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Traumatic brain injury (TBI) and blunt thoracic aortic injury (BTAI) are the top two leading causes of death after blunt force trauma. Patients presenting with concomitant BTAI and TBI pose a specific challenge with respect to management strategy, because the optimal hemodynamic parameters are conflicting between the two pathologies. Early thoracic endovascular aortic repair (TEVAR) is often performed, even for minimal aortic injuries, to allow for the higher blood pressure parameters required for TBI management. However, the optimal timing of TEVAR for the treatment of BTAI in patients with concomitant TBI remains an active matter of controversy.The Aortic Trauma Foundation international prospective multicenter registry was used to identify all patients who had undergone TEVAR for BTAI in the setting of TBI from 2015 to 2020. The primary outcomes included delayed ischemic or hemorrhagic stroke, in-hospital mortality, and aortic-related mortality. The outcomes were examined among patients who had undergone TEVAR at emergent (6 vs ≥6 hours) or urgent (24 vs ≥24 hours) intervals.A total of 100 patients (median age, 43 years; 79% men; median injury severity score, 41) with BTAI (Society for Vascular Surgery BTAI grade 1, 3%; grade 2, 10%; grade 3, 78%; grade 4, 9%) and concomitant TBI who had undergone TEVAR were identified. Emergent repair was performed for 51 patients (51%). Comparing emergent repair (6 hours) to urgent repair (≥6 hours), no difference was found in delayed cerebral ischemic events (2.0% vs 4.1%; P = .614), in-hospital mortality (15.7% vs 22.4%; P = .389), or aortic-related mortality (2.0% vs 2.0%; P = .996) and no patient had experienced delayed hemorrhagic stroke. Likewise, repairs conducted in an urgent (24 hours) setting showed no differences compared with those completed in an emergent (≥24 hours) setting regarding delayed ischemic stroke (2.6% vs 4.3%; P = .548), in-hospital mortality (18.2% vs 21.7%; P = .764), or aortic-related mortality (1.3% vs 4.3%; P = .654), and no patient had experienced delayed hemorrhagic stroke.In contrast to prior retrospective efforts, results from the Aortic Trauma Foundation international prospective multicenter registry have demonstrated that neither emergent nor urgent TEVAR for patients with concomitant BTAI and TBI was associated with delayed stroke, in-hospital mortality, or aortic-related mortality. In these patients, the timing of TEVAR did not have an effect on the outcomes. Therefore, the decision to intervene should be guided by individual patient factors rather than surgical timing.

Multiple-choice testing with dichotomous scoring is one of the most common assessment methods utilized in undergraduate education. Determining students’ perceptions toward different types of multiple-choice testing formats is important for effective assessment. The present study compared two alternative multiple-choice testing formats used in a second-year required chemistry course: (i) Immediate Feedback Assessment Technique (IFAT®) and (ii) Personal Point Allocation (PPA). Both testing methods allow for partial credit, but only the IFAT® provides immediate feedback on students’ responses. Both survey and interview data indicated that, overall, most students preferred IFAT® to the PPA testing method. These positive ratings were related to potential increase in reward, ease of use, and confidence. IFAT® was also perceived to be less stress producing and anxiety provoking than PPA. Interview data not only supported these findings, but also indicated individual differences in preference for each of these two methods. Additionally, students’ feedback on strategies used for either testing method and suggestions on how to improve the methods are discussed.

Frozen section evaluation of head and neck squamous cell carcinoma (SCC) is critical for margin status and subsequent patient therapy. In this study, we retrospectively reviewed the rate of frozen-permanent section discrepancies in blocks with two frozen section levels compared to ≥ three levels in oral cavity and oropharyngeal SCCs. A search of the cases with both intraoperative frozen sections and corresponding permanent sections for SCCs in the oral cavity and oropharynx was performed. Frozen sections and permanent slides were compared. The nature of discrepancies was assigned to one of the following: change in diagnosis, margin status, or distance of the tumor from the margin. The cause of the discrepancy was designated as one of the following: block sampling, gross sampling, interpretation, or technical error. The pathologist experience, frozen section technical experience, and intraoperative impact of each discrepancy were also evaluated. A total of 654 frozen and corresponding permanent blocks were assessed. For 532 of the frozen section blocks, two levels were cut, while 122 frozen section blocks had ≥ three levels. Thirty-five frozen-permanent section discrepancies were observed (5.4% of all blocks). Among these, 2.5% had a possible or definitive intraoperative impact. The percentage of discrepancies in the ≥ three levels group (5.7%) was slightly higher than the two-level group (5.3%), and this difference was not statistically significant. For the two-level group, the overall block sampling error rate was 4.5%. This was not significantly different from the 4.1% block sampling error rate seen in the ≥ three levels group. The rate of block sampling discrepancy did not show significant differences based on attending or frozen section technical experience. A change in margin distance (closer margin detected on permanent) occurred in 4% of the blocks and involved 16% of the patients. This review of oral cavity and oropharynx SCCs frozen/permanent section discrepancies shows that the error rate is not significantly different depending on the number of levels cut. The results suggest that always performing more than two frozen section levels may not yield a decreased discrepancy rate. A change in margin distance occurred quite frequently, but only in rare cases it had a definitive impact on the intraoperative management. Given the importance of correct intraoperative diagnosis in patient management, additional levels may be warranted depending on the clinical scenario.

Plasmablastic lymphomas and plasmablastic myelomas are malignancies with overlapping clinical and pathological features which pose a diagnostic dilemma and are known to be aggressive with a poor outcome. CD38 is a common immunophenotypic maker for both these malignancies and provides a rationale for using daratumumab-based regimes. We describe a 57-year-old male with a history of end-stage renal disease who underwent a deceased-donor renal transplant maintained on chronic immunosuppression who presented with ascites and was found to have abdominal adenopathy and a lytic lesion in the humerus and diagnosed with a post-transplant lymphoproliferative disorder with features intermediate between plasmablastic lymphoma and plasmablastic myeloma. The patient was subsequently treated with a daratumumab-based regime with an excellent response. This case highlights a rare scenario that poses a diagnostic and therapeutic challenge. As there is no standard of care for the treatment of both these malignancies, this case report also describes the use of daratumumab with a good long-term outcome, especially when the pathological distinction between the two entities is difficult.

