Pandemic Response Requires Research Samples: A U.S. Safety-Net Hospital's Experience and Call for National Action.

Biorepositories provide a critical resource for gaining knowledge of emerging infectious diseases and offer a mechanism to rapidly respond to outbreaks; the emergence of the novel coronavirus, SARS-CoV-2, has proved their importance. During the COVID-19 pandemic, the absence of centralized, national biorepository efforts meant that the onus fell on individual institutions to establish sample repositories. As a safety-net hospital, Boston Medical Center (BMC) recognized the importance of creating a COVID-19 biorepository to both support critical science at BMC and ensure representation in research for its urban patient population, most of whom are from underserved communities. This article offers a realistic overview of the authors' experience in establishing this biorepository at the onset of the COVID-19 pandemic during the height of the first surge of cases in Boston, Massachusetts, with the hope that the challenges and solutions described are useful to other institutions. Going forward, funders, policymakers, and infectious disease and public health communities must support biorepository implementation as an essential element of future pandemic preparedness.

Risk of type 2 diabetes mellitus in women with prior hypertensive disorders of pregnancy: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: The association between a history of hypertensive disorders of pregnancy (HDP) and subsequent type 2 diabetes (referred to throughout as diabetes) remains inconclusive. We reviewed the most recent evidence to quantify the association of previous HDP with incident diabetes. METHODS: A systematic search of MEDLINE, Embase and CINAHL was performed up to 17 February 2020 to identify observational studies of the association between HDP (pre-eclampsia or gestational hypertension) and incident diabetes. Studies of women with pre-pregnancy diabetes were excluded. Two independent reviewers screened citations and abstracted results. Study quality was assessed in duplicate using the Newcastle-Ottawa Scale. Random-effects models were used to pool effect estimates. Heterogeneity was assessed using the I2 statistic. RESULTS: After screening 4617 citations, 16 cohort studies with a total of 3,095,457 participants were included (unspecified HDP n = 5, pre-eclampsia only n = 4, gestational hypertension and pre-eclampsia n = 7). Risks of subsequent diabetes were significantly higher in women with a history of any HDP (HDP: adjusted hazard ratio [aHR] 2.24, 95% CI 1.95, 2.58; gestational hypertension: aHR 2.19 [95% CI 1.69, 2.84]; pre-eclampsia: aHR 2.56 [95% CI 2.02, 3.24]; preterm pre-eclampsia: aHR 3.05 [95% CI 2.05, 4.56]). The association between HDP and diabetes persisted in studies that adjusted for gestational diabetes mellitus (aHR 2.01 [95% CI 1.77, 2.28]). CONCLUSIONS/INTERPRETATION: HDP are independently associated with a higher risk of diabetes. Further study is needed to determine how HDP contribute to diabetes risk prediction to develop evidence-based screening and prevention strategies. Graphical abstract.

Neoadjuvant therapy versus direct to surgery for T4 colon cancer: meta-analysis.

BACKGROUND: Despite persistently poor oncological outcomes, approaches to the management of T4 colonic cancer remain variable, with the role of neoadjuvant therapy unclear. The aim of this review was to compare oncological outcomes between direct-to-surgery and neoadjuvant therapy approaches to T4 colon cancer. METHODS: A librarian-led systematic search of MEDLINE, Embase, the Cochrane Library, Web of Science, and CINAHL up to 11 February 2020 was performed. Inclusion criteria were primary research articles comparing oncological outcomes between neoadjuvant therapies or direct to surgery for primary T4 colonic cancer. Based on PRISMA guidelines, screening and data abstraction were undertaken in duplicate. Quality assessment was carried out using Cochrane risk-of-bias tools. Random-effects models were used to pool effect estimates. This study compared pathological resection margins, postoperative morbidity, and oncological outcomes of cancer recurrence and overall survival. RESULTS: Four studies with a total of 43 063 patients met the inclusion criteria. Compared with direct to surgery, neoadjuvant therapy was associated with increased rates of margin-negative resection (odds ratio (OR) 2.60, 95 per cent c.i. 1.12 to 6.02; n = 15 487) and 5-year overall survival (pooled hazard ratio 1.42, 1.10 to 1.82, I2 = 0 per cent; n = 15 338). No difference was observed in rates of cancer recurrence (OR 0.42, 0.15 to 1.22; n = 131), 30-day minor (OR 1.12, 0.68 to 1.84; n = 15 488) or major (OR 0.62, 0.27 to 1.44; n = 15 488) morbidity, or rates of treatment-related adverse effects. CONCLUSION: Compared with direct to surgery, neoadjuvant therapy improves margin-negative resection rates and overall survival.

