Concentration Enrichment in a Dissolving Microdroplet: Accessing Sub-nanomolar Electroanalysis.

Droplet evaporation has previously been used as a concentration enrichment strategy; however, the measurement technique of choice requires quantification in rather large volumes. Electrochemistry has recently emerged as a method to robustly probe volumes even down to the attoliter (10-18 L) level. We present a concentration enrichment strategy based on the dissolution of a microdroplet placed on the surface of a Au ultramicroelectrode (radius ∼ 6.25 µm). By precisely positioning a 1,2-dichloroethane microdroplet onto the ultramicroelectrode with a microinjector, we are able to track the droplet's behavior optically and electrochemically. Because the droplet spontaneously dissolves over time, given the relative solubility of 1,2-dichloroethane in the water continuous phase, the change in volume with time enriches the concentration of the redox probe (Cp2*(Fe)II) in the droplet. We demonstrate robust electrochemical detection down to sub-nM (800 pM) concentrations of Cp2*(Fe)II. For this droplet, 800 pM constitutes only about 106 molecules. We extend the strategy in a single-blind study to determine unknown concentrations, emphasizing the promise of the new methodology. These results take voltammetric quantification easily to the sub-µM regime.

Trans-Synaptic Degeneration Following Acute Optic Neuritis in Multiple Sclerosis.

OBJECTIVE: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans-synaptic degeneration, and determine its clinical relevance. METHODS: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed-effects linear regression models were used. RESULTS: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non-AON cohort (-0.76% vs -0.22% per year [p = 0.01] for occipital GM, -1.83% vs -0.32% per year [p = 0.008] for calcarine GM, -1.17% vs -0.67% per year [p = 0.02] for thalamus), whereas rates of whole-brain, cortical GM, non-occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON-induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole-brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON. INTERPRETATION: These results provide in-vivo evidence for anterograde trans-synaptic degeneration following AON in PwMS, and suggest that trans-synaptic degeneration may be related to clinically-relevant visual outcomes. ANN NEUROL 2023;93:76-87.

Amplifying the electrochemical footprint of <1000 molecules in a dissolving microdroplet.

The ability of analytical strategies to detect and positively identify molecules under extremely dilute conditions is important for the growth and expansion of analytical techniques and instrumentation. At present, few measurement science techniques can robustly approach the measurement of just a few thousand molecules. Here, we present an electrochemical platform for the detection and positive identification of fewer than 1000 molecules of decamethylferrocene ((Cp*)2FeII). We achieve this remarkable detection threshold by trapping (Cp*)2FeII in a 1,2-dichloroethane microdroplet, which is allowed to dissolve into an aqueous continuous phase while on a gold microelectrode (radius ∼6.25 µm). Because electrochemistry is not sensitive enough to observe the charge of less than 1000 molecules, we dissolved µM amounts hexacyanoferrate(III) in the aqueous continuous phase. The biphasic reaction between hexacyanoferrate(III) and Cp2*(Fe)II allows for a feedback loop when the microelectrode is biased sufficiently negative to reduce Cp2*(Fe)III. This feedback loop, a typical EC' catalytic mechanism, amplifies the electrochemical signal of Cp2*(Fe)II when the droplet is of small enough dimensions for feedback to occur. Our results demonstrate that clever biphasic reactions can be coupled with dissolving microdroplets to access extremely low limits of quantitation in electroanalysis.

'High hopes for treatment': Australian stakeholder perspectives of the clinical translation of advanced neurotherapeutics for rare neurological diseases.