BACKGROUND/OBJECTIVES To record the prevalence of ocular sarcoidosis (OS) cases present in Northern Ireland as diagnosed using the International Workshop on Ocular Sarcoidosis (IWOS) classification, 2019. There are currently no data regarding OS in this population. SUBJECTS/METHODS Retrospective case review of OS cases as identified by IWOS criteria 2019. Mid-year population estimates were used to calculate disease prevalence. Additional data collected included uveitis features, ocular complications and the presence of ocular only or multi-system disease. RESULTS A total of 86 patients were identified meeting the criteria for a diagnosis of OS, and the prevalence of OS in Northern Ireland was estimated to be 4.5 cases per 100,000. The most common type of uveitis was panuveitis in 36% of cases, and the most common ocular complication was ocular hypertension in 36% of cases and detectable glaucomatous changes in 10%. Overall, 80% of cases presenting with ocular only sarcoidosis subsequently developed second organ involvement at a rate of 14%/person-years. The most common extra-ocular site of sarcoidosis was pulmonary. CONCLUSIONS The Northern Ireland population has a relatively high prevalence of OS compared with other European countries. OS presenting with only ocular involvement progressed to second organ involvement in 80% of patients at a rate of 14%/person-years. Raised intra-ocular pressure with or without glaucomatous damage was a frequent finding. Thoracic CT imaging should be requested if clinical suspicion of OS exists and the presence of lymphopenia has utility in diagnosis with concurrent use of systemic ACE inhibitors.

Objectives This paper looks at patients with a diagnosis of tubulointerstitial nephritis and uveitis (TINU) presenting to the Northern Ireland regional adult and paediatric uveitis service in the Belfast Health and Social Care Trust. The demographic distribution, treatment required and the visual and renal outcomes of these patients are documented. Methods Data were collected retrospectively on 24 patients with TINU using the Northern Ireland Electronic Care Record, central pathology records alongside the adult and paediatric uveitis databases from 2011 to 2021. Patients were categorised into two groups using the Mandeville classification system. Standard Uveitis Nomenclature (SUN) was used to classify the uveitis. Results The population prevalence is at least 12.6 cases per million based on a population of 1.9 million. Nineteen of 24 cases were definite TINU and five of 24 probable. Seventeen out of 24 had biopsy-positive TIN, all of which met all of the Mandeville clinical diagnostic features required for a definite diagnosis. All but one presented with acute bilateral anterior uveitis. The paediatric cases ranged from age 12 to 18 at age of onset with a mean age of 14. Of the 18 adult onset cases, the age ranged from 20 to 76 years. The mean age of onset for the adult cases was 53 years. Of these patients 71% were female; 42% required second-line immunosuppression for ocular disease. Visual acuity was maintained. Follow-up time ranged from 3 months to 16 years. No patient developed long-term renal impairment. Conclusions TINU is a cause of uveitis in both the paediatric and adult populations. In Northern Ireland average age with TINU was older than much of the published literature. Long-term immunosuppression for uveitis may be required as ongoing ocular, rather than renal inflammation seemed to require treatment.

Purpose Prone positioning during the COVID-19 pandemic has become increasingly used as an adjunct to increase oxygenation in critical care patients. It is associated with an adverse event profile. This study sought to investigate the occurrence of ocular injuries reported in prone versus supine groups in adult critical care. Design Systematic review and meta-analysis. Methods A systematic review and meta-analysis were carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed, SCOPUS, and the Cochrane Library were searched. The search period was January 1, 1990, to July 1, 2020. Results Eleven randomized controlled trials were included, with 2,247 patients. Twenty-eight events were recorded in 3 trials (174 patients) and no events in the other 8 trials (2,073 patients). The rates of eye injury were 5 events in 1,158 patients (1.30%) and 13 events in 1,089 patients (1.19%) in the prone and supine groups, respectively, which were reduced to 2 of 1,158 patients (0.17%) and 2 of 1,089 patients (0.18%), respectively, when reports of eye or eyelid edema were removed. Meta-analysis demonstrated no significant differences between groups with (an OR of 1.40 (95% CI: 0.37–5.27) and without (OR: 0.78; 95% CI: 0.11–5.73) reported edema. Conclusions This meta-analysis showed no significant difference in the rate of reported ocular injury between prone and supine critical care groups. These rates remain higher than the incidence reported during general anesthesia. There is a need for studies in critical care settings in which ocular injury is an end-point and which include extended patient follow-up.

Implantable drug depots have the capacity to locally meet therapeutic requirements by maximizing local drug efficacy and minimizing potential systemic side effects. Tubular organs including the gastrointestinal tract, respiratory tract and vasculature all manifest with endoluminal disease. The anatomic distribution of localized drug delivery for these organs using existing therapeutic modalities is limited. Application of local depots in a circumferential and extended longitudinal fashion could transform our capacity to offer effective treatment across a range of conditions. Here we report the development and application of a kirigami-based stent platform to achieve this. The stents comprise a stretchable snake-skin-inspired kirigami shell integrated with a fluidically driven linear soft actuator. They have the capacity to deposit drug depots circumferentially and longitudinally in the tubular mucosa of the gastrointestinal tract across millimetre to multi-centimetre length scales, as well as in the vasculature and large airways. We characterize the mechanics of kirigami stents for injection, and their capacity to engage tissue in a controlled manner and deposit degradable microparticles loaded with therapeutics by evaluating these systems ex vivo and in vivo in swine. We anticipate such systems could be applied for a range of endoluminal diseases by simplifying dosing regimens while maximizing drug on-target effects through the sustained release of therapeutics and minimizing systemic side effects. A kirigami-inspired stent-based system has been developed for extended local drug delivery to the gastrointestinal and respiratory tracts as well as the vascular system.