A Whole New World: A Medical Student's Reflection on the Moments Before Surgery for Breast Cancer.

Medical school clerkship offers third year medical students multiple opportunities to acquire clinical experience through real patient interactions and integration into the healthcare teams of different specialties. As part of the general surgery rotation, medical students are invited to scrub in to assist with surgeries-a chance to simultaneously gain medical knowledge while developing technical skills. In what is often an impersonal experience for most patients, students are encouraged to consider the patient's perspective throughout their surgical journey from the pre-operative to post-operative stages. In this reflection, a third year medical student discusses her experience on the moments before breast surgery. From the point of view of a breast cancer patient, she reflects on the impact of a mastectomy on a patient's identity and comments on the importance of empathy in helping a patient grapple with their unique illness experience.

Effect of Unimodal and Multimodal Sensorimotor Interventions on Oral Feeding Outcomes in Preterm Infants: An Evidence-Based Systematic Review.

BACKGROUND: Preterm infants often experience difficulty with the transition from tube to oral feeding. While many unimodal and multimodal sensorimotor interventions have been generated to optimize oral feeding skills, there has been little cohesion between interventions. PURPOSE: The aims of this systematic review were to examine the effect of sensorimotor interventions on oral feeding outcomes and to determine whether multimodal interventions lead to better oral feeding performances than unimodal interventions. SEARCH STRATEGY: A systematic search of CINAHL, Embase, MEDLINE, and PsycINFO databases was conducted. Studies were reviewed to assess the types of interventions used to improve transition to full oral feeding, volume intake, weight gain, and length of hospital stay. RESULTS: The search identified 35 articles. Twenty-six studies examined a unimodal intervention, with the majority focusing on oral sensorimotor input and the others on tactile, auditory, and olfactory input. Nine studies assessed multimodal interventions, with the combination of tactile and kinesthetic stimulation being most common. Results varied across studies due to large differences in methodology, and caution is warranted when interpreting results across studies. The heterogeneity in the studies made it difficult to make any firm conclusions about the effects of sensorimotor interventions on feeding outcomes. Overall, evidence on whether multimodal approaches can lead to better oral feeding outcomes than a unimodal approach was insufficient. IMPLICATIONS FOR PRACTICE: The use of sensorimotor interventions to optimize feeding outcomes in preterm infants varies based on methods used and modalities. These factors warrant caution by clinicians who use sensorimotor interventions in the neonatal intensive care unit. IMPLICATIONS FOR RESEARCH: Large randomized clinical trials using a standardized approach for the administration of sensorimotor input are needed to further establish the effects on feeding outcomes in preterm infants.

Evolution of Network Synchronization during Early Epileptogenesis Parallels Synaptic Circuit Alterations.

In secondary epilepsy, a seizure-prone neural network evolves during the latent period between brain injury and the onset of spontaneous seizures. The nature of the evolution is largely unknown, and even its completeness at the onset of seizures has recently been challenged by measures of gradually decreasing intervals between subsequent seizures. Sequential calcium imaging of neuronal activity, in the pyramidal cell layer of mouse hippocampal in vitro preparations, during early post-traumatic epileptogenesis demonstrated rapid increases in the fraction of neurons that participate in interictal activity. This was followed by more gradual increases in the rate at which individual neurons join each developing seizure, the pairwise correlation of neuronal activities as a function of the distance separating the pair, and network-wide measures of functional connectivity. These data support the continued evolution of synaptic connectivity in epileptic networks beyond the latent period: early seizures occur when recurrent excitatory pathways are largely polysynaptic, while ongoing synaptic remodeling after the onset of epilepsy enhances intranetwork connectivity as well as the onset and spread of seizure activity.

Signals and learning rules guiding oculomotor plasticity.

The learning of motor skills is thought to occur largely through trial and error; however, the error signals and rules controlling the induction of motor learning have not been fully elucidated. We evaluated the learning rules that translate the sensory and motor cues available during training into learned changes in the gain and phase of the vestibulo-ocular reflex (VOR) of mice. Contrary to previous theories, neither the phase of retinal image motion relative to head motion nor the phase of retinal image motion relative to eye movement could consistently predict the direction of the learned change in the gain of the VOR across all training conditions tested. Instead, the phase of the gaze movement relative to head motion during training was the best predictor of whether learning would increase or decrease the gain of the VOR. Learned changes in the phase of the VOR were best predicted by a different cue--the phase of the eye movement relative to head motion during training. These results provide new constraints on the neural mechanisms implementing the adaptive calibration of the VOR by cerebellum-dependent motor learning.

