An online intervention for carers to manage behavioral symptoms in motor neuron disease (MiNDToolkit): a randomized parallel multi-center feasibility trial.

BACKGROUND: Evidence on management of behavioral symptoms in motor neuron disease (MND) is lacking. The MiNDToolkit, an online psychoeducational platform, supports carers dealing with behavioral symptoms (BehSymp). The study objectives were to ascertain recruitment and retention rates, carer and healthcare professional (HCP) use of the platform, and completion of online assessments, to inform a full-scale trial. Design: Randomized, parallel, multi-center, feasibility trial. SETTING: England and Wales, across diverse MND services; recruitment from July/21 to November/22; last participant follow-up in March/23. PARTICIPANTS: Carers of people with motor neuron disease (PwMND) with BehSymp, recruited through MND services. After confirming eligibility, participants completed screening and baseline assessments online via the MiNDToolkit platform and were randomized centrally in a 1:1 ratio to MiNDToolkit or control. INTERVENTION: MiNDToolkit offered tailored modules to carers for the 3-month study period. Carers in the intervention group could receive additional support from MiNDToolkit trained HCPs. The control group was offered access to the intervention at the end of the study. Data were collected on platform usage and psychosocial variables. MAIN OUTCOMES: One hundred and fifty-one carers from 11 sites were invited to join the study (letter, face-to-face); 30 were screened; 29 were randomized. Fifteen people were allocated to the control arm; 14 to intervention. Carers were mostly female; median age for was 62.5 (IQR: 58, 68; intervention) and 57 (IQR: 56, 70; controls). Study retention was high (24/29 = 82.76%); carers engaged with the platform on average 14 times (median (IQR):14.0 (10.0, 18.5)) during the study period. CONCLUSION: The MiNDToolkit study was feasible and well accepted by carers and trained HCPs. A definitive trial is warranted.

Virtual urgent care is here to stay: driving toward safe, equitable, and sustainable integration within emergency medicine.

BACKGROUND: Virtual care in Canada rapidly expanded during the COVID-19 pandemic in a low-rules environment in response to pressing needs for ongoing access to care amid public health restrictions. Emergency medicine specialists now face the challenge of advising on which virtual urgent care services ought to remain as part of comprehensive emergency care. Consideration must be given to safe, quality, and appropriate care as well as issues of equitable access, public demand, and sustainability (financial and otherwise). The aim of this project was to summarize current literature and expert opinion and formulate recommendations on the path forward for virtual care in emergency medicine. METHODS: We formed a working group of emergency medicine physicians from across Canada working in a variety of practice settings. The virtual care working group conducted a scoping review of the literature and met monthly to discuss themes and develop recommendations. The final recommendations were circulated to stakeholders for input and subsequently presented at the 2023 Canadian Association of Emergency Physicians (CAEP) Academic Symposium for discussion, feedback, and refinement. RESULTS: The working group developed and reached unanimity on nine recommendations addressing the themes of system design, equity and accessibility, quality and patient safety, education and curriculum, financial models, and sustainability of virtual urgent care services in Canada. CONCLUSION: Virtual urgent care has become an established service in the Canadian health care system. Emergency medicine specialists are uniquely suited to provide leadership and guidance on the optimal delivery of these services to enhance and complement emergency care in Canada.

RéSUMé: CONTEXTE: Les soins virtuels au Canada ont rapidement pris de l'ampleur pendant la pandémie de COVID-19 dans un environnement où les règles sont peu strictes, en réponse aux besoins urgents d'accès continu aux soins dans un contexte de restrictions en santé publique. Les spécialistes de la médecine d'urgence sont maintenant confrontés au défi de conseiller sur les services de soins d'urgence virtuels qui devraient rester dans le cadre des soins d'urgence complets. Il faut tenir compte des soins sécuritaires, de qualité et appropriés, ainsi que des questions d'accès équitable, de la demande publique et de la durabilité (financière et autre). L'objectif de ce projet était de résumer la littérature actuelle et l'opinion d'experts et de formuler des recommandations sur la voie à suivre pour les soins virtuels en médecine d'urgence. MéTHODES: Nous avons formé un groupe de travail composé de médecins urgentistes de partout au Canada qui travaillent dans divers milieux de pratique. Le groupe de travail sur les soins virtuels a effectué un examen de la portée de la documentation et s'est réuni chaque mois pour discuter des thèmes et formuler des recommandations. Les recommandations finales ont été distribuées aux intervenants pour obtenir leurs commentaires, puis présentées au symposium universitaire 2023 de l'Association canadienne des médecins d'urgence (ACMU) pour discussion, rétroaction et perfectionnement. RéSULTATS: Le groupe de travail a élaboré et atteint l'unanimité sur neuf recommandations portant sur les thèmes de la conception du système, de l'équité et de l'accessibilité, de la qualité et de la sécurité des patients, de l'éducation et des programmes, des modèles financiers et de la viabilité des services virtuels de soins d'urgence au Canada. CONCLUSION : Les soins d'urgence virtuels sont devenus un service établi dans le système de santé canadien. Les spécialistes en médecine d'urgence sont particulièrement bien placés pour fournir un leadership et des conseils sur la prestation optimale de ces services afin d'améliorer et de compléter les soins d'urgence au Canada.