Across the globe, radical conservative political forces and ideas are influencing and even transforming the landscape of international politics. Yet IR is remarkably ill-equipped to understand and engage these new challenges. Unlike political theory or domestic political analyses, conservatism has no distinctive place in the fields’ defining alternatives of realism, liberalism, Marxism, and constructivism. This paper seeks to provide a point of entry for such engagement by bringing together what may seem the most unlikely of partners: critical theory and the New Right. Important parts of today’s New Right represent self-conscious appropriations of Critical themes and thinkers—turning them to self-declared “reactionary” ends. Developing outside the confines of the academy, these forms of thought have woven insights from across Critical theory into new and mobilizing forms of conservative ideology, seeking to link that ideology to social forces that play increasingly active roles in global politics. Our intention here is not to somehow blame Critical perspectives for the ideas of the New Right, either directly or by association. Rather, we seek to show how an engagement with Critical theory helps us understand the New Right, while also demonstrating some of the direct challenges the New Right poses for critical perspectives.

Background We aimed to assess the cost effectiveness of intravitreal ranibizumab (Lucentis), aflibercept (Eylea) and bevacizumab (Avastin) for the treatment of macular oedema due to central retinal vein occlusion. Methods We calculated costs and quality-adjusted life-years from the UK National Health Service and Personal Social Services perspective. We performed a within-trial analysis using the efficacy, safety, resource use and health utility data from a randomised controlled trial (LEAVO) over 100 weeks. We built a discrete event simulation to model long-term outcomes. We estimated utilities using the Visual-Functioning Questionnaire-Utility Index, EQ-5D and EQ-5D with an additional vision question. We used standard UK costs sources for 2018/19 and a cost of £28 per bevacizumab injection. We discounted costs and quality-adjusted life-years at 3.5% annually. Results Bevacizumab was the least costly intervention followed by ranibizumab and aflibercept in both the within-trial analysis (bevacizumab: £6292, ranibizumab: £13,014, aflibercept: £14,328) and long-term model (bevacizumab: £18,353, ranibizumab: £30,226, aflibercept: £35,026). Although LEAVO did not demonstrate bevacizumab to be non-inferior for the visual acuity primary outcome, the three interventions generated similar quality-adjusted life-years in both analyses. Bevacizumab was always the most cost-effective intervention at a threshold of £30,000 per quality-adjusted life-year, even using the list price of £243 per injection. Conclusions Wider adoption of bevacizumab for the treatment of macular oedema due to central retinal vein occlusion could result in substantial savings to healthcare systems and deliver similar health-related quality of life. However, patients, funders and ophthalmologists should be fully aware that LEAVO could not demonstrate that bevacizumab is non-inferior to the licensed agents.

Portal vein aneurysms are rare pathologic entities. A 3.7-cm portal vein aneurysm was incidentally discovered in an 80-year-old male patient on imaging for acute abdominal pain secondary to an incarcerated diaphragmatic hernia. The aneurysm was resected, and primary repair of the portal vein was performed during a second-look operation after repair of the incarcerated hernia. Operative intervention was chosen for this patient because of the aneurysm's size and the additional indication for abdominal exploration.

BACKGROUND: One of the most frequent complications of coronary artery bypass grafting (CABG) is pleural effusion. Limited previous studies have found post-CABG pleural effusion to be associated with increased length-of-stay and greater morbidity post-CABG. Despite this the associations of this common complication are poorly described. This study sought to identify modifiable risk factors for effusion post-CABG. METHODS: A retrospective cohort study of prospectively collected data assessed patients who underwent CABG over two-years. Data was collected for risk factors and sequelae related to pleural effusion requiring drainage. RESULTS: A total of 409 patients were included. Average age was 64.9±10.2 years, 330 (80.7%) were male. 59 (14.4%) patients underwent drainage of pleural effusion post-CABG. Effusions were drained on average 9.9±8.4 days post-CABG. Earlier removal of drain tubes and removal near time of extubation were associated with development of pleural effusion. Post-CABG pleural effusion was associated with post-operative renal impairment (P

Purpose To describe the surgical technique and examine the feasibility and outcomes following robotic pelvic exenteration and extended pelvic resection for rectal and/or urological malignancy. Materials and methods We present a case series of seven patients with locally advanced or synchronous urological and/or rectal malignancy who underwent robotic total or posterior pelvic exenteration between 2012-2016. Results In total, we included seven patients undergoing pelvic exenteration or extended pelvic resection. The mean operative time was 485±157 minutes and median length of stay was 9 days (6-34 days). There was only one Clavien-Dindo complication grade 3 which was a vesicourethral anastomotic leak requiring rigid cystoscopy and bilateral ureteric catheter insertion. Eighty-five percent of patients had clear colorectal margins with a median margin of 3.5 mm (0.7-8.0 mm) while all urological margins were clear. Six out of seven patients had complete (grade 3) total mesorectal excision. Three patients experienced recurrence at a median of 22 months (21-24 months) post-operatively. Of the three recurrences, one was systemic only whilst two were both local and systemic. One patient died from complications of dual rectal and prostate cancer 31 months after the surgery. Conclusions We report a large series examining robotic pelvic exenteration or extended pelvic resection and describe the surgical technique involved. The robotic approach to pelvic exenteration is highly feasible and demonstrates acceptable peri-operative and oncological outcomes. It has the potential to benefit patients undergoing this highly complex and morbid procedure.

This paper examines the concept of community in the context of U2’s ‘360°’ tour (2009–2011). It contributes to leisure studies by offering a detailed insight into the production of, sense of belong...

Accurate staging of high-risk localised, advanced, and metastatic prostate cancer is becoming increasingly more important in guiding local and systemic treatment. Gallium-68 prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has increasingly been utilised globally to assess the local and metastatic burden of prostate cancer, typically in biochemically recurrent or advanced disease. Following our previous meta-analysis, a high-volume series has been reported highlighting the utility ofTo perform a systematic review and meta-analysis to update reported predictors of positiveWe performed critical reviews of MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science databases in July 2018 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Quality assessment was performed using Quality Assessment if Diagnostic Accuracy Studies-2 tool. Meta-analyses of proportions were performed using a random-effect model. Summary sensitivity and specificity values were obtained by fitting bivariate hierarchical regression models.A total of 37 articles including 4790 patients were analysed. For patients with biochemical recurrence, positiveGa-68-PSMA PET improves detection of metastases with biochemical recurrence, particularly at low pre-PET PSA levels of0.2ng/ml (33%) and 0.2-0.5ng/ml (45%). Ga-68-PSMA-PET produces favourable sensitivity and specificity profiles on meta-analysis of pooled data. This analysis highlights different anatomic patterns of metastatic spread according to PSMA PET in the primary and biochemically recurrent settings.Gallium-68 prostate-specific membrane antigen positron emission tomography is now an established imaging technique that has been developed in response to inadequacies in standard of care imaging modalities to improve the detection of metastatic disease in prostate cancer, particularly in the setting of disease recurrence. To date, this imaging modality in the setting of primary staging is controversial, given the paucity of data. In light of the growing body of evidence, we summarised the data to date to provide clinicians with an overview of this imaging modality.