A candidate mechanism underlying the variance of interictal spike propagation.

Synchronous activation of neural networks is an important physiological mechanism, and dysregulation of synchrony forms the basis of epilepsy. We analyzed the propagation of synchronous activity through chronically epileptic neural networks. Electrocorticographic recordings from epileptic patients demonstrate remarkable variance in the pathways of propagation between sequential interictal spikes (IISs). Calcium imaging in chronically epileptic slice cultures demonstrates that pathway variance depends on the presence of GABAergic inhibition and that spike propagation becomes stereotyped following GABA receptor blockade. Computer modeling suggests that GABAergic quenching of local network activations leaves behind regions of refractory neurons, whose late recruitment forms the anatomical basis of variability during subsequent network activation. Targeted path scanning of slice cultures confirmed local activations, while ex vivo recordings of human epileptic tissue confirmed the dependence of interspike variance on GABA-mediated inhibition. These data support the hypothesis that the paths by which synchronous activity spreads through an epileptic network change with each activation, based on the recent history of localized activity that has been successfully inhibited.

Aligning Virtual Care in Canada with the Needs of Older Adults.

Public health measures associated with coronavirus disease (COVID-19) have accelerated the adoption of virtual health care across Canada. We explore the opportunities that virtual care presents in achieving the Quadruple Aim and challenges to navigate, through the lens of care for older adults. In particular, we recommend virtual care-related policies related to older adults that address (a) limited uptake among the socio-economically disadvantaged, (b) user-centered design of virtual care technologies, and (c) integration of iterative evaluations to ensure equitable and efficient achievement of desired outcomes. As virtual care accelerates forward, we must not leave older Canadians behind.

The screening performance of glucose challenge test for gestational diabetes in twin pregnancies: a systematic review and meta-analysis.

BACKGROUND: The screening accuracy of the 50 g-glucose challenge test (50 g-GCT) for gestational diabetes (GDM) has been described in singleton pregnancies. Given the physiologic differences and greater increase in insulin resistance in twin compared with singleton pregnancies, the performance of the 50 g-GCT in twin pregnancies may differ. OBJECTIVES: To perform a systematic review on the screening performance of the 50 g-GCT for gestational diabetes in twin pregnancies. DATA SOURCES: Ovid Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL). STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: We included randomized controlled trials or cohort studies that evaluated the screening accuracy of the 50 g-GCT for GDM in twin pregnancies using the two-step approach. The primary outcome was the positive predictive value of the 50 g-GCT for GDM using the 140 mg/dL (7.8 mmol/L) threshold. STUDY APPRAISAL AND SYNTHESIS METHODS: Methodological quality of included studies was assessed using the QUADAS-2 tool. The positive predictive value (PPV) was pooled for studies that used similar test characteristics. RESULTS: From 2044 citations, 7 retrospective cohort studies with a total of 55,597 participants were included (6.5% twins and 93.5% singletons). The majority of studies evaluated a 50-g GCT cutoff point of 140 mg/dL. The pooled PPV for a threshold of 140 mg/dL (7.8 mmol/L) for twins was 22.58% (95% CI: 0.1912-0.2647, I2=34.1%). The 50-g GCT screen positive rate in twin pregnancies was higher than that in singleton pregnancies. None of the studies performed routine OGTT. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The PPV of 50 g-GCT for GDM in twin pregnancies when using a threshold of 140 mg/dL (7.8 mmol/L) is approximately 23%. There is currently no data on the sensitivity and specificity of the 50 g-GCT in twins.

Interventions and Outcomes for Neoadjuvant Treatment of T4 Colon Cancer: A Scoping Review.