Frequency-dependent diffusion kurtosis imaging in the human brain using an oscillating gradient spin echo sequence and a high-performance head-only gradient.

Measuring the time/frequency dependence of diffusion MRI is a promising approach to distinguish between the effects of different tissue microenvironments, such as membrane restriction, tissue heterogeneity, and compartmental water exchange. In this study, we measure the frequency dependence of diffusivity (D) and kurtosis (K) with oscillating gradient diffusion encoding waveforms and a diffusion kurtosis imaging (DKI) model in human brains using a high-performance, head-only MAGNUS gradient system, with a combination of b-values, oscillating frequencies (f), and echo time that has not been achieved in human studies before. Frequency dependence of diffusivity and kurtosis are observed in both global and local white matter (WM) and gray matter (GM) regions and characterized with a power-law model ∼Λ*fθ. The frequency dependences of diffusivity and kurtosis (including changes between fmin and fmax, Λ, and θ) vary over different WM and GM regions, indicating potential microstructural differences between regions. A trend of decreasing kurtosis over frequency in the short-time limit is successfully captured for in vivo human brains. The effects of gradient nonlinearity (GNL) on frequency-dependent diffusivity and kurtosis measurements are investigated and corrected. Our results show that the GNL has prominent scaling effects on the measured diffusivity values (3.5∼5.5% difference in the global WM and 6∼8% difference in the global cortex) and subsequently affects the corresponding power-law parameters (Λ, θ) while having a marginal influence on the measured kurtosis values (<0.05% difference) and power-law parameters (Λ, θ). This study expands previous OGSE studies and further demonstrates the translatability of frequency-dependent diffusivity and kurtosis measurements to human brains, which may provide new opportunities to probe human brain microstructure in health and disease.

Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

The Relationship Between Partial and Full Range of Motion Deadlift 1-Repetition Maximum: A Technical Note.

ABSTRACT: Gillingham, B, Bishop, A, Higa, GK, Adams, KJ, and DeBeliso, M. The relationship between partial and full range of motion deadlift 1-repetition maximum: a technical note. J Strength Cond Res 37(4): 909-914, 2023-The full range of motion (FROM) or partial range of motion (PROM) deadlift (DL) are often included in resistance training (RT) programs and are performed by strength athletes in competition. This study examined the relationship between the FROM and PROM 1-repetition maximum (1RM) DL and if the PROM 1RM DL can be estimated by the FROM 1RM DL. Eighteen National Collegiate Athletic Association wrestlers (20.8 ± 1.2 years, 176.0 ± 5.2 cm, 78.9 ± 10.6 kg) performed a warm-up followed by the assessment of the FROM and PROM 1RM DLs. The FROM DLs were executed with a starting position of the bar resting on the lifting platform. Partial range of motion DLs were executed in a power rack with the bar starting position at ≈2.54 cm above the patella. Regression analysis was employed to estimate PROM 1RM DL based on FROM 1RM DL, body height, and mass. A Pearson's correlation coefficient ( r ) was used to compare the PROM 1RM DL with FROM 1RM DL. A dependent t test was used to compare the PROM 1RM DL and FROM 1RM DL scores (α < 0.05). The PROM 1RM DL scores (226.0 ± 40.6 kg) were significantly greater than the FROM 1RM DL scores (191.7 ± 37.2 kg) ( p < 0.05: effect size = 0.92). The PCC between the PROM and FROM 1RM DL was r = 0.85 ( p < 0.05). The regression coefficient for the FROM 1RM DL was significant ( p < 0.05; R = 0.85, R2 = 0.73). The regression coefficients for body mass and height were not significant ( p > 0.05). The PROM and FROM DL may be interchangeable modalities within an RT program, and the PROM 1RM DL can be accurately predicted by the FROM 1RM DL.

