively healthy older adults, in the absence of neurodegenerative disorders. Previous studies have reported age-related domain-specific changes in older adults, showing increased difficulty encoding and processing object information but minimal to no impairment in processing spatial information compared with younger adults. However, few of these studies have examined age-related changes in the encoding of concurrently presented object and spatial stimuli, specifically the integration of both spatial and nonspatial (object) information. To more closely resemble real-life memory encoding and the integration of both spatial and nonspatial information, the current study developed a new experimental paradigm with novel environments that allowed for the placement of different objects in different positions within the environment. The results show that older adults have decreased performance in recognizing changes of the object position within the spatial context but no significant differences in recognizing changes in the identity of the object within the spatial context compared with younger adults. These findings suggest there may be potential age-related differences in the mechanisms underlying the representations of complex environments and furthermore, the integration of spatial and nonspatial information may be differentially processed relative to independent and isolated representations of object and spatial information.

Dear Readers,Project Hx is a collection of narratives and photographs with a goal to highlight the rich diversity of the medical community. It is a portraiture of people’s stories and backgrounds, their experiences and adventures in healthcare, and ultimately a way to show a human side behind the oftentimes faceless nature of medicine. We aim to document these stories and perspectives in the form of biographical interviews and portrait photography as a way to provide our audience with daily glimpses into the human lives surrounding medicine. The people interviewed portray only a fraction of the countless number of unique attitudes and ideologies that represent the medical community, but we hope that it can serve as kindling for continued conversation. While reading the stories, please keep in mind that narratives are powerful only when they are genuine. They can be genuine only under the climate of acceptance and open-mindedness. Thus, we hope that each story is received free of judgment and prejudice.This year’s fourth issue is particularly personal, as it explores the thoughts and opinions that medical students and healthcare providers have regarding mental health in medicine, and their own personal journey towards finding strength in this profession. Given the intimate nature of this theme, most of our interviewees opted towards anonymity, but we are grateful that they were willing to step forward to reveal their personal struggles, and put a face - though not in the literal sense - on the true reality of mental health challenges that come with the rigorous journey towards becoming a physician.Sincerely,Project Hx TeamUC Irvine School of MedicineEditor-In-Chiefs: Thalia Nguyen, Soe Thein; Design Editor: May Hui

Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo, the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter‐dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health. [ABSTRACT FROM AUTHOR]

The European corn borer (Ostrinia nubilalis) is an agricultural pest and burgeoning model for research on speciation, seasonal adaptation and insect resistance management. Although previous work in O. nubilalis has identified genes associated with differences in life cycle, reproduction, and resistance to Bt toxins, the general lack of a robust gene‐editing protocol for O. nubilalis has been a barrier to functional validation of candidate genes. Here, we demonstrate an efficient and practical methodology for heritable gene mutagenesis in O. nubilalis using the CRISPR/Cas9 genome editing system. Precise loss‐of‐function (LOF) mutations were generated at two circadian clock genes, period (per) and pigment‐dispersing factor receptor (pdfr), and a developmental gene, prothoracicotropic hormone (ptth). Precluding the need for a visible genetic marker, gene‐editing efficiency remained high across different single guide RNAs (sgRNA) and germline transmission of mutations to F1 offspring approached 100%. When single or dual sgRNAs were injected at a high concentration, gene‐specific phenotypic differences in behaviour and development were identified in F0 mutants. Specifically, F0 gene mutants demonstrated that PER, but not PDFR, is essential for normal timing of eclosion. PTTH F0 mutants were significantly heavier and exhibited a higher incidence of diapause. This work will accelerate future studies of gene function in O. nubilalis and facilitate the development of similar screens in other Lepidopteran and non‐model insects. [ABSTRACT FROM AUTHOR]