INTRODUCTION: Advanced therapies offer unprecedented opportunities for treating rare neurological disorders (RNDs) in children. However, health literacy, perceptions and understanding of novel therapies need elucidation across the RND community. This study explored healthcare professionals' and carers' perspectives of advanced therapies in childhood-onset RNDs. METHODS: In this mixed-methodology cross-sectional study, 20 healthcare professionals (clinicians, genetic counsellors and scientists) and 20 carers completed qualitative semistructured interviews and custom-designed surveys. Carers undertook validated psychosocial questionnaires. Thematic and quantitative data analysis followed. RESULTS: Participants described high positive interest in advanced therapies, but low knowledge of, and access to, reliable information. The substantial 'therapeutic gap' and 'therapeutic odyssey' common to RNDs were recognised in five key themes: (i) unmet need and urgency for access; (ii) seeking information; (iii) access, equity and sustainability; (iv) a multidisciplinary and integrated approach to care and support and (v) difficult decision-making. Participants were motivated to intensify RND clinical trial activity and access to advanced therapies; however, concerns around informed consent, first-in-human trials and clinical trial procedures were evident. There was high-risk tolerance despite substantial uncertainties and knowledge gaps. RNDs with high mortality, increased functional burdens and no alternative therapies were consistently prioritised for the development of advanced therapies. However, little consensus existed on prioritisation to treatment access. CONCLUSIONS: This study highlights the need to increase clinician and health system readiness for the clinical translation of advanced therapeutics for RNDs. Co-development and use of educational and psychosocial resources to support clinical decision-making, set therapeutic expectations and promotion of equitable, effective and safe delivery of advanced therapies are essential. PATIENT OR PUBLIC CONTRIBUTION: Participant insights into the psychosocial burden and information need to enhance the delivery of care in this formative study are informing ongoing partnerships with families, including co-production and dissemination of psychoeducational resources featuring their voices hosted on the Sydney Children's Hospitals Network website SCHN Brain-Aid Resources.

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations.

The natural product goldenseal is a clinical inhibitor of CYP3A activity, as evidenced by a 40%-60% increase in midazolam area under the plasma concentration versus time curve (AUC) after coadministration with goldenseal. The predominant goldenseal alkaloids berberine and (-)-ß-hydrastine were previously identified as time-dependent CYP3A inhibitors using human liver microsomes. Whether these alkaloids contribute to the clinical interaction, as well as the primary anatomic site (hepatic vs. intestinal) and mode of CYP3A inhibition (reversible vs. time-dependent), remain uncharacterized. The objective of this study was to mechanistically assess the pharmacokinetic goldenseal-midazolam interaction using an integrated in vitro-in vivo-in silico approach. Using human intestinal microsomes, (-)-ß-hydrastine was a more potent time-dependent inhibitor of midazolam 1'-hydroxylation than berberine (KI and kinact: 8.48 µM and 0.041 minutes-1, respectively, vs. >250 µM and ∼0.06 minutes-1, respectively). Both the AUC and Cmax of midazolam increased by 40%-60% after acute (single 3-g dose) and chronic (1 g thrice daily × 6 days) goldenseal administration to healthy adults. These increases, coupled with a modest or no increase (≤23%) in half-life, suggested that goldenseal primarily inhibited intestinal CYP3A. A physiologically based pharmacokinetic interaction model incorporating berberine and (-)-ß-hydrastine successfully predicted the goldenseal-midazolam interaction to within 20% of that observed after both chronic and acute goldenseal administration. Simulations implicated (-)-ß-hydrastine as the major alkaloid precipitating the interaction, primarily via time-dependent inhibition of intestinal CYP3A, after chronic and acute goldenseal exposure. Results highlight the potential interplay between time-dependent and reversible inhibition of intestinal CYP3A as the mechanism underlying natural product-drug interactions, even after acute exposure to the precipitant. SIGNIFICANCE STATEMENT: Natural products can alter the pharmacokinetics of an object drug, potentially resulting in increased off-target effects or decreased efficacy of the drug. The objective of this work was to evaluate fundamental mechanisms underlying the clinically observed goldenseal-midazolam interaction. Results support the use of an integrated approach involving established in vitro assays, clinical evaluation, and physiologically based pharmacokinetic modeling to elucidate the complex interplay between multiple phytoconstituents and various pharmacokinetic processes driving a drug interaction.

Clinical characteristics of Australian treatment-naïve patients with classical Hodgkin lymphoma from the lymphoma and related diseases registry.

Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real-world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first-line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced-stage disease, and 48% of patients with the early-stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced-stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early-stage disease, and 88% in advanced-stage disease. Early progression-free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies.

Left ventricular aneurysm versus pseudoaneurysm: Diagnosis in the era of multi-modality imaging and 3D-printing.