Cutaneous plaques associated with a putative novel papillomavirus type in a horse.

CASE HISTORY AND CLINICAL FINDINGS: A 6-year-old Thoroughbred mare developed multiple flat plaques, < 1 cm in diameter, on the left front fetlock. These were treated topically using 5-fluorouracil and resolved after 4 weeks. However, additional similar plaques developed on the left front pastern 5 months later. These lesions resolved within 3 months without treatment. PATHOLOGICAL AND MOLECULAR FINDINGS: One plaque that developed initially and one plaque that developed later were examined histologically. Both consisted of well-demarcated foci of moderate epidermal hyperplasia. Scattered throughout both plaques were cells showing evidence of papillomavirus-induced cell changes and the same papillomaviral DNA sequence was amplified from both lesions using PCR. As the novel sequence had 79.1% similarity to a partial sequence previously amplified from an equine cutaneous wart and 67.9% similarity to Equus caballus papillomavirus type 1, these results indicate detection of a putative novel papillomavirus type. DIAGNOSIS: Multiple cutaneous plaques due to infection by a novel papillomavirus type. CLINICAL RELEVANCE: Unlike more typical equine cutaneous warts which generally appear as pedunculated and filiform masses, the lesions in this horse appeared as raised plaques. With the exception of aural plaques that are confined to the ears, localised clusters of papillomaviral plaques have not been previously described in horses. The lesions contained subtle histological evidence of papillomavirus infection and careful examination is required to differentiate these plaques from pre-neoplastic lesions. The plaques contained a putative novel papillomavirus type. These results increase the spectrum of papillomavirus-induced skin disease in horses.

Germline polymorphisms in MGMT associated with temozolomide-related myelotoxicity risk in patients with glioblastoma treated on NRG Oncology/RTOG 0825.

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions: Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients.

mm-wave Rydberg-Rydberg transitions gauge intermolecular coupling in a molecular ultracold plasma.

Out-of-equilibrium, strong correlation in a many-body system can trigger emergent properties that act to constrain the natural dissipation of energy and matter. Signs of such self-organization appear in the avalanche, bifurcation, and quench of a state-selected Rydberg gas of nitric oxide to form an ultracold, strongly correlated ultracold plasma. Work reported here focuses on the initial stages of avalanche and quench and uses the mm-wave spectroscopy of an embedded quantum probe to characterize the intermolecular interaction dynamics associated with the evolution to plasma. Double-resonance excitation prepares a Rydberg gas of nitric oxide composed of a single selected state of principal quantum number, n0. Penning ionization, followed by an avalanche of electron-Rydberg collisions, forms a plasma of NO+ ions and weakly bound electrons, in which a residual population of n0 Rydberg molecules evolves to a state of high orbital angular momentum, ℓ. Predissociation depletes the plasma of low-ℓ molecules. Relaxation ceases and n0ℓ(2) molecules with ℓ ≥ 4 persist for very long times. At short times, varying excitation spectra of mm-wave Rydberg-Rydberg transitions mark the rate of electron-collisional ℓ-mixing. Deep depletion resonances that persist for long times signal energy redistribution in the basis of central-field Rydberg states. The widths and asymmetries of Fano line shapes witness the degree to which coupling in the arrested bath (i) broadens the allowed transition and (ii) mixes the local network of levels in the ensemble.

The relationship between provider age and opioid prescribing behavior.

OBJECTIVES: The relationship between provider age and quality of care is theoretically indeterminate. Older providers are more experienced, which could lead to a positive relationship between age and quality, but providers' practice patterns could become outdated as technology and scientific knowledge change, which could lead to a negative relationship between age and quality. However, little work has investigated the provider age/quality relationship, and no work has investigated the relationship between provider age and opioid prescribing behavior. STUDY DESIGN: We analyze Medicare Part D data to investigate how opioid prescribing differs by provider age. METHODS: We use regression analysis to estimate the effect of provider age, holding other factors constant. RESULTS: We find that older providers prescribe significantly more opioids, with the gap between older and younger providers increasing from 2010 to 2015. CONCLUSIONS: Assuming that older physicians follow patterns of previous generations, anticipated retirement of older providers and entry by younger providers will tend to reduce opioid volumes, undoing at least in part the rapid increase since 2000.