Stress is a potent modulator of brain function and particularly mnemonic processes. While chronic stress is associated with long-term deficits in memory, the effects of acute stress on mnemonic functions are less clear as previous reports have been inconsistent. Some studies suggest that cortisol, a stress hormone that modulates biological changes in response to stress, may enhance memory consolidation and impair memory retrieval. However, other studies report no effect of cortisol on either memory consolidation or retrieval. These discrepancies could be due to differences in the timing and sequencing of the experimental procedures or individual differences in participants' stress response. In the present study, we examined the effect of increased cortisol levels due to acute stress, induced by the Trier Social Stress Test (TSST), on a pattern separation memory task while differentiating the distinct stages of memory processing and controlling for the effects of diurnal variation. Sixty-nine young adults completed a 2-d study in which subjects either underwent the TSST immediately following the encoding part of the memory task, targeting memory consolidation, or immediately prior to the recognition part of the memory task on the second day, targeting memory retrieval. Control subjects completed the same study procedures but underwent a control version of the TSST that did not induce a stress response. Mnemonic discrimination of highly similar stimuli was enhanced by stress induced during consolidation with better discrimination showing a significant correlation with increased cortisol responses. Stress induced during memory retrieval showed no significant effect on memory performance. These findings suggest that stress induced changes in cortisol differentially affect the consolidation and retrieval stages of memory function.

PurposeCystinosis is caused by a deficiency in the lysosomal cystine transporter, cystinosin (CTNS gene), resulting in cystine crystal accumulation in tissues. In eyes, crystals accumulate in the cornea causing photophobia and eventually blindness. Hematopoietic stem progenitor cells (HSPCs) rescue the kidney in a mouse model of cystinosis. We investigated the potential for HSPC transplantation to treat corneal defects in cystinosis.MethodsWe isolated HSPCs from transgenic DsRed mice and systemically transplanted irradiated Ctns-/- mice. A year posttransplantation, we investigated the fate and function of HSPCs by in vivo confocal and fluorescence microscopy (IVCM), quantitative RT-PCR (RT-qPCR), mass spectrometry, histology, and by measuring the IOP. To determine the mechanism by which HSPCs may rescue disease cells, we transplanted Ctns-/- mice with Ctns-/- DsRed HSPCs virally transduced to express functional CTNS-eGFP fusion protein.ResultsWe found that a single systemic transplantation of wild-type HSPCs prevented ocular pathology in the Ctns-/- mice. Engraftment-derived HSPCs were detected within the cornea, and also in the sclera, ciliary body, retina, choroid, and lens. Transplantation of HSPC led to substantial decreases in corneal cystine crystals, restoration of normal corneal thickness, and lowered IOP in mice with high levels of donor-derived cell engraftment. Finally, we found that HSPC-derived progeny differentiated into macrophages, which displayed tunneling nanotubes capable of transferring cystinosin-bearing lysosomes to diseased cells.ConclusionsTo our knowledge, this is the first demonstration that HSPCs can rescue hereditary corneal defects, and supports a new potential therapeutic strategy for treating ocular pathologies.

Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival. [ABSTRACT FROM AUTHOR]

Background: We have developed the bispectral electroencephalography (BSEEG) method for detection of delirium and prediction of poor outcomes. Aims: To improve the BSEEG method by introducing a new EEG device. Method: In a prospective cohort study, EEG data were obtained and BSEEG scores were calculated. BSEEG scores were filtered on the basis of standard deviation (s.d.) values to exclude signals with high noise. Both non-filtered and s.d.-filtered BSEEG scores were analysed. BSEEG scores were compared with the results of three delirium screening scales: the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), the Delirium Rating Scale-Revised-98 (DRS) and the Delirium Observation Screening Scale (DOSS). Additionally, the 365-day mortalities and the length of stay (LOS) in the hospital were analysed. Results: We enrolled 279 elderly participants and obtained 620 BSEEG recordings; 142 participants were categorised as BSEEG-positive, reflecting slower EEG activity. BSEEG scores were higher in the CAM-ICU-positive group than in the CAM-ICU-negative group. There were significant correlations between BSEEG scores and scores on the DRS and the DOSS. The mortality rate of the BSEEG-positive group was significantly higher than that of the BSEEG-negative group. The LOS of the BSEEG-positive group was longer compared with that of the BSEEG-negative group. BSEEG scores after s.d. filtering showed stronger correlations with delirium screening scores and more significant prediction of mortality. Conclusions: We confirmed the usefulness of the BSEEG method for detection of delirium and of delirium severity, and prediction of patient outcomes with a new EEG device. [ABSTRACT FROM AUTHOR]