While adjuvant treatment of colon cancers that penetrate the serosa (T4) have been well-established, neoadjuvant strategies have yet to be formally evaluated. Our objective was to perform a scoping review of eligibility criteria, treatment regimens, and primary outcomes for neoadjuvant approaches to T4 colon cancer. A librarian-led, systematic search of MEDLINE, Embase, Cochrane Library, Web of Science, and CINAHL up to 11 February 2020 was performed. Primary research evaluating neoadjuvant treatment in T4 colon cancer were included. Screening and data abstraction were performed in duplicate; analyses were descriptive or thematic. A total of twenty studies were included, most of which were single-arm, single-center, and retrospective. The primary objectives of the literature to date has been to evaluate treatment feasibility, tumor response, disease-free survival, and overall survival in healthy patients. Conventional XELOX and FOLFOX chemotherapy were the most commonly administered interventions. Rationale for selecting a specific regimen and for treatment eligibility criteria were poorly documented across studies. The current literature on neoadjuvant strategies for T4 colon cancer is overrepresented by single-center, retrospective studies that evaluate treatment feasibility and efficacy in healthy patients. Future studies should prioritize evaluating clear selection criteria and rationale for specific neoadjuvant strategies. Validation of outcomes in multi-center, randomized trials for XELOX and FOLFOX have the most to contribute to the growing evidence for this poorly managed disease.

Patient engagement in the development of best practices for transitions from hospital to home: a scoping review.

OBJECTIVES: To explore the extent of patient engagement in the development of best practice reports related to transitions from hospital to home. DESIGN: Scoping review. DATA SOURCES: Electronic databases (MEDLINE, EMBASE, CINAHL, Scopus, Trip Database, DynaMed Plus and Public Health Plus) and multiple provincial regulatory agency and healthcare organisation websites. ELIGIBILITY CRITERIA: We included best practice reports related to the transition from hospital to a long-term care facility, community dwelling or rehabilitation centre. We included documents disseminated in English between 1947 and 2019. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened for eligibility and one extracted and analysed data using a data extraction tool we developed based on established patient engagement frameworks. Only records actively engaging patients were analysed (n=11). The methodological quality of actively engaging patients was assessed using domain 2 (item 5) of stakeholder involvement from the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. RESULTS: The search yielded 1921 citations of which 23 met the inclusion criteria and were included for narrative synthesis. These were disseminated between 1995 and 2019, with 18 (78%) published after 2010. Most were conducted in North America (USA 43%, Canada 22%), Europe (UK 30%) and Australia (4%). Eleven (48%) actively involved patients, of which only two involved patients across all stages of development. Most involved patients through direct or indirect consultation. The mean AGREE II domain 2 item 5 score (of those that actively engaged patients) was 5.9 out of 7. CONCLUSIONS: Only half of existing best practice reports related to the transition from hospital to home actively involved patients in report development. However, the extent of patient engagement has been increasing over time. More organisations should strive to engage patients throughout the best practice development process and provide patients with opportunities for shared leadership.

Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei.

Serotonin neurons of the dorsal and median raphe nuclei (DR, MR) collectively innervate the entire forebrain and midbrain, modulating diverse physiology and behavior. To gain a fundamental understanding of their molecular heterogeneity, we used plate-based single-cell RNA-sequencing to generate a comprehensive dataset comprising eleven transcriptomically distinct serotonin neuron clusters. Systematic in situ hybridization mapped specific clusters to the principal DR, caudal DR, or MR. These transcriptomic clusters differentially express a rich repertoire of neuropeptides, receptors, ion channels, and transcription factors. We generated novel intersectional viral-genetic tools to access specific subpopulations. Whole-brain axonal projection mapping revealed that DR serotonin neurons co-expressing vesicular glutamate transporter-3 preferentially innervate the cortex, whereas those co-expressing thyrotropin-releasing hormone innervate subcortical regions in particular the hypothalamus. Reconstruction of 50 individual DR serotonin neurons revealed diverse and segregated axonal projection patterns at the single-cell level. Together, these results provide a molecular foundation of the heterogenous serotonin neuronal phenotypes.

A saturation hypothesis to explain both enhanced and impaired learning with enhanced plasticity.

Across many studies, animals with enhanced synaptic plasticity exhibit either enhanced or impaired learning, raising a conceptual puzzle: how enhanced plasticity can yield opposite learning outcomes? Here, we show that the recent history of experience can determine whether mice with enhanced plasticity exhibit enhanced or impaired learning in response to the same training. Mice with enhanced cerebellar LTD, due to double knockout (DKO) of MHCI H2-Kb/H2-Db (KbDb-/-), exhibited oculomotor learning deficits. However, the same mice exhibited enhanced learning after appropriate pre-training. Theoretical analysis revealed that synapses with history-dependent learning rules could recapitulate the data, and suggested that saturation may be a key factor limiting the ability of enhanced plasticity to enhance learning. Optogenetic stimulation designed to saturate LTD produced the same impairment in WT as observed in DKO mice. Overall, our results suggest that the recent history of activity and the threshold for synaptic plasticity conspire to effect divergent learning outcomes.