Femoral Neck Stress Fractures: An Updated Review.

Femoral neck stress fractures represent a relatively rare spectrum of injuries that most commonly affect military recruits and endurance athletes. If unrecognized and if proper treatment is not initiated, this condition carries potentially devastating consequences. Patients will typically present with an insidious onset, atraumatic hip, and groin pain that is relieved with rest. The condition may be initially misdiagnosed because radiographs are often normal. Magnetic resonance imaging has demonstrated superior specificity, sensitivity, and accuracy compared with other diagnostic modalities in identifying and classifying stress fractures of the femoral neck. Treatment algorithms are based on the MRI fracture morphology and presence of an intra-articular effusion. Nonsurgical management consists of a period of non-weight-bearing followed by gradual return to activity. Surgical management consists of prophylactic fracture fixation with cannulated screws to prevent fracture progression. If left untreated, patients may progress to a complete displaced femoral neck fracture, which can be associated with complications that include nonunion, osteonecrosis of the femoral head, and long-term disability. These poor outcomes emphasize the importance of early diagnosis and treatment of incomplete femoral neck stress fractures.

Independently validated sex-specific nomograms for predicting survival in patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825.

BACKGROUND/PURPOSE: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. METHODS: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. RESULTS: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. CONCLUSIONS: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ .

Secret messengers: Extracellular RNA communication in the immune system.

One of the hallmarks of the immune system is a dynamic landscape of cellular communication through the secretion of soluble factors, production of cell-bound ligands, and expression of surface receptors. This communication affects all aspects of immune cell behavior, integrates the responses of immune cells in tissues, and is fundamental to orchestrating effective immunity. Recent pioneering work has shown that the transfer of ribonucleic acids (RNAs) constitutes a novel mode of cellular communication. This communication involves diverse RNA species, with short noncoding RNAs especially enriched in the extracellular space. These RNAs are highly stable and selectively packaged for secretion. Transferred RNAs have functions in target cells that both mirror their cell-intrinsic roles and adopt novel mechanisms of action. These extracellular RNAs both impact the behavior of individual immune cells and participate in local and systemic immune responses. The impacts of RNA communication on immune cells and disease states have important implications for the development of novel clinical biomarkers and innovative therapeutic designs in immune-related disease. In this review, we will discuss the foundation of knowledge that is establishing RNA communication as an active and functional process in the immune system.

Replicability in measures of attentional set-shifting task performance predicting chronic heavy drinking in rhesus monkeys.

This study was designed to replicate and extend a previous report that the increase in performance of an attentional set-shifting task (ASST) in rhesus monkeys predicted their future alcohol drinking status as a heavy drinker (HD) or non-heavy drinker (NHD). A cohort of 6 young adult male monkeys was trained and tested under the same ASST and then underwent a alcohol self-administration protocol that maintained open-access (22 hours/day) choice of alcohol or water 7 days/week for approximately 6 months. The average improvement in performance in the ASST, as measured by a performance index, was replicated in the cohort of 6 monkeys when compared to the increase in the task performance in a previous cohort of 9 male monkeys. The alcohol self-administration protocol was then used to determine the drinking status (HD: n = 4 or NHD: n = 2) of the replicate cohort, which was accurately predicted by the performance on the ASST. Finally, individuals from both cohorts could be combined based on future drinking status of HD (n = 8) or NHD (n = 7), and the association with pre-alcohol ASST performance remained. Specifically, monkeys that had lower rates of PI improvement were more likely to become HDs. To our knowledge, this is the first study to replicate that deficits in the set-shifting performance can predict chronic heavy alcohol drinking in primates.

APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis.

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. RESULTS: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. CONCLUSIONS: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a 'Warburg like' endophenotype that is observable in young females decades prior to clinically manifest AD.

Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3-4 months old) infused with oligomeric Aß peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aß plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders.

Oral Gavage Delivery of Stable Isotope Tracer for In Vivo Metabolomics.