Despite improved knowledge regarding disease causality, new drug targets, and enabling technologies, the attrition rate for compounds entering clinical trials has remained consistently high for several decades, with an average 90% failure rate. These failures are manifested in an inability to reproduce efficacy findings from animal models in humans and/or the occurrence of unexpected safety issues, and reflect failures in T1 translation. Similarly, an inability to sequentially demonstrate compound efficacy and safety in Phase IIa, IIb, and III clinical trials represents failures in T2 translation. Accordingly, T1 and T2 translation are colloquially termed 'valleys of death'. Since T2 translation dealt almost exclusively with clinical trials, T3 and T4 translational steps were added, with the former focused on facilitating interactions between laboratory- and population-based research and the latter on 'real world' health outcomes. Factors that potentially lead to T1/T2 compound attrition include: the absence of biomarkers to allow compound effects to be consistently tracked through development; a lack of integration/'de-siloing' of the diverse discipline-based and technical skill sets involved in drug discovery; the industrialization of drug discovery, which via volume-based goals often results in quantity being prioritized over quality; inadequate project governance and strategic oversight; and flawed decision making based on unreliable/irreproducible or incomplete data. A variety of initiatives have addressed this problem, including the NIH National Center for Advancing Translational Sciences (NCATS), which has focused on bringing an unbiased academic perspective to translation, to potentially revitalize the process. This commentary provides an overview of the basic concepts involved in translation, along with suggested changes in the conduct of biomedical research to avoid valleys of death, including the use of Translational Scoring as a tool to avoid translational attrition and the impact of the FDA Accelerated Approval Pathway in lowering the hurdle for drug approval. © 2021 Wiley Periodicals LLC.

GNAO1 encodes Gαo, a heterotrimeric G protein alpha subunit in the Gi/o family. In this report, we used a Gnao1 mouse model “G203R” previously described as a “gain-of-function” Gnao1 mutant with movement abnormalities and enhanced seizure susceptibility. Here, we report an unexpected second mutation resulting in a loss-of-function Gαo protein and describe alterations in central synaptic transmission.Whole cell patch clamp recordings from Purkinje cells (PCs) in acute cerebellar slices from Gnao1 mutant mice showed significantly lower frequencies of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) compared to WT mice. There was no significant change in sEPSCs or mEPSCs. Whereas mIPSC frequency was reduced, mIPSC amplitudes were not affected, suggesting a presynaptic mechanism of action. A modest decrease in the number of molecular layer interneurons was insufficient to explain the magnitude of IPSC suppression. Paradoxically, Gi/o inhibitors (pertussis toxin), enhanced the mutant-suppressed mIPSC frequency and eliminated the difference between WT and Gnao1 mice. While GABAB receptor regulates mIPSCs, neither agonists nor antagonists of this receptor altered function in the mutant mouse PCs. This study is the first electrophysiological investigation of the role of Gi/o protein in cerebellar synaptic transmission using an animal model with a loss-of-function Gi/o protein.Significance StatementThis is the first report on the electrophysiological mechanisms of a movement disorder animal model with monoallelic Gnao1 loss. This study illustrates the role of Gαo protein in regulating GABA release in mouse cerebellum. This study could also facilitate the discovery of new drugs or drug repurposing for GNAO1-associated disorders. Moreover, since GNAO1 shares pathways with other genes related to movement disorders, developing drugs for the treatment of GNAO1-associated movement disorders could further the pharmacological intervention for other monogenic movement disorders.

Progressive renal decline is associated with increasing oxidative stress. However, the majority of studies have investigated endogenous antioxidants in predominantly advanced stages of kidney disease. Many traditional risk factors associated with renal dysfunction have been linked with cognitive decline as the kidneys and brain share comparable anatomic and haemodynamic characteristics that leave them susceptible to common pathogenic mechanisms. The objective of this study was to examine serum dietary antioxidants and their association with renal function characterised by estimated glomerular filtration rate (eGFR) in a cross-sectional analysis of 570 participants. High performance liquid chromatography quantified serum levels of retinol, α-tocopherol, γ-tocopherol and six carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein, lycopene and zeaxanthin) in participants. Multiple regression analyses were used to evaluate associations while adjusting for potential confounders. A sensitivity analysis was performed in cognitively-intact participants only. Serum levels of the xanthophyll carotenoid lutein were positively associated with eGFR in analyses adjusted for age (years), gender, smoking, APOE4 status and Alzheimer’s disease. Retinol was inversely associated with eGFR, although was no longer significant in the smaller sensitivity analysis. Our findings identify significant associations between the xanthophyll carotenoids and eGFR. Further investigations are required to confirm these findings.

Purpose: To evaluate anatomic–functional associations at sites of retinal lesions in retinal vein occlusion (RVO).Methods: This pilot, prospective, observational study was conducted at the Northern Ireland Clinical Research Facility (NICRF) of Queen's University and the Belfast Health and Social Care Trust, Northern Ireland, between August 1, 2018, and September 30, 2019. The study included 10 treatment-naïve patients with RVO (10 RVO eyes and 10 fellow eyes). There were 81 points/sites assessed for each eye at baseline; six patients were re-assessed 6 months after anti-vascular endothelial growth factor therapy at the same locations. We investigated associations between retinal sensitivity and presence of structural RVO lesions, including retinal ischemia, hemorrhages, intraretinal fluid (IRF) and subretinal fluid outside the foveal/parafoveal regions. Comparisons were made between RVO eyes and fellow eyes at baseline, and between RVO eyes at baseline and at 6 months after treatment. Regression models were used to investigate anatomic–functional associations.Results: At baseline, strong associations were found between reduced retinal sensitivity and presence of ischemia (estimate = −2.08 dB; P < 0.001), intraretinal fluid (estimate = −7.82 dB; P < 0.001), and subretinal fluid (estimate = −8.66 dB; P < 0.001). Resolution of subretinal fluid but not intraretinal fluid was associated with improved function (estimate = 2.40 dB [P = 0.022]; estimate = 1.16 dB [P = 0.228], respectively). However, reperfusion of ischemic retina, observed in 31 of 486 points (6%) 6 months after anti-vascular endothelial growth factor therapy, was associated with a further decrease in retinal sensitivity (estimate = −2.34 dB; P = 0.035).Conclusions: Retinal sensitivity was decreased at sites of RVO lesions. Decreased function at sites of retinal ischemia did not recover after treatment, even when reperfusion occurred.