Cross-Platform Comparison of Four Leading Technologies for Detecting EGFR Mutations in Circulating Tumor DNA from Non-Small Cell Lung Carcinoma Patient Plasma.

Analysis of circulating tumor DNA (ctDNA) is emerging as a powerful tool for guiding targeted therapy and monitoring tumor evolution in patients with non-small cell lung cancer (NSCLC), especially when representative tissue biopsies are not available. Here, we have compared the ability of four leading technology platforms to detect epidermal growth factor receptor (EGFR) mutations (L858R, exon 19 deletion, T790M and G719X) in ctDNA from NSCLC patients. Two amplification refractory mutation systems (cobas-ARMS and ADx-ARMS), a droplet digital polymerase chain reaction (ddPCR) and a next-generation sequencing (Firefly NGS) platform were included in the comparison. Fifteen EGFR mutations across twenty NSCLC patients were identified. Firefly NGS, cobas-ARMS and ddPCR all displayed superior sensitivity while ADx-ARMS was better suited for the qualitative detection of EGFR mutations with allele frequency higher than 1% in plasma and tissue samples. We observed high coincidence between the plasma and tissue EGFR mutational profiles for three driver mutations (L858R, exon 19 deletion and G719X) that are known targets of first generation EGFR-TKI therapies among patients who relapsed. Discrepancies between tissue and plasma EGFR mutational profiles were mainly attributable to spatial and temporal tumor heterogeneity, mutation inhibition due to therapy response and drug resistance (T790M). This study illustrates the challenges associated with selection of a technology platform for EGFR ctDNA analysis in the context of treatment evaluation and drug resistance detection.

Subcutaneous metastases from early stage esophageal adenocarcinoma case report.

The identification of subcutaneous metastatic lesions from primary visceral malignancies has increased over time, probably due to an increase in the awareness of their presentation and an increase in cancer survival times. Although the rate of subcutaneous metastases from breast,lung and colon cancer is more significant, the incidence of subcutaneous metastases from esophageal carcinomas is very low. These metastatic lesions usually present metachronously and may signify advanced disease and poor prognosis. We report three cases with early stage esophageal adenocarcinoma treated with surgery with curative intent presenting with subcutaneous metastases two months, two years and three years after their esophagectomy.

An amino-acid taste receptor.

The sense of taste provides animals with valuable information about the nature and quality of food. Mammals can recognize and respond to a diverse repertoire of chemical entities, including sugars, salts, acids and a wide range of toxic substances. Several amino acids taste sweet or delicious (umami) to humans, and are attractive to rodents and other animals. This is noteworthy because L-amino acids function as the building blocks of proteins, as biosynthetic precursors of many biologically relevant small molecules, and as metabolic fuel. Thus, having a taste pathway dedicated to their detection probably had significant evolutionary implications. Here we identify and characterize a mammalian amino-acid taste receptor. This receptor, T1R1+3, is a heteromer of the taste-specific T1R1 and T1R3 G-protein-coupled receptors. We demonstrate that T1R1 and T1R3 combine to function as a broadly tuned L-amino-acid sensor responding to most of the 20 standard amino acids, but not to their D-enantiomers or other compounds. We also show that sequence differences in T1R receptors within and between species (human and mouse) can significantly influence the selectivity and specificity of taste responses.

The receptors for mammalian sweet and umami taste.

Sweet and umami (the taste of monosodium glutamate) are the main attractive taste modalities in humans. T1Rs are candidate mammalian taste receptors that combine to assemble two heteromeric G-protein-coupled receptor complexes: T1R1+3, an umami sensor, and T1R2+3, a sweet receptor. We now report the behavioral and physiological characterization of T1R1, T1R2, and T1R3 knockout mice. We demonstrate that sweet and umami taste are strictly dependent on T1R-receptors, and show that selective elimination of T1R-subunits differentially abolishes detection and perception of these two taste modalities. To examine the basis of sweet tastant recognition and coding, we engineered animals expressing either the human T1R2-receptor (hT1R2), or a modified opioid-receptor (RASSL) in sweet cells. Expression of hT1R2 in mice generates animals with humanized sweet taste preferences, while expression of RASSL drives strong attraction to a synthetic opiate, demonstrating that sweet cells trigger dedicated behavioral outputs, but their tastant selectivity is determined by the nature of the receptors.