Stable isotope-resolved metabolomics (SIRM) is a powerful tool for understanding disease. Advances in SIRM techniques have improved isotopic delivery and expanded the workflow from exclusively in vitro applications to in vivo methodologies to study systemic metabolism. Here, we report a simple, minimally-invasive and cost-effective method of tracer delivery to study SIRM in vivo in laboratory mice. Following a brief fasting period, we orally administered a solution of [U-13C] glucose through a blunt gavage needle without anesthesia, at a physiological dose commonly used for glucose tolerance tests (2 g/kg bodyweight). We defined isotopic enrichment in plasma and tissue at 15, 30, 120, and 240 min post-gavage. 13C-labeled glucose peaked in plasma around 15 min post-gavage, followed by period of metabolic decay and clearance until 4 h. We demonstrate robust enrichment of a variety of central carbon metabolites in the plasma, brain and liver of C57/BL6 mice, including amino acids, neurotransmitters, and glycolytic and tricarboxylic acid (TCA) cycle intermediates. We then applied this method to study in vivo metabolism in two distinct mouse models of diseases known to involve dysregulation of glucose metabolism: Alzheimer's disease and type II diabetes. By delivering [U-13C] glucose via oral gavage to the 5XFAD Alzheimer's disease model and the Lepob/ob type II diabetes model, we were able to resolve significant differences in multiple central carbon pathways in both model systems, thus providing evidence of the utility of this method to study diseases with metabolic components. Together, these data clearly demonstrate the efficacy and efficiency of an oral gavage delivery method, and present a clear time course for 13C enrichment in plasma, liver and brain of mice following oral gavage of [U-13C] glucose-data we hope will aid other researchers in their own 13C-glucose metabolomics study design.

The use of multiple hypothesis-generating methods in an outbreak investigation of Escherichia coli O121 infections associated with wheat flour, Canada 2016-2017.

A Canadian outbreak investigation into a cluster of Escherichia coli O121 was initiated in late 2016. When initial interviews using a closed-ended hypothesis-generating questionnaire did not point to a common source, cases were centrally re-interviewed using an open-ended approach. The open-ended interviews led cases to describe exposures with greater specificity, as well as food preparation activities. Data collected supported hypothesis generation, particularly with respect to flour exposures. In March 2017, an open sample of Brand X flour from a case home, and a closed sample collected at retail of the same brand and production date, tested positive for the outbreak strain of E. coli O121. In total, 76% (16/21) of cases reported that they used or probably used Brand X flour or that it was used or probably was used in the home during their exposure period. Crucial hypothesis-generating techniques used during the course of the investigation included a centralised open-ended interviewing approach and product sampling from case homes. This was the first outbreak investigation in Canada to identify flour as the source of infection.

Outcomes Following the Urgent Surgical Management of Displaced Femoral Neck Stress Fractures.

OBJECTIVES: To review the clinical course, complication rates, and mid-term functional outcomes associated with the treatment of displaced femoral neck stress fractures (FNSFs). DESIGN: Retrospective Case Series. SETTING: Military Tertiary Referral Center. PATIENTS: Twenty-one operatively treated displaced FNSFs between 2002 and 2015. INTERVENTION: Urgent reduction and fixation was performed. If nonunion developed, an intertrochanteric osteotomy was performed. MAIN OUTCOME MEASUREMENTS: Nonunion, osteonecrosis (ON) of the femoral head, conversion to arthroplasty, modified Harris Hip Score, pain score, and Hip Outcome Score (HOS). RESULTS: Two (9.1%) patients developed nonunion. Both united after revision with intertrochanteric osteotomy. ON developed in one patient (4.8%) who was converted to arthroplasty. Average pain score at final follow-up was 2.0 (range 0-5). Average Modified Harris Hip Score was 84 (range 54-100). Average HOS Activities of Daily Living subscale was 80.9 (range 45.6-100). Average HOS Sport subscale was 69.8 (range 27.8-100). Larger displacement on injury films correlated with lower Modified Harris Hip Scores (P = 0.048) and lower HOS Sports Subscale Single Assessment Numeric Evaluation (P = 0.023). The need for an open reduction trended toward being a risk factor for nonunion (P = 0.081). CONCLUSIONS: This study represents the largest series of patients undergoing urgent surgery for displaced FNSFs. Nonunion and ON is found at a similar rate to what is reported in the young traumatic literature. Pain and outcome scores compare favorably to other hip pathology in young adults. Initial injury severity is variably correlated to final outcome scores. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.