The sialic acid-binding immunoglobulin-type lectin Siglec-15 is a promising target to cancer immunotherapy in several tumor types. The present study aimed to investigate Siglec-15 expression in gastric cancer (GC) patient tissue and to evaluate its clinical value. Siglec-15 expression was evaluated by immunohistochemistry with 71 patients. Siglec-15 staining was observed in tumor cells of 53 (74.64%) patients, with significant association with histologic classification and angiolymphatic invasion (p

Background and Objective Community mitigation strategies could help reduce COVID-19 incidence, but there are few studies that explore associations nationally and by urbanicity. In a national county-level analysis, we examined the probability of being identified as a county with rapidly increasing COVID-19 incidence (rapid riser identification) during the summer of 2020 by implementation of mitigation policies prior to the summer, overall and by urbanicity. Methods We analyzed county-level data on rapid riser identification during June 1–September 30, 2020 and statewide closures and statewide mask mandates starting March 19 (obtained from state government websites). Poisson regression models with robust standard error estimation were used to examine differences in the probability of rapid riser identification by implementation of mitigation policies (P-value Results Counties in states that closed for 0–59 days were more likely to become a rapid riser county than those that closed for >59 days, particularly in nonmetropolitan areas. The probability of becoming a rapid riser county was 43% lower among counties that had statewide mask mandates at reopening (adjusted prevalence ratio = 0.57; 95% confidence intervals = 0.51–0.63); when stratified by urbanicity, associations were more pronounced in nonmetropolitan areas. Conclusions These results underscore the potential value of community mitigation strategies in limiting the COVID-19 spread, especially in nonmetropolitan areas.

Endovascular reinterventions are often performed after previous open or endovascular aortic procedures. We used the GREAT (Global Registry for Endovascular Aortic Treatment) database to compare the outcomes between these groups. We also compared reintervention of any type with a group of patients who had undergone primary endovascular abdominal aortic aneurysm repair (EVAR).All patients enrolled in GREAT were grouped according to a previous EVAR or open abdominal aortic procedure (OAP). Univariate analysis was performed using the χA total of 3974 subjects who had undergone EVAR with follow-up data available were included in the GREAT. Of the 3974 procedures, 196 (4.9%) were reinterventions (49 after OAP and 147 after previous EVAR). Reintervention after previous EVAR showed a trend toward a greater endoleak rate through 2 years (13.6% vs 4.1%; P = .07), although no difference was found in the occurrence of the intervention (12.2% vs 17.7%; P = .37). Reintervention after OAP resulted in higher all-cause mortality through 2 years of follow-up (32.7% vs 17.7%; P = .0.03). The predictors of mortality included prior OAP, renal insufficiency, and the use of cutdown for access. Compared with the patients who had undergone primary endovascular repair, patients in the reintervention cohort were older (75.3 years vs 73.3 years; P = .0005), had had only femoral artery access used (95.8% vs 90.3%; P .0001), and were more likely to have undergone aortic branch vessel procedures (32.3% vs 13.3%; P .0001). Both all-cause and aorta-related mortality through 2 years was higher in the reintervention group than in the primary EVAR group (21.4% vs 12.5% [P = .0003; and 4.6% vs 1% [P .0001], respectively). On multivariate analysis, the predictors of aortic-related mortality included reintervention, renal insufficiency, chronic obstructive pulmonary disease, underweight body mass index, increasing aortic diameter, and the use of brachial artery or other arterial access sites.Endovascular reintervention for aortic pathology was associated with higher mortality than was primary EVAR. Reinterventions after prior OAPs were associated with higher mortality than were prior EVARs.

Blunt thoracic aortic injury (BTAI) is the second leading cause of death from blunt trauma. In the present study, we aimed to determine the outcomes of medical management (MM) for BTAI. We hypothesized from the results of several previously reported studies, that patients with a minimal aortic injury (BTAI grades 1 and 2) could safely be treated with definitive MM alone.The Aortic Trauma Foundation international prospective multicenter registry was used to examine the demographics, injury characteristics, management, and outcomes of patients with BTAI. We analyzed a subset of patients for whom MM was initiated as definitive therapy.From November 2016 to April 2020, 432 patients (median age, 41 years; 76% male; median injury severity score, 34) with BTAI (Society for Vascular Surgery grade 1, 23.6%; grade 2, 14.4%; grade 3, 51.2%; grade 4, 10.9%) were evaluated. Of the 432 patients, 245 (57%) had received MM in the initial period and 114 (26.4%) had received MM as the planned definitive therapy (grade 1, 59.6%; grade 2, 23.7%; grade 3, 15.8%; grade 4, 0.9%). The most common mechanism of BTAI was a motor vehicle collision (60.4%). Hypotension was present on arrival in 74 patients (17.2%). Continuous titratable infusion of antihypertensive medication was used for 49.1%, followed by intermittent bolus administration (29.8%), with beta-blockers (74.6%) the most common agent used. Treatments were targeted to a goal systolic blood pressure for 83.3%, most often to a target goal systolic blood pressure120 mm Hg (66.3%). The MM goals based on blood pressure control were attained in 64.0% (73 of 114). Twelve patients (10.5%; grade 1, 1; grade 2, 0; grade 3, 10; grade 4, 1) had required subsequent intervention after MM. Eleven patients (9.6%) had undergone thoracic endovascular aortic repair and one (0.9%) had required open repair for a grade 4 injury. The overall in-hospital mortality for patients selected for definitive MM was 7.9%. No aortic-related deaths had occurred in the patients receiving definitive MM.Approximately one in four patients with BTAI will receive MM as definitive therapy. The variation in the pharmacologic therapies used is considerable. MM for patients with minimal aortic injury (BTAI grades 1 and 2) is safe and effective, with a low overall intervention rate and no aortic-related deaths. These findings support the use of definitive MM for grade 2 BTAI.

Tumor suppressor genes are highly affected during the development of leukemia, including circadian clock genes. Circadian rhythms constitute an evolutionary molecular machinery involving many genes, such as BMAL1, CLOCK, CRY1, CRY2, PER1, PER2, REV-ERBa, and RORA, for tracking time and optimizing daily life during day-night cycles and seasonal changes. For circulating blood cells many of these genes coordinate their proliferation, output, and function, and therein lies their importance for the development of leukemia. Recent findings suggest that environmental pollutants may affect circadian rhythms and thus affect cancer development and treatment. Such environmental pollutants are often found in mixtures and include benzene, tobacco smoke, pesticides and microplastics. Our understanding of the molecular basis for the interaction mechanisms within complex mixtures is also growing, confirming the plausible occurrence of synergistic (superadditive effect) and antagonistic (cancellation effect) actions of pollutant cocktails. In this work, we discuss the relationship of environmental pollutants and the alteration of circadian rhythms that potentially may cause leukemia. We highlight the need of additional dimensions and perhaps a paradigm shift for future studies in relation to continuously growing magnitude of environmental pollution using multitude of disciplines such as development of high throughput reporter cell lines, other cell screening methods, contaminant measurements in leukemia patients, advanced pharmacology and toxicological measurement of mixtures and highly efficient computer analysis including artificial intelligence, among others.

The assessment of behavioral outcomes is a central component of neuroscientific research, which has required continuous technological innovations to produce more detailed and reliable findings. In this article, we provide an in-depth review on the progress and future implications for three model organisms (mouse, rat, and Drosophila) essential to our current understanding of behavior. By compiling a comprehensive catalog of popular assays, we are able to compare the diversity of tasks and usage of these animal models in behavioral research. This compilation also allows for the evaluation of existing state-of-the-art methods and experimental applica- tions, including optogenetics, machine learning, and high-throughput behavioral assays. We go on to discuss novel apparatuses and inter-species analyses for centrophobism, feeding behavior, aggression and mating par- adigms, with the goal of providing a unique view on comparative behavioral research. The challenges and recent advances are evaluated in terms of their translational value, ethical procedures, and trustworthiness for behavioral research.

More than 320 million people live with depression in the world, a disorder that severely limits psychosocial functioning and diminishes quality of life. The prevalence of major depression is almost two times higher in women than in men. However, the molecular mechanisms of its sex-specific pathophysiology are still poorly understood. Drosophila melanogaster is an established model for neurobiological research of depression-like states, as well as for the study of molecular and genetic sex differences in the brain. Here, we investigated sex-specific effects on forced-climbing locomotion (negative geotaxis) and gene expression of a fly model of depression-like phenotypes induced by levodopa administration, which was previously shown to impair normal food intake, mating frequency, and serotonin concentration. We observed that both males and females show deficits in the forced-climbing paradigm; however, modulated by distinct gene expression patterns after levodopa administration. Our results suggest that Drosophila models can be a valuable tool for identifying the molecular mechanisms underlying the difference of depressive disorder prevalence between men and women.

ObjectivesPercutaneous cervical cordotomy (PCC) is an interventional ablative procedure in the armamentarium for cancer pain treatment, but there is limited evidence to support its use. This study aimed to assess the effectiveness and safety of PCC.MethodsAnalysis was undertaken of the first national (UK) prospective data repository of adult patients with cancer undergoing PCC for pain treatment. The relationship between pain and other outcomes before and after PCC was examined using appropriate statistical methods.ResultsData on 159 patients’ PCCs (performed from 1 January 2012 to 6 June 2017 in three centres) were assessed: median (IQR) age was 66 (58–71) years, 47 (30%) were female. Mesothelioma was the most common primary malignancy (57%). The median (IQR) time from cancer diagnosis to PCC assessment was 13.3 (6.2–23.2) months; PCC to follow-up was 9 (8–25) days; and survival after PCC was 1.3 (0.6–2.8) months. The mean (SD) for ‘average pain’ using a numerical rating scale was 6 (2) before PCC and 2 (2) at follow-up, and for ‘worst pain’ 9 (1) and 3 (3), respectively. The median (IQR) reduction in strong opioid dose at follow-up was 50% (34–50). With the exception of ‘activity’, all health-related quality of life scores (5-level version of EuroQol-5 Dimension) either improved or were stable after PCC. Six patients (4%) had PCC-related adverse events.ConclusionsPCC is an effective treatment for cancer pain; however, findings in this study suggest PCC referrals tended to be late in patients’ disease trajectories. Further study into earlier treatment and seeking international consensus on PCC outcomes will further enhance opportunities to improve patient care.

Lemierre's syndrome (LS) is a pharyngeal infection complicated by infectious jugular vein thrombosis and septic emboli. Most commonly caused by Fusobacterium necrophorum, it may result in metastatic infection, especially when antibiotic treatment is delayed. Patients with LS are often healthy adults between 16 and 30 years who present with prolonged symptoms of pharyngitis, lateral neck pain, and fever. Other symptoms may include shortness of breath, tachycardia, and hypotension. When administered promptly, antibiotics can act as an effective treatment. However, complications may arise that require additional intervention. Herein, we report a case of LS in a young adult, complicated by severe pleural effusions that required surgical decortication.

