Psychometric Evaluation of Cognitive and Positive Valence Tasks Chosen for the NIMH Research Domain Criteria Project.

The NIMH Research Domain Criteria (RDoC) initiative seeks to utilize multidimensional patterns of socio-cognitive behavior to improve understanding of mental illness. We aimed to evaluate the psychometric properties of a subset of RDoC tasks. Specifically, we investigated two positive valence tasks and five cognitive tasks. Participants (N = 320) were recruited through an online research platform. We used generalizability theory to estimate reliability, and factor analysis to examine factor structure. Reliability was average to excellent with some notable exceptions. Factor analysis results raised concerns about whether the factor structure of task scores aligns with the proposed RDoC model. Effects of cognitive manipulations generally supported the construct representation of tasks. Results indicate that the majority of RDoC task scores examined have acceptable reliability or can be made reliable through modest increases in task length. Future research in diverse populations is needed to better understand the factor structure of RDoC cognitive and positive valence measures.

Feasibility of Acquiring Neuroimaging Data from Adults with Acquired Brain Injuries before and after a Yoga Intervention.

BACKGROUND: To date, no one has prospectively evaluated yoga intervention-induced changes in brain structure or function in adults with acquired brain injuries (ABI). Thus, this study was conducted to test the feasibility of acquiring neuroimaging data from adults with ABI before and after a yoga intervention. METHODS: This was a single-arm intervention feasibility study that included 12 adults with chronic (i.e., greater than 6 months post-injury) ABI and self-reported limitations in balance. Neuroimaging data were acquired before and after yoga. The yoga intervention was completed once per week for eight weeks. Feasibility objectives and benchmarks were established a priori. RESULTS: Most feasibility objectives and benchmarks were achieved. The goal of recruiting 12 participants was successfully achieved, and 75% of participants were retained throughout the study (goal of 80%). All imaging feasibility benchmarks were met; rs-fMRI and fNIRS data were acquired safely, data were of acceptable quality, and data pre-processing procedures were successful. Additionally, improvements were detected in balance after yoga, as group-level balance was significantly better post-yoga compared to pre-yoga, p = 0.043. CONCLUSIONS: These findings indicate it is feasible to acquire neuroimaging data from adults with ABI before and after a yoga intervention. Thus, future prospective studies are warranted.

COVID-19 Oximetry @home: evaluation of patient outcomes.

BACKGROUND: COVID-19 has placed unprecedented demands on hospitals. A clinical service, COVID-19 Oximetry @home (CO@h) was launched in November 2020 to support remote monitoring of COVID-19 patients in the community. Remote monitoring through CO@h aims to identify early patient deterioration and provide timely escalation for cases of silent hypoxia, while reducing the burden on secondary care. METHODS: We conducted a retrospective service evaluation of COVID-19 patients onboarded to CO@h from November 2020 to March 2021 in the North Hampshire (UK) community led service (a collaboration of 15 General Practitioner (GP) practices covering 230 000 people). We have compared outcomes for patients admitted to Basingstoke and North Hampshire Hospital who were CO@h patients (COVID-19 patients with home monitoring of oxygen saturation (SpO2; n=115), with non-CO@h patients (those directly admitted without being monitored by CO@h (n=633)). Crude and adjusted OR analysis was performed to evaluate the effects of CO@h on patient outcomes of 30-day mortality, Intensive care unit (ICU) admission and hospital length of stay greater than 3, 7, 14 and 28 days. RESULTS: Adjusted ORs for CO@h show an association with a reduction for several adverse patient outcome: 30-day hospital mortality (p<0.001, OR 0.21, 95% CI 0.08 to 0.47), hospital length of stay larger than 3 days (p<0.05, OR 0.62, 95% CI 0.39 to 1.00), 7 days (p<0.001, OR 0.35, 95% CI 0.22 to 0.54), 14 days (p<0.001, OR 0.22 95% CI, 0.11 to 0.41), and 28 days (p<0.05, OR 0.21, 95% CI 0.05 to 0.59). No significant reduction ICU admission was observed (p>0.05, OR 0.43, 95% CI 0.15 to 1.04). Within 30 days of hospital admission, there were no hospital readmissions for those on the CO@h service as opposed to 8.7% readmissions for those not on the service. CONCLUSIONS: We have demonstrated a significant association between CO@h and better patient outcomes; most notably a reduction in the odds of hospital lengths of stays longer than 7, 14 and 28 days and 30-day hospital mortality.

Risk Factors for Brain Health in Agricultural Work: A Systematic Review.