In this case report, we illustrate the contemporary use of multi-modality cardiac imaging and three-dimensional (3D)-printing in the diagnosis and precise surgical planning of a large ventricular aneurysm with an extensive thrombus burden after myocardial infarction. We further discuss an integrated multimodality approach in the evaluation of ventricular outpouchings.

Endogenous Retrovirus RNA Expression Differences between Race, Stage and HPV Status Offer Improved Prognostication among Women with Cervical Cancer.

Endogenous human retroviruses (ERVs) are remnants of exogenous retroviruses that have integrated into the human genome. Using publicly available RNA-seq data from 63 cervical cancer patients, we investigated the expression of ERVs in cervical cancers. Four aspects of cervical cancer were investigated: patient ancestral background, tumor HPV type, tumor stage and patient survival. Between the racial subgroups, 74 ERVs were significantly differentially expressed, with Black Americans having 30 upregulated and 44 downregulated (including MER21C, HERV9-int, and HERVH-int) ERVs when compared to White Americans. We found that 3313 ERVs were differentially expressed between HPV subgroups, including MER41A, HERVH-int and HERVK9. There were 28 downregulated (including MLT1D and HERVH-int) and 61 upregulated (including MER41A) ERVs in locally advanced-stage compared to early-stage samples. Tissue microarrays of cervical cancer patients were used to investigate the protein expression of ERVs with protein coding potential (i.e., HERVK and ERV3). Significant differences in protein expression of ERV3 (p = 0.000905) were observed between early-stage and locally advanced-stage tumors. No significant differential expression at the protein level was found for HERVK7 (p = 0.243). We also investigated a prognostic model, supplementing a baseline prediction model using FIGO stage, age and HPV positivity with ERVs data. The expression levels of all ERVs in the HERVd were input into a Lasso-Cox proportional hazards model, developing a predictive 67-ERV panel. When ERVs expression levels were supplemented with the clinical data, a significant increase in prognostic power (p = 9.433 × 10-15) relative to that obtained with the clinical parameters alone (p = 0.06027) was observed. In summary, ERV RNA expression in cervical cancer tumors is significantly different among racial cohorts, HPV subgroups and disease stages. The combination of the expression of certain ERVs in cervical cancers with clinical factors significantly improved prognostication compared to clinical factors alone; therefore, ERVs may serve as future prognostic biomarkers and therapeutic targets. Novelty and Impact: When endogenous retroviral (ERV) expression signatures were combined with currently employed clinical prognosticators of relapse of cervical cancer, the combination outperformed prediction models based on clinical prognosticators alone. ERV expression signatures in tumor biopsies may therefore be useful to help identify patients at greater risk of recurrence. The novel ERV expression signatures or adjacent genes possibly impacted by ERV expression described here may also be targets for the development of future therapeutic interventions.

Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling.

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations, and these processes are often susceptible to saturation at high concentrations, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship. We used the models for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and models for styrene and caffeine to explore how exposure route, frequency, and duration impact the IEC relationships in rat and human exposures. We also analyzed available plasma concentration data for 2,4-dichlorophenoxyacetic acid to demonstrate how a PBPK modeling approach can be an alternative to common statistical methods for analyzing dose proportionality. A PBPK modeling approach can be a valuable tool used in the early stages of a chemical safety assessment program to optimize the design of longer-term animal toxicity studies or to interpret study results.

Hernia-to-neck ratio is associated with emergent ventral hernia repair.