Introduction. Paraneoplastic limbic encephalitis (PLE) is a rare disease that presents as rapid onset dementia characterized by short-term memory loss (STM), anxiety, and behavioral changes. Anti-NMDAR antibodies are unfrequently reported in PLE associated with small-cell lung cancer (SCLC). Given that PLE can precede the diagnosis of cancer, it is very important that once infectious, metabolic, nutritional, or structural disorders associated with short-term memory loss are ruled out that vigorous effort must be made to rule out underlying malignancy. Case. We report a rare case of PLE as the presenting symptom of SCLC. A 72-year-old male with history of COPD was brought to the ED by his wife after he was found to have short-term memory loss, including forgetfulness of his wedding anniversary the day before, and anxiety. Neurological exam showed impaired short-term recall on MOCA. CT head showed no evidence of infarct. Lumbar puncture was performed which showed lymphocytic pleocytosis, a nonspecific inflammatory change. CSF panel was negative for HSV, Neisseria, Hemophilus, E. coli, and HIV. Initial EEG was unremarkable, though a repeat EEG showed mild slowing of the posterior dominant rhythm consistent with mild encephalopathy. MRI showed equivocal increased FLAIR on T2-weighted images in the bilateral temporal lobes, left greater than right. CTA thorax showed bulky mediastinal and right hilar LAD. FNA of the R4 lymph node revealed SCLC. The NM bone scan showed no osteoblastic lesions. While the serum autoantibody panel was positive for anti-NMDAR, the CSF autoantibody panel returned entirely negative. Chemotherapy with etoposide and cisplatin was started on Day 4 of admission. The patient’s neurological symptoms showed improvement following chemotherapy. Conclusion. This case highlights the importance of recognizing short-term memory loss as a feature of PLE.

This study uses eye-tracking technology to assess the differences in gaze behaviours between ophthalmologists of different experience levels while interpreting retinal images of diabetic retinopathy. The differences in gaze behaviours before and after a teaching intervention which introduced a suggested search strategy is also investigated. A total of 9 trainees and 10 consultant ophthalmologists interpreted six retinal images. They were then shown a 5-min tutorial that demonstrated a search strategy. This was followed by six further retinal image interpretations. Participants completed questionnaires indicating clinical signs seen, appropriate retinopathy grade, and confidence. Eye movements were tracked during each interpretation.Overall, trainees compared to consultants demonstrated more uncertain and unstructured gaze behaviours. Trainee eye gaze metrics included: longer interpretation time, 36.5 s (SD = 6.2 vs. 31.4 s) (SD = 4.2) (p = 0.024), higher visit count, 17.38 visits (SD = 5.13) versus 12.18 visits(SD = 2.64) (p = 0.01), higher proportion of fixation, 57.0 per cent (SD = 5) versus 50.5 per cent (SD = 5) (p = 0.05) and shorter time to first fixation, 0.232 s (SD = 0.10) versus 0.821 s (SD = 0.77) (p = 0.001), respectively. The teaching intervention resulted in more focused gaze patterns in both groups. Pre-intervention and post-intervention mean proportion fixation on areas of interest were 38.6 per cent (SD = 6.8) and 51.8 per cent (SD = 13.9) for the trainee group, respectively, and 39.9 per cent (SD = 4.1) and 50.9 per cent (SD = 9.3) for the consultant group (p = 0.01).Consultants used more systematic and efficient approaches than trainees during interpretation. After the introduction of a suggested search strategy, trainees showed trends towards consultant eye gaze behaviours. Eye tracking gives an interesting insight into the thought processes of physicians carrying out complex tasks. The implication is that eye tracking may have future use in teaching and assessment. Its use in objectively assessing different teaching strategies could be a valuable tool for medical education.

To explore the association between loneliness and efficacy to engage in health behaviors that are known to reduce the risk of early mortality in people with serious mental illness (SMI). This secondary data analysis was based on a cross-sectional study of 113 participants with SMI residing in New Hampshire. Ordinary Least Squares regressions were used to examine bivariate relationships between variables of interest. Participants had a primary mental health diagnosis of major depressive disorder (37.2%), schizophrenia spectrum disorder (28.3%), bipolar disorder (29.2%), or posttraumatic stress disorder (5.3%). High levels of loneliness were associated with low levels of self-efficacy to manage chronic diseases (p = 0.0001), as well as low levels of self-efficacy to manage psychological well-being (R2 = .31; F = 9.49, p = 0.0001; RMSE = 1.66). Loneliness may serve as a barrier to healthy behaviors, and thus, contribute to early mortality among people with SMI. The growing body of literature that demonstrates the importance of addressing loneliness in people with SMI should stimulate policymakers and researchers to target loneliness as a mechanism to address early mortality in people with SMI.

CONTEXT: Preterm birth is associated with incident heart failure in children and young adults. OBJECTIVE: To determine the effect size of preterm birth on cardiac remodeling from birth to young adulthood. DATA SOURCES: Data sources include Medline, Embase, Scopus, Cochrane databases, and clinical trial registries (inception to March 25, 2020). STUDY SELECTION: Studies in which cardiac phenotype was compared between preterm individuals born at DATA EXTRACTION: Random-effects models were used to calculate weighted mean differences with corresponding 95% confidence intervals. RESULTS: Thirty-two observational studies were included (preterm = 1471; term = 1665). All measures of left ventricular (LV) and right ventricular (RV) systolic function were lower in preterm neonates, including LV ejection fraction (P = .01). Preterm LV ejection fraction was similar from infancy, although LV stroke volume index was lower in young adulthood. Preterm LV peak early diastolic tissue velocity was lower throughout development, although preterm diastolic function worsened with higher estimated filling pressures from infancy. RV longitudinal strain was lower in preterm-born individuals of all ages, proportional to the degree of prematurity (R2 = 0.64; P = .002). Preterm-born individuals had persistently smaller LV internal dimensions, lower indexed LV end-diastolic volume in young adulthood, and an increase in indexed LV mass, compared with controls, of 0.71 g/m2 per year from childhood (P = .007). LIMITATIONS: The influence of preterm-related complications on cardiac phenotype could not be fully explored. CONCLUSIONS: Preterm-born individuals have morphologic and functional cardiac impairments across developmental stages. These changes may make the preterm heart more vulnerable to secondary insults, potentially underlying their increased risk of early heart failure.

Functional limitations persist in obese patients after total knee arthroplasty (TKA). This study assessed the effect of an exercise program (EP) and fitness trackers (FT) in obese patients with TKA. Sixty patients 1 year after orthopedic surgery were recruited and received a 16-week tailored EP; half were randomized to receive an FT. FT had no measurable effect compared with EP alone. EP improved knee range of motion, strength, and quality-of-life scores. This study provides preliminary evidence that a 16-week EP in obese individuals 1 year post TKA is feasible and effective in improving function and quality of life.