Certain exposures related to agricultural work have been associated with neurological disorders. To date, few studies have included brain health measurements to link specific risk factors with possible neural mechanisms. Moreover, a synthesis of agricultural risk factors associated with poorer brain health outcomes is missing. In this systematic review, we identified 106 articles using keywords related to agriculture, occupational exposure, and the brain. We identified seven major risk factors: non-specific factors that are associated with agricultural work itself, toluene, pesticides, heavy metal or dust exposure, work with farm animals, and nicotine exposure from plants. Of these, pesticides are the most highly studied. The majority of qualifying studies were epidemiological studies. Nigral striatal regions were the most well studied brain area impacted. Of the three human neuroimaging studies we found, two focused on functional networks and the third focused on gray matter. We identified two major directions for future studies that will help inform preventative strategies for brain health in vulnerable agricultural workers: (1) the effects of moderators such as type of work, sex, migrant status, race, and age; and (2) more comprehensive brain imaging studies, both observational and experimental, involving several imaging techniques.

Detecting the Inverted-U in fMRI Studies of Schizophrenia: A Comparison of Three Analysis Methods.

OBJECTIVE: Cognitive tasks are used to probe neuronal activity during functional magnetic resonance imaging (fMRI) to detect signs of aberrant cognitive functioning in patients diagnosed with schizophrenia (SZ). However, nonlinear (inverted-U-shaped) associations between neuronal activity and task difficulty can lead to misinterpretation of group differences between patients and healthy comparison subjects (HCs). In this paper, we evaluated a novel method for correcting these misinterpretations based on conditional performance analysis. METHOD: Participants included 25 HCs and 27 SZs who performed a working memory (WM) task (N-back) with 5 load conditions while undergoing fMRI. Neuronal activity was regressed onto: 1) task load (i.e., parametric task levels), 2) marginal task performance (i.e., performance averaged over all load conditions), or 3) conditional task performance (i.e., performance within each load condition). RESULTS: In most regions of interest, conditional performance analysis uniquely revealed inverted-U-shaped neuronal activity in both SZs and HCs. After accounting for conditional performance differences between groups, we observed few difference in both the pattern and level of neuronal activity between SZs and HCs within regions that are classically associated with WM functioning (e.g., posterior dorsolateral prefrontal and parietal association cortices). However, SZs did show aberrant activity within the anterior dorsolateral prefrontal cortex. CONCLUSIONS: Interpretations of differences in neuronal activity between groups, and of associations between neuronal activity and performance, should be considered within the context of task performance. Whether conditional performance-based differences reflect compensation, dedifferentiation, or other processes is not a question that is easily resolved by examining activation and performance data alone.

Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1.

In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.

Conducting large, repeated, multi-game economic experiments using mobile platforms.

We demonstrate the possibility of conducting synchronous, repeated, multi-game economic decision-making experiments with hundreds of subjects in-person or remotely with live streaming using entirely mobile platforms. Our experiment provides important proof-of-concept that such experiments are not only possible, but yield recognizable results as well as new insights, blurring the line between laboratory and field experiments. Specifically, our findings from 8 different experimental economics games and tasks replicate existing results from traditional laboratory experiments despite the fact that subjects play those games/task in a specific order and regardless of whether the experiment was conducted in person or remotely. We further leverage our large subject population to study the effect of large (N = 100) versus small (N = 10) group sizes on behavior in three of the scalable games that we study. While our results are largely consistent with existing findings for small groups, increases in group size are shown to matter for the robustness of those findings.

A double-slit experiment with human subjects.

We study a sequence of "double-slit" experiments designed to perform repeated measurements of an attribute in a large pool of subjects using Amazon's Mechanical Turk. Our findings contrast the prescriptions of decision theory in novel and interesting ways. The response to an identical sequel measurement of the same attribute can be at significant variance with the initial measurement. Furthermore, the response to the sequel measurement depends on whether the initial measurement has taken place. In the absence of the initial measurement, the sequel measurement reveals additional variability, leading to a multimodal frequency distribution which is largely absent if the first measurement has taken place.

Latent Variable Modeling and Adaptive Testing for Experimental Cognitive Psychopathology Research.