BACKGROUND: The ratio of hernia size to fascial defect size, termed the hernia-to-neck ratio (HNR), has been proposed as a novel predictive factor for umbilical hernia complications. HNR ≥ 2.5 has been suggested to warrant surgery due to association with bowel strangulation, incarceration, and necrosis. The aim of this study was to evaluate the association between HNR and emergent ventral hernia repair at our institution. METHODS: A retrospective cohort study was performed of consecutive patients with ventral hernias evaluated at a large safety-net hospital from 2017 to 2019. Patients who required emergent ventral hernia repair were compared to patients who did not require repair at latest follow-up. HNR was calculated using a previously described method: maximal hernia sac size and maximal fascial defect size (termed "hernia neck size") were measured in the sagittal plane on CT scan. Data are described as mean ± standard deviation and median (interquartile range). RESULTS: A total of 166 patients were included: 84 (51%) required emergent hernia repair and 82 (49%) did not undergo repair. Median follow-up was 19 (8-27) months. Patient groups were similar except the emergent repair group had more males (50% vs. 34%, p = 0.03), umbilical hernias (93% vs. 56%, p < 0.01), recurrent hernias (31% vs. 15%, p < 0.01), and lower mean BMI (34.3 ± 9.9 vs. 39.1 ± 6.5, p < 0.01). Hernia sac size did not differ between groups (5.8 [3.8-8.4] cm vs. 6.1 [3.5-11.8] cm, p = 0.45). Hernia neck size was significantly smaller in the emergent repair group (1.5 [2.3-3.5] cm vs. 3.4 [1.8-6.2] cm, p < 0.01). Hernia-to-neck ratio was significantly higher in the emergent repair group (2.4 [1.8-3.1] vs. 1.7 [1.1-2.9], p < 0.01). CONCLUSION: This study demonstrated an association between higher HNR and increased risk of emergent ventral hernia repair. Future studies will evaluate the use of HNR to risk-stratify patients with ventral hernias in a safety-net hospital.

Chemoenzymatic Synthesis of Select Intermediates and Natural Products of the Desferrioxamine E Siderophore Pathway.

The NIS synthetase family of enzymes responsible for the biosynthesis of siderophores is increasingly associated with bacterial virulence. Proteins in this class represent outstanding potential drug targets, assuming that basic biochemical and structural characterizations can be completed. Towards this goal, we have mated an improved synthesis of the non-commercial amino acid N-hydroxy-N-succinylcadaverine (HSC, 6) with an isothermal titration calorimetry (ITC) assay that profiles the iterative stages of HSC trimerization and macrocyclization by NIS synthetase DesD from Streptomyces coelicolor. HSC synthesis begins with multigram-scale Gabrielle and tert-butyl N-(benzyloxy)carbamate alkylations of 1-bromo-5-chloropentane following prior literature, but the end-game reported herein has two advantages for greater material throughput: (1) hydrogenolysis of benzyl ether and Cbz blocking groups is best accomplished with Pearlman's catalyst at 40 psi of H2 and (2) purification of neutral (zwitterionic) HSC is effected by simple flash chromatography over silica gel in MeOH. HSC is subsequently shown to be a substrate for NIS synthetase DesD, which catalyzes three successive amide bond syntheses via adenyl monophosphate ester intermediates. We quantify and present the iterative and overall enzyme kinetic constants associated with formation of the cyclotrimeric siderophore desferrioxamine E (dfoE, 1).

Progressive Multiple Sclerosis Is Associated with Faster and Specific Retinal Layer Atrophy.

OBJECTIVE: Therapeutic development in progressive multiple sclerosis (PMS) has been hampered by a lack of reliable biomarkers to monitor neurodegeneration. Optical coherence tomography (OCT)-derived retinal measures have been proposed as promising biomarkers to fulfill this role. However, it is unclear whether retinal atrophy persists in PMS, exceeds normal aging, or can be distinguished from relapsing-remitting multiple sclerosis (RRMS). METHODS: 178 RRMS, 186 PMS, and 66 control participants were followed with serial OCT for a median follow-up of 3.7 years. RESULTS: The estimated proportion of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell + inner plexiform layer (GCIPL) thinning in multiple sclerosis (MS) attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. However, independent of age, PMS was associated with faster pRNFL (-0.34 ± 0.09%/yr, p < 0.001) and GCIPL (-0.27 ± 0.07%/yr, p < 0.001) thinning, as compared to RRMS. In both MS and controls, higher baseline age was associated with faster inner nuclear layer (INL) and outer nuclear layer (ONL) thinning. INL and ONL thinning were independently faster in PMS, as compared to controls (INL:-0.09 ± 0.04%/yr, p = 0.03; ONL:-0.12 ± 0.06%/yr, p = 0.04), and RRMS (INL:-0.10 ± 0.04%/yr, p = 0.01; ONL:-0.13 ± 0.05%/yr, p = 0.01), whereas they were similar in RRMS and controls. Unlike RRMS, disease-modifying therapies (DMTs) did not impact rates of retinal layer atrophy in PMS. INTERPRETATION: PMS is associated with faster retinal atrophy independent of age. INL and ONL measures may be novel biomarkers of neurodegeneration in PMS that appear to be unaffected by conventional DMTs. The effects of aging on rates of retinal layer atrophy should be considered in clinical trials incorporating OCT outcomes. ANN NEUROL 2020;87:885-896.

Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment.

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process. The approach refers to the dose above which the systemic exposures depart from being proportional to external doses. This non-linear external-internal dose relationship arises from saturation or limitation of TK process(es), such as absorption or metabolism. The importance of TK information is widely acknowledged when assessing human health risks arising from exposures to environmental chemicals, as TK determines the amount of chemical at potential sites of toxicological responses. However, there have been differing opinions and interpretations within the scientific and regulatory communities related to the validity and application of the KMD concept. A multi-stakeholder working group, led by the Health and Environmental Sciences Institute (HESI), was formed to provide an opportunity for impacted stakeholders to address commonly raised scientific and technical issues related to this topic and, more specifically, a weight of evidence approach is recommended to inform design and dose selection for repeated dose animal studies. Commonly raised challenges related to the use of TK data for dose selection are discussed, recommendations are provided, and illustrative case examples are provided to address these challenges or refute misconceptions.

Prevalence of the carbapenem-heteroresistant phenotype among ESBL-producing Escherichia coli and Klebsiella pneumoniae clinical isolates.

OBJECTIVES: Carbapenem-heteroresistant (cHR) Enterobacteriaceae strains have been reported worldwide; however, the prevalence among clinical ESBL-producing Enterobacteriaceae isolates obtained from patients with repeated hospital admissions remains largely unknown. METHODS: Heteroresistance was screened by disc diffusion and confirmed by a modified population analysis profiling (PAP) method against ertapenem, imipenem, meropenem and ceftolozane/tazobactam. MIC testing was performed by broth microdilution against carbapenems and a panel of agents with potential activity against ESBL-producing strains. RESULTS: One hundred and seventy-three ESBL-producing meropenem-susceptible Escherichia coli and Klebsiella pneumoniae isolates were selected for testing. A total of 519 bacteria/carbapenem combinations were screened by disc diffusion; 84 combinations were identified as cHR. Modified PAP confirmed 70 bacteria/carbapenem combinations as heteroresistant; most (63%, 44/70) confirmed cHR colonies grew within the ertapenem zone of inhibition, followed by imipenem (30%, 21/70), then meropenem (7%, 5/70). In total, one-third of the unique patient isolates (32%, 55/173) were identified as being heteroresistant to at least one carbapenem; of those patients, 16% (9/55) had a carbapenem-non-susceptible isolate on subsequent visits. Only two cHR isolates screened positive for ceftolozane/tazobactam heteroresistance (1%, 2/173), of which one was confirmed heteroresistant by modified PAP. cHR isolates were more likely to be collected from a non-urinary source (e.g. respiratory) compared with non-cHR isolates (31% versus 19%, P = 0.02). MIC distributions of all tested antibiotic agents did not differ between non-cHR and cHR isolates. CONCLUSIONS: Our findings raise concerns for the continued use of carbapenems as first-line therapy for ESBL infections and for the potential selection for strains with full carbapenem resistance.

Outcomes of laparoscopic hiatal hernia repair based on surgical specialty: thoracic versus general surgeons.

BACKGROUND: Hiatal Hernia Repairs (HHR) are performed by both general surgeons (GS) and thoracic surgeons (TS). However, there are limited literature with respect to outcomes of HHR based on specialty training. The objective of this study was to compare the utilization, perioperative outcomes, and cost for HHR performed by GS versus TS. METHODS: The Vizient database was used to identify patients who underwent elective laparoscopic HHR between October 2014 and June 2018. Patients were grouped according to surgeon's specialty (GS vs. TS). Patient demographics and outcomes including in-hospital mortality were compared between groups. RESULTS: During the study period 13,764 patients underwent HHR by either GS or TS. GS performed 9930 (72%) cases while TS performed 3834 (28%) cases. There was no significant difference between GS versus TS with regard to serious morbidity (1.28% vs. 1.30%, p = 0.97) or mortality (0.10% vs. 0.21%, p = 0.19). The mortality index was 0.24 for GS versus 0.45 for TS. Compared to TS, laparoscopic HHR performed by GS was associated with a shorter LOS (2.57 days vs. 2.72 days, p < 0.001) and lower mean hospital costs ($7139 vs. $8032, p < 0.0001). CONCLUSIONS: Within the context of academic centers, laparoscopic HHRs are mostly performed by GS with comparable outcome between general versus thoracic surgeons.