Myxopapillary ependymoma (MPE) is a relatively common neoplasm arising primarily in the filum terminale/lumbosacral region of the spinal cord. It is designated as a grade I tumor in the most recent WHO Classification of Tumours of the CNS, although aggressive clinical behavior can be observed, especially in cases arising in an extradural location. Anaplastic transformation in MPE is exceedingly rare with 10%–50%), necrosis, and focal vascular proliferation. Targeted next-generation sequencing panels revealed no definitive pathogenic mutations or fusion proteins in either case. Copy number profiling, methylation profiling, and t-Distributed Stochastic Neighbor Embedding were performed to investigate the molecular characteristics of these tumors. To the best of our knowledge, these are the first reported cases of MPE with anaplastic features with methylation profiling data. In addition, we review the literature and discuss common histologic and molecular findings associated with anaplastic features in MPE.

Aim To evaluate rural paediatric diabetic telehealth clinics including whether they meet clinical standards, provide equivalent care to central clinics, families were satisfied and difficulties were encountered. Methods An audit of a telehealth service for children and adolescents with type 1 diabetes mellitus at four rural sites was conducted. The case notes for each patient for 2019 were reviewed to determine if standards of paediatric diabetic care were met. Interviews were conducted at a clinic at each site with the child, parent(s) and staff attending the clinics. A retrospective review of difficulties in service provision was undertaken with staff. Results Nineteen children and adolescents were seen in the telehealth clinics over the year. Eighteen (95%) were seen four times with point-of-care measurement of glycosylated haemoglobin (HbA1c) and growth by the consultant paediatrician and diabetic nurse educator. Complication screening was achieved on time for 15 (78%) patients, with the remaining patients having had the tests ordered. Eleven (56%) patients were reviewed by a dietician, six (33%) by social worker and five (27%) by psychologist. All patients and parents reported receiving good support for their diabetes without any preferring to attend the central clinic. There were no significant technical difficulties. Conclusion Providing paediatric diabetic care through a telehealth service at rural hospitals meets standards of care and was provided without technical difficulties. It is preferred by patients and their parents to attending a central clinic. A model of service is presented that may be replicated elsewhere in Australia.

To reveal new insights into statin cognitive effects, we performed an observational study on a population-based sample of 245,731 control and 55,114 statin-taking individuals from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups (within 5–10 years). Subjects were classified depending on age (up to 65 and over 65 years) and treatment duration (1–4 years, 5–10 years and over 10 years). Data were adjusted for health- and cognition-related covariates. Subjects generally improved in test performance with repeated assessment and middle-aged persons performed better than older persons. The effect of statin use differed considerably between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. Our analysis suggests a modulatory impact of age on the cognitive side effects of statins, revealing a possible reason for profoundly inconsistent findings on statin-related cognitive effects in the literature. The study highlights the importance of characterising modifiers of statin effects to improve knowledge and shape guidelines for clinicians when prescribing statins and evaluating their side effects in patients.

Cell mediated immunity of the honey bee (Apis mellifera) involves the activity of several hemocyte populations, currently defined by morphological features and lectin binding characteristics. The objective of the present study was to identify molecular markers capable of characterizing subsets of honey bee hemocytes. We developed and employed monoclonal antibodies with restricted reactions to functionally distinct hemocyte subpopulations. Melanizing cells, known as oenocytoids, were defined by an antibody to prophenoloxidase, aggregating cells were identified by the expression of Hemolectin, and phagocytic cells were identified by a marker expressed on granulocytes. We anticipate that this combination of antibodies not only allows for the detection of functionally distinct hemocyte subtypes, but will help to further the exploration of hematopoietic compartments, as well as reveal details of the honey bee cellular immune defense against parasites and microbes.

Alzheimer’s Disease (AD) therapeutics based on the amyloid hypothesis have repeatedly failed in clinical trials. Together with numerous reports that amyloid is present in brains from aged individuals without cognitive dysfunction, this suggests that the association of amyloid with AD is collateral rather than causal. However, the preeminence of the amyloid hypothesis has resulted in the ‘systematic …thwart[ing of] alternative approaches’ to AD/dementia driven by a ‘cabal’ of amyloid acolytes who have effectively controlled the ideas funded and published, which startups received venture investment and which programs were advanced in biopharmaceutical companies where they consulted. As a result, dementia research is estimated to be 15–30 years behind where it could be with conflicting data ignored in favor of the amyloid dogma and clinical trial failures being ascribed to faulty design or inadequacies in the compound selection process including flawed animal models. Major concerns regarding the precise diagnosis of AD/dementia and conflicting views on the validated status of fluid biomarker assays have resulted in trials that included patients with unknown amyloid pathologies. With the failure of the amyloid approach, emerging data on the role(s) of vascular, mitochondrial and synaptic network dysfunction, infection, diabetes, sleep, hearing loss, the gut microbiome and neuroinflammation/ innate immune function as dementia targets are driving research in new directions bolstered by recent findings on the genetic, omics and systems biology associated with AD/dementia. In moving forward, lessons learnt from the amyloid debacle should be used to enhance the objective identification of AD/dementia therapeutics as a multifactorial disease syndrome.

TO THE EDITOR: Inherited thrombocytopenias are associated with bleeding of all types of severity depending on the reduction in platelet count and whether there is altered platelet function.[1][1] The normal range for platelet counts varies by up to threefold, but an individual’s platelet count is

Most children suspected of Non Accidental Injury (NAI) will undergo a number of haematological investigations to exclude coagulation defects. Investigations should be dependent on the clinical presentation but often there can be an over or under-requesting of haematological investigations. The correct interpretation of results is reliant on an understanding of both the physiological processes involved in coagulation in children of different ages and of the laboratory testing of the coagulation systems. Age-specific, population-based studies of bruising and bleeding patterns in normal children, NAI children and children with congenital bleeding disorders may be helpful in limiting the number of investigations undertaken for suspected NAI. Investigation of suspected Non Accidental Injury requires a multidisciplinary approach; close liaison between the haematology laboratory and the requesting clinician is integral to this approach. This article describes the use of a staged approach to laboratory investigation.