The adaptation of experimental cognitive tasks into measures that can be used to quantify neurocognitive outcomes in translational studies and clinical trials has become a key component of the strategy to address psychiatric and neurological disorders. Unfortunately, while most experimental cognitive tests have strong theoretical bases, they can have poor psychometric properties, leaving them vulnerable to measurement challenges that undermine their use in applied settings. Item response theory-based computerized adaptive testing has been proposed as a solution but has been limited in experimental and translational research due to its large sample requirements. We present a generalized latent variable model that, when combined with strong parametric assumptions based on mathematical cognitive models, permits the use of adaptive testing without large samples or the need to precalibrate item parameters. The approach is demonstrated using data from a common measure of working memory-the N-back task-collected across a diverse sample of participants. After evaluating dimensionality and model fit, we conducted a simulation study to compare adaptive versus nonadaptive testing. Computerized adaptive testing either made the task 36% more efficient or score estimates 23% more precise, when compared to nonadaptive testing. This proof-of-concept study demonstrates that latent variable modeling and adaptive testing can be used in experimental cognitive testing even with relatively small samples. Adaptive testing has the potential to improve the impact and replicability of findings from translational studies and clinical trials that use experimental cognitive tasks as outcome measures.

Ileostomy After Intestinal Transplantation: The First in Depth Report on Techniques, Complications, and Outcomes.

BACKGROUND: Temporary ileostomy during intestinal transplantation (ITx) is the standard technique for allograft monitoring. A detailed analysis of the ITx ileostomy has never been reported. METHODS: A retrospective review of a single-center ITx database was performed. The analysis was divided into ileostomy formation and takedown episodes. RESULTS: One hundred thirty-five grafts underwent ileostomy formation, and 79 underwent ileostomy takedown. Median age at ITx was 7.7 years and weight was 23 kg. Allograft types were intestine (22%), liver/intestine (55%), multivisceral (16%), and modified multivisceral (7%). Sixty-four percent had 1-stage ITx, whereas 36% required 2-staged ITx. Final ileostomy types were end (20%), loop (10%), distal blowhole (59%), and proximal blowhole (11%). Ileostomy formation: Thirty-one grafts had complications (23%), including prolapse (26%), ischemia (16%), and parastomal hernia (19%). Twelve required surgical revision. There were no significant differences in graft type, ileostomy type, survival, and ileostomy takedown rate between grafts with and without complications. Colon inclusive grafts had higher complication rates (P = 0.002). Ileostomy takedown: Ileostomy takedown occurred at a median of 422 days post-ITx. Twenty-five complications occurred after 22 takedowns (28%), including small bowel obstruction (27%) and abscess (18%). Fifteen grafts required surgical correction. Recipients with complications had longer hospital stay (17 versus 9 d; P = 0.001) than those without complications. Graft type, ileostomy type, and survival were not different. CONCLUSIONS: The first of its kind analysis of the surgical ileostomy after ITx reveals that most recipients can undergo successful ileostomy formation/takedown, complication rates are significant but within an acceptable range, and complications do not affect survival. This study demonstrates that the routine use of transplant ostomies remains an acceptable practice after ITx. However, true analysis of risk and benefit will require a randomized control trial.

Comparison of Outcomes with Semi-mechanical and Circular Stapled Intrathoracic Esophagogastric Anastomosis following Esophagectomy.

BACKGROUND: Several techniques have been described for esophagogastric anastomosis following esophagectomy. This study compared the outcomes of circular stapled anastomoses with semi-mechanical technique using a linear stapler. METHODS: Perioperative data were extracted from a contemporaneously collected database of all consecutive esophagectomies for cancer with intrathoracic anastomoses performed in the Trent Oesophago-Gastric Unit between January 2015 and April 2018. Anastomotic techniques: circular stapled versus semi-mechanical, were evaluated and outcomes were compared. The primary outcome was anastomotic leak rate. Secondary outcomes included anastomotic stricture, overall complication rates, length of stay (LOS) and 30 day all-cause mortality. RESULTS: One hundred and fifty-nine consecutive esophagectomies with intrathoracic anastomosis were performed during the study period. There were no significant differences between the two groups in terms of age, American Society of Anaesthesiologists score, Charlson comorbidity index and neoadjuvant therapies received. Circular stapled anastomoses were performed in 85 patients, while 74 patients received a semi-mechanical anastomosis. Clavien-Dindo complications II or more were higher in the circular stapled group (p = 0.02). There were 16 (10%) anastomotic leaks overall, three (4%) in semi-mechanical group versus 13 (15%) in the circular stapled group (p < 0.019). There was no statistically significant difference between the two groups in terms of LOS, 30-day mortality or the need for endoscopic dilatation of the anastomosis at 3 months follow-up. CONCLUSION: The move from a circular stapled to a semi-mechanical intrathoracic anastomosis has been associated with a reduced postoperative anastomotic leak rate following esophagectomy for esophageal cancer.

Nontraumatic rupture of the costal margin: a single-center experience.

BACKGROUND: Rupture of the costal margin is uncommon. Whilst most often seen after major trauma, we describe its occurrence in patients with no direct chest trauma. METHODS: A search was performed in our thoracic surgery database for all patients with rupture of the costal margin. Patients were excluded if the injury was a result of trauma. Data were collected on sex, age, body mass index, profession, past medical history, smoking status, presenting complaint, mechanism of injury, and management. RESULTS: There were 9 patients with rupture of the costal margin that was caused in all cases by a severe coughing fit. All patients were male and the mean age was 62.5 years (range 47-76 years). Chronic obstructive pulmonary disease was present in 6 cases. Presentations included a palpable defect (5 cases), cough (9 cases), and chest pain (6 cases). On radiological examination, all patients had widening of the rib space, 4 had associated rib fractures, and 5 had lung herniation. Time from injury to presentation was 12 months (range 1-24 months). All patients underwent surgery and were followed-up for 59 months (range 8-129 months). Two patients suffered major complications in the immediate postoperative period. CONCLUSIONS: Rupture of the costal margin, in the absence of direct trauma, is characterized by pain, a palpable defect, and lung herniation. It is associated with widening of the rib space and rib fractures, and can be treated surgically with success but not without significant risks.

Multicomponent analysis of the tumour microenvironment reveals low CD8 T cell number, low stromal caveolin-1 and high tenascin-C and their combination as significant prognostic markers in non-small cell lung cancer.

The complex interplay of the tumour microenvironment (TME) and its role in disease progression and response to therapy is poorly understood. The majority of studies to date focus on individual components or molecules within the TME and so lack the power correlative analysis. Here we have performed a multi-parameter analysis of the TME in 62 resectable non-small cell lung cancer (NSCLC) specimens detailing number and location of immune infiltrate, assessing markers of cancer-associated fibroblasts, caveolin-1 and tenascin-C, and correlating with clinicopathological details, as well as markers of disease progression such as epithelial-to-mesenchymal transition (EMT). The influence of individual parameters on overall survival was determined in univariate and multivariate analysis and the combination of risk factors and interplay between components analysed. Low numbers of CD8 T cells, low stromal levels of caveolin-1 or high levels of tenascin-C were significant prognostic markers of decreased overall survival in both univariate and multivariate analysis. Patients with two or more risk factors had dramatically reduced overall survival and those with all three a median survival of just 7.5 months. In addition, low levels of tumour E-cadherin correlated with reduced immune infiltrate into the tumour nests, possibly linking EMT to the avoidance of CD8 T cell control. The multicomponent approach has allowed identification of the dominant influences on overall survival, and exploration of the interplay between different components of the TME in NSCLC.

Discovery of Novel, Orally Bioavailable ß-Amino Acid Azaindole Inhibitors of Influenza PB2.

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.

Benefits of the Nephros Dual Stage Ultrafilter in Chronic Hemodialysis Patients: Evidence for Improved ESA Responsiveness.

Installation of the Nephros Dual Stage Ultrafilter (DSU) added to a conventional hemodialysis unit to achieve ultrapure dialysate was tested in a group of 23 stable outpatients on chronic hemodialysis. Comparing the 6-month period prior to the installation of the filters (as baseline) to the 6-month period after the installation of the filters, we found a significant 40% reduction in the darbepoetin dose needed to maintain a stable hemoglobin level (p < 0.001). In addition, surrogate inflammatory markers, WBC count and serum albumin level, showed small but statistically significant improvements (p = 0.008 and p = 0.042, respectively). In conclusion, the use of the Nephros DSU to further reduce endotoxin exposure in chronic hemodialysis patients can result in improved erythropoiesis-stimulating agent (ESA) responsiveness and a lower ESA dose.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors.

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor-derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non-small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753-63. ©2016 AACR.

Isolated axillary lymph node metastasis in oesophageal adenocarcinoma.

Oesophageal adenocarcinoma metastatic to the axilla is a rare occurrence. The authors present a case of a woman who developed an axillary metastasis from a completely excised oesophageal adenocarcinoma with no prior evidence of nodal disease. With aggressive local treatment, including multiple local operations and radiotherapy, she remains alive and disease-free 12 years after her diagnosis following surgical resection of her axillary metastasis with adjuvant radiotherapy. This case report suggests that there are occasions when aggressive local treatment of apparently isolated metastases can result in a cure.