Evolving changes of minimally invasive esophagectomy: a single-institution experience.

BACKGROUND: Initial adoption of minimally invasive esophagectomy (MIE) began in the late 1990s but its surgical technique, perioperative management, and outcome continues to evolve. METHODS: The aim of this study was to examine the evolving changes in the technique, outcome, and new strategies in management of postoperative leaks after MIE was performed at a single institution over a two-decade period. A retrospective chart review of 75 MIE operations was performed between November 2011 and September 2018 and this was compared to the initial series of 104 MIE operations performed by the same group between 1998 and 2007. Operative technique, outcomes, and management strategies of leaks were compared. RESULTS: There were 65 males (86.7%) with an average age of 61 years. The laparoscopic/thoracoscopic Ivor Lewis esophagectomy became the preferred MIE approach (49% of cases in the initial vs. 95% in the current series). Compared to the initial case series, there was no significant difference in median length of stay (8 vs. 8 days), major complications (12.5% vs. 14.7%, p = 0.68), incidence of leak (9.6% vs. 10.6%, p = 0.82), anastomotic stricture (26% vs. 32.0%, p = 0.38), or in-hospital mortality (2.9% vs. 2.6%, p = 0.47). Management of esophageal leaks has changed from primarily thoracotomy ± diversion initially (50% of leak cases) to endoscopic stenting ± laparoscopy/thoracoscopy currently (87.5% of leak cases). CONCLUSION: In a single-institutional series of MIE over two decades, there was a shift toward a preference for the laparoscopic/thoracoscopic Ivor Lewis approach with similar outcomes. The management of postoperative leaks drastically changed with predilection toward minimally invasive option with endoscopic drainage and stenting.

emagnification: A tool for estimating effect-size magnification and performing design calculations in epidemiological studies.

Artificial effect-size magnification (ESM) may occur in underpowered studies, where effects are reported only because they or their associated p-values have passed some threshold. Ioannidis (2008, Epidemiology 19: 640-648) and Gelman and Carlin (2014, Perspectives on Psychological Science 9: 641-651) have suggested that the plausibility of findings for a specific study can be evaluated by computation of ESM, which requires statistical simulation. In this article, we present a new command called emagnification that allows straightforward implementation of such simulations in Stata. The commands automate these simulations for epidemiological studies and enable the user to assess ESM routinely for published studies using user-selected, study-specific inputs that are commonly reported in published literature. The intention of the command is to allow a wider community to use ESMs as a tool for evaluating the reliability of reported effect sizes and to put an observed statistically significant effect size into a fuller context with respect to potential implications for study conclusions.

Fluctuating NMDA Receptor Subunit Levels in Perirhinal Cortex Relate to Their Dynamic Roles in Object Memory Destabilization and Reconsolidation.

Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M1 muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M1 receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M1 receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient.

Judgement aggregation in scientific collaborations: The case for waiving expertise.

The fragmentation of academic disciplines forces individuals to specialise. In doing so, they become experts over their narrow area of research. However, ambitious scientific projects, such as the search for gravitational waves, require them to come together and collaborate across disciplinary borders. How should scientists with expertise in different disciplines treat each others' expert claims? An intuitive answer is that the collaboration should defer to the opinions of experts. In this paper we show that under certain seemingly innocuous assumptions, this intuitive answer gives rise to an impossibility result when it comes to aggregating the beliefs of experts to deliver the beliefs of a collaboration as a whole. We then argue that when experts' beliefs come into conflict, they should waive their expert status.

Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study.

On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non-invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis.