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Ocular mycobacterial infections are an under-recognized cause of morbidity in the domestic cat. This study aimed to explore the distribution, histopathological appearance, and severity of feline ocular mycobacterial lesions, and to characterize the immune cell population with immunohistochemistry. Routine histological staining with hematoxylin and eosin, and Masson's trichrome, was performed to identify ocular lesions and assign an inflammation score based on the number of cells present. Acid-fast bacilli were detected with Ziehl-Neelsen, and immunohistochemistry for ionized calcium-binding adaptor protein-1 (Iba1), calprotectin, cluster of differentiation 3 (CD3), and Pax5 was undertaken on formalin-fixed paraffin-embedded tissue samples from 24 cases of ocular mycobacteriosis. Posterior or panuveitis with concurrent retinitis was identified in 20/24 cases (83%), with retinal detachment in 16/20 (80%) of these cases. Choroidal lesions had the highest median inflammation score. Ziehl-Neelsen-positive organisms were detected in 20/24 cases (83%), with the highest prevalence of acid-fast bacilli detected in choroidal lesions (16/20, 80%). Lesions were typically granulomatous to pyogranulomatous, characterized by abundant numbers of Iba1-positive macrophages, followed by calprotectin-positive granulocytes and monocytes, fewer T cells, and rarer B cells. However, where iritis was identified, inflammation was typically lymphoplasmacytic (11/16 cases, 69%). Where diagnostic testing was performed, tuberculosis (ie, infection with Mycobacterium bovis , Mycobacterium microti , or a nonspeciated Mycobacterium tuberculosis -complex pathogen) was diagnosed in 20/22 cats (91%), with Mycobacterium lepraemurium infection identified in the other 2/22 cats (9%). These results suggest the choroid is the primary site of lesion development in most cases of feline ocular mycobacteriosis, and inflammatory changes are associated with the presence of mycobacteria localized to ocular tissues.

Background: Oral anti-cancer treatments such as adjuvant endocrine therapies (AET) for breast cancer survivors are commonly used but adherence is a challenge. Few low-touch, scalable interventions exist to increase ET adherence., Purpose: To evaluate the acceptability, feasibility, and initial efficacy of a low-touch, remotely-delivered values plus AET education intervention (REACH) to promote AET adherence., Methods: A mixed-methods trial randomized 88 breast cancer survivors 1:1 to REACH or Education alone. Wisepill real-time electronic adherence monitoring tracked monthly AET adherence during a 1-month baseline through 6-month follow-up (FU) (primary outcome). Patient-reported outcomes were evaluated through 3- and 6-month FU (secondary). Multiple indices of intervention feasibility and acceptability were evaluated. Qualitative exit interviews (n = 38) further assessed participants' perceptions of feasibility/acceptability and recommendations for intervention adaptation., Results: The trial showed strong feasibility and acceptability, with an eligible-to-enrolled rate of 85%, 100% completion of the main intervention sessions, and "good" intervention satisfaction ratings on average. For Wisepill-assessed AET adherence, REACH outperformed Education for Month 1 of FU (p = .027) and not thereafter. Participants in REACH maintained high adherence until Month 4 of FU, whereas in Education, adherence declined significantly in Month 1. Conditions did not differ in self-reported adherence, positive affective attitudes, future intentions, or necessity beliefs. REACH trended toward less negative AET attitudes than Education at 3-month FU (p = .057) reflecting improvement in REACH (p = .004) but not Education (p = .809). Exploratory moderator analyses showed that average to highly positive baseline AET affective attitudes and oncologist-patient communication each predicted higher adherence following REACH than Education; low levels did not. Participants identified recommendations to strengthen the interventions., Conclusions: REACH, a low-touch values intervention, showed good feasibility and acceptability, and initial promise in improving objectively-assessed AET adherence among breast cancer survivors (relative to education alone). Future research should target improving REACH's tailoring and endurance., (© Society of Behavioral Medicine 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Idiopathic intracranial hypertension (IIH) is a disease of raised intracranial pressure (ICP) of unknown etiology. Reductions in glucocorticoid metabolism are associated with improvements in IIH disease activity. The basal IIH glucocorticoid metabolism is yet to be assessed., Objective: The objective of this study was to determine the basal glucocorticoid phenotype in IIH and assess the effects of weight loss on the IIH glucocorticoid phenotype., Design: A retrospective case-control study and a separate exploratory analysis of a prospective randomized intervention study were carried out., Methods: The case-control study compared female IIH patients to BMI, age, and sex-matched controls. In the randomized intervention study, different IIH patients were randomized to either a community weight management intervention or bariatric surgery, with patients assessed at baseline and 12 months. Glucocorticoid levels were determined utilizing 24-h urinary steroid profiles alongside the measurement of adipose tissue 11β-HSD1 activity., Results: Compared to control subjects, patients with active IIH had increased systemic 11β-hydroxysteroid dehydrogenase (11β-HSD1) and 5α-reductase activity. The intervention study demonstrated that weight loss following bariatric surgery reduced systemic 11β-HSD1 and 5α-reductase activity. Reductions in these were associated with reduced ICP. Subcutaneous adipose tissue explants demonstrated elevated 11β-HSD1 activity compared to samples from matched controls., Conclusion: The study demonstrates that in IIH, there is a phenotype of elevated systemic and adipose 11β-HSD1 activity in excess to that mediated by obesity. Bariatric surgery to induce weight loss was associated with reductions in 11β-HSD1 activity and decreased ICP. These data reflect new insights into the IIH phenotype and further point toward metabolic dysregulation as a feature of IIH.

Purpose: Although chemotherapy is standard of care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a "cold" tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC., Patients and Methods: Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety; secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates., Results: PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8+ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients' liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P = 0.017) suggested a dose-efficacy correlation. The host HLA genotype predicted multi-antigen-specific T-cell responses (P = 0.01) indicative of clinical outcome., Conclusions: PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting., (©2022 The Authors; Published by the American Association for Cancer Research.)

Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as signal transducer and activator of transcription, STAT, inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by platelet agonists. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: There have been more than 425 million COVID-19 infections worldwide. Post-COVID illness has become a common, disabling complication of this infection. Therefore, it presents a significant challenge to global public health and economic activity., Methods: Comprehensive clinical assessment (symptoms, WHO performance status, cognitive testing, CPET, lung function, high-resolution CT chest, CT pulmonary angiogram and cardiac MRI) of previously well, working-age adults in full-time employment was conducted to identify physical and neurocognitive deficits in those with severe or prolonged COVID-19 illness., Results: 205 consecutive patients, age 39 (IQR30.0-46.7) years, 84% male, were assessed 24 (IQR17.1-34.0) weeks after acute illness. 69% reported ≥3 ongoing symptoms. Shortness of breath (61%), fatigue (54%) and cognitive problems (47%) were the most frequent symptoms, 17% met criteria for anxiety and 24% depression. 67% remained below pre-COVID performance status at 24 weeks. One third of lung function tests were abnormal, (reduced lung volume and transfer factor, and obstructive spirometry). HRCT lung was clinically indicated in <50% of patients, with COVID-associated pathology found in 25% of these. In all but three HRCTs, changes were graded 'mild'. There was an extremely low incidence of pulmonary thromboembolic disease or significant cardiac pathology. A specific, focal cognitive deficit was identified in those with ongoing symptoms of fatigue, poor concentration, poor memory, low mood, and anxiety. This was notably more common in patients managed in the community during their acute illness., Conclusion: Despite low rates of residual cardiopulmonary pathology, in this cohort, with low rates of premorbid illness, there is a high burden of symptoms and failure to regain pre-COVID performance 6-months after acute illness. Cognitive assessment identified a specific deficit of the same magnitude as intoxication at the UK drink driving limit or the deterioration expected with 10 years ageing, which appears to contribute significantly to the symptomatology of long-COVID., Competing Interests: The authors have declared that no competing interests exist.

Objective: Obesity is a risk factor for idiopathic intracranial hypertension (IIH) and obstructive sleep apnoea (OSA). We aimed to determine the prevalence of OSA in IIH and evaluate the diagnostic performance of OSA screening tools in IIH. Additionally, we evaluated the relationship between weight loss, OSA and IIH over 12 months., Methods: A sub-study of a multi-centre, randomised controlled parallel group trial comparing the impact of bariatric surgery vs. community weight management intervention (CWI) on IIH-related outcomes over 12 months (IIH:WT). OSA was assessed using home-based polygraphy (ApneaLink Air, ResMed) at baseline and 12 months. OSA was defined as an apnoea-hypopnoea index (AHI) ≥ 15 or ≥ 5 with excessive daytime sleepiness (Epworth Sleepiness Scale ≥11 )., Results: Of the 66 women in the IIH: WT trial, 46 were included in the OSA sub-study. OSA prevalence was 47% (n = 19). The STOP-BANG had the highest sensitivity (84%) compared to the Epworth Sleepiness Scale (69%) and Berlin (68%) to detect OSA. Bariatric surgery resulted in greater reductions in AHI vs. CWI (median [95%CI] AHI reduction of  - 2.8 [ - 11.9, 0.7], p = 0.017). Over 12 months there was a positive association between changes in papilloedema and AHI (r = 0.543, p = 0.045), despite adjustment for changes in the body mass index (R 2  = 0.522, p = 0.017)., Conclusion: OSA is common in IIH and the STOP-BANG questionnaire was the most sensitive screening tool. Bariatric surgery improved OSA in patients with IIH. The improvement in AHI was associated with improvement in papilloedema independent of weight loss. Whether OSA treatment has beneficial impact on papilloedema warrants further evaluation., Trial Registration Number: IIH: WT is registered as ISRCTN40152829 and on ClinicalTrials.gov as NCT02124486 (28/04/2014)., (© 2021. The Author(s).)

Objectives: To identify and describe histological and immunohistochemical criteria that may differentiate between skin and lymph node lesions associated with Mycobacterium (M.) bovis and M. microti in a diagnostic pathology setting., Materials and Methods: Archived skin and lymph node biopsies of tuberculous lesions were stained with haematoxylin and eosin, Ziehl-Neelsen and Masson's Trichrome. Immunohistochemistry was performed to detect the expression of calprotectin, CD3 and Pax5. Samples were scored for histological parameters (i.e. granulomas with central necrosis versus small granulomas without central necrosis, percentage necrosis and/or multinucleated giant cells), number of acid-fast bacilli (bacterial index) and lesion percentage of fibrosis and positive immunohistochemical staining., Results: Twenty-two samples were examined (M. bovis n=11, M. microti n=11). When controlling for age, gender and tissue, feline M. bovis-associated lesions more often featured large multi-layered granulomas with central necrosis. Conversely, this presentation was infrequent in feline M. microti-associated lesions, where small granulomas without central necrosis predominated. The presence of an outer fibrous capsule was variable in both groups, as was the bacterial index. There were no differences in intralesional expression of immunohistochemical markers., Clinical Significance: Differences in the histological appearance of skin and lymph node lesions may help to infer feline infection with either M. bovis or M. microti at an earlier stage when investigating these cases, informing clinicians of the potential zoonotic risk. Importantly, cases of tuberculosis can present with numerous acid-fast bacilli. This implies that a high bacterial index does not infer infection with non-zoonotic non-tuberculous mycobacteria., (© 2021 The Authors. Journal of Small Animal Practice published by John Wiley & Sons Ltd on behalf of British Small Animal Veterinary Association.)

Background: Evidence has shown that male involvement is associated with improved maternal health outcomes. In rural Tanzania, men are the main decision makers and may determine women's access to health services and ultimately their health outcomes. Despite efforts geared towards enhancing male participation in maternal health care, their involvement in antenatal care (ANC) remains low. One barrier that impacts men's participation is the fear and experience of social stigma. This study, builds on previous findings about men's perspectives in attending antenatal care appointments in Misungwi district in Tanzania, examining more closely the fear of social stigma amongst men attending ANC together with their partners., Methods: Twelve individual interviews and five focus group discussions were conducted using semi-structured questionnaires with fathers and expectant fathers. In-depth interviews were conducted with health providers, volunteer community health workers and village leaders. Interviews were audiotaped, and transcripts were transcribed and translated to English. Transcripts were organized in NVivo V.12 then analyzed using thematic approach., Results: Three main themes were found to create fear of social stigma for men: 1. Fear of HIV testing; 2. Traditional Gender Norms and 3. Insecurity about family social and economic status., Conclusion: Respondent's experiences reveal that fear of social stigma is a major barrier to attend ANC services with their partners. Attention must be given to the complex sociocultural norms and social context that underly this issue at the community level. Strategies to address fear of social stigma require an understanding of the real reasons some men do not attend ANC and require community engagement of community health workers (CHWs), government officials and other stakeholders who understand the local context., (© 2022. The Author(s).)

Early initiation of antiretroviral therapy (ART) in acute HIV infection (AHI) is effective at limiting seeding of the HIV viral reservoir, but little is known about how the resultant decreased antigen load affects long-term Ab development after ART. We report here that Env-specific plasma antibody (Ab) levels and Ab-dependent cellular cytotoxicity (ADCC) increased during the first 24 weeks of ART and correlated with Ab levels persisting after 48 weeks of ART. Participants treated in AHI stage 1 had lower Env-specific Ab levels and ADCC activity on ART than did those treated later. Importantly, participants who initiated ART after peak viremia in AHI developed elevated cross-clade ADCC responses that were detectable 1 year after ART initiation, even though clinically undetectable viremia was reached by 24 weeks. These data suggest that there is more germinal center (GC) activity in the later stages of AHI and that Ab development continues in the absence of detectable viremia during the first year of suppressive ART. The development of therapeutic interventions that can enhance earlier development of GCs in AHI and Abs after ART initiation could provide important protection against the viral reservoir that is seeded in individuals treated early in the disease.

Tuberculosis (TB), caused by infection with members of the Mycobacterium tuberculosis -complex, is one of the oldest known infectious disease entities, resulting in the death of millions of humans each year. It also results in a substantial degree of morbidity and mortality in animal species. Extrapulmonary TB is well recognized in humans, and the eye is one site that can be affected. Studies seeking to understand ocular TB have often relied on animal models; however, these have their limitations and may not truly reflect what happens in humans. We wish to raise awareness among ophthalmologists and vision scientists of naturally occurring cases of ocular TB in animals, namely cattle and domestic cats, and the possibilities of gaining further understanding of this presentation of TB by adopting a collaborative approach. This will hopefully improve outcomes for both human and animal patients.

Mycobacterial infections cause a reasonable burden of morbidity and mortality in global feline populations, many of which are 'Vulnerable' or 'Endangered'. Identifying these infections may facilitate efforts to protect these animals. An interferon-gamma (IFNγ) release assay (IGRA) to diagnose mycobacteriosis in domestic cats has been adapted for use in lions; however, the development of species-specific antibodies may be laborious. Therefore, we investigated whether anti-cat IFNγ antibodies can bind to recombinant IFNγ (rIFNγ) from other Felidae species, permitting use of the feline IGRA in a wider range of felids. Unique Felidae IFNγ protein sequences and their corresponding coding nucleotide sequence were identified from online databases; plasmids with an IFNγ-gene insert were synthesised to transform E. coli-DH5α and subsequently transfect HEK 293 T cells to secrete rIFNγ. Enzyme-linked immunosorbent assay using a commercial anti-cat IFNγ kit was performed to detect rIFNγ from Felidae, the domestic dog and cattle. Five unique rIFNγ Felidae proteins were synthesised; anti-cat IFNγ antibodies were able to bind to all five proteins, while cross-reactivity with canine and bovine rIFNγ was negligible. This suggests that anti-cat IFNγ antibodies are sufficient for detection of IFNγ across other Felidae species, namely the lion, tiger, cheetah, cougar, Iberian lynx and the Canadian lynx., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Accurate and comprehensive assessment of platelet function across cohorts of donors may be key to understanding the risk of thrombotic events associated with cardiovascular disease, and, hence, to help personalize the application of antiplatelet drugs. However, platelet function tests can be difficult to perform and analyze; they also can be unreliable or uninformative and poorly standardized across studies. The Platelet Phenomic Analysis (PPAnalysis) assay and associated open-source software platform were developed in response to these challenges. PPAnalysis utilizes preprepared freeze-dried microtiter plates to provide a detailed characterization of platelet function. The automated analysis of the high-dimensional data enables the identification of subpopulations of donors with distinct platelet function phenotypes. Using this approach, we identified that the sensitivity of a donor's platelets to an agonist and their capacity to generate a functional response are distinct independent metrics of platelet reactivity. Hierarchical clustering of these metrics identified 6 subgroups with distinct platelet phenotypes within healthy cohorts, indicating that platelet reactivity does not fit into the traditional simple categories of "high" and "low" responders. These platelet phenotypes were found to exist in 2 independent cohorts of healthy donors and were stable on recall. PPAnalysis is a powerful tool for stratification of cohorts on the basis of platelet reactivity that will enable investigation of the causes and consequences of differences in platelet function and drive progress toward precision medicine., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

A subset of patients with coronavirus disease 2019 (COVID-19) become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill patients with COVID-19 are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesized that platelets might be susceptible to activation by anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies and might contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike immunoglobulin G enhanced platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcγRIIA, and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by the therapeutic small molecules R406 (fostamatinib) and ibrutinib, which inhibit tyrosine kinases Syk and Btk, respectively, or by the P2Y12 antagonist cangrelor., (© 2021 by The American Society of Hematology.)

Platelets react rapidly to vascular injury and undergo activation in response to a range of stimuli to limit blood loss. Many platelet function tests measure endpoint responses after a defined time period and not the rate of platelet activation. However, the rate at which platelets convert extracellular stimuli into a functional response is an essential factor in determining how efficiently they can respond to injury, bind to a forming thrombus, and signal to recruit other platelets. This paper describes a flow cytometry-based platelet function assay that enables simultaneous data acquisition and sample stimulation and utilizes newly developed bespoke open-source software (Kinetx) to enable quantitative kinetic measurements of platelet granule release, fibrinogen binding, and intracellular calcium flux. Kinetix was developed in R so that users can alter parameters such as degree of smoothing, identification of outlying data points, or time scales. To aid users unfamiliar with the R environment, Kinetix analysis of data can be performed by a single command. Together, this allows real-time platelet activation metrics, such as rate, acceleration, time to peak-rate, time to peak-calcium, and qualitative shape changes, to be accurately and reproducibly measured and categorized. Kinetic measurements of platelet activation give a unique insight into platelets' behavior during the first stages of activation and may provide a method of predicting the recruitment of platelets into a forming thrombus.

Based on material originating from five amber collections of Eocene Baltic amber, Protostomopsis pandema gen. et sp. nov. is described and illustrated using X-ray micro-computed tomography. It is the first formally described extinct species of Cerylonidae, and the first known Palaearctic representative of the subfamily Ostomopsinae. As such, the new species extends the temporal range of the family Cerylonidae by approximately 45 Ma.

Cognitive impairments have been reported in idiopathic intracranial hypertension; however, evidence supporting these deficits is scarce and contributing factors have not been defined. Using a case-control prospective study, we identified multiple domains of deficiency in a cohort of 66 female adult idiopathic intracranial hypertension patients. We identified significantly impaired attention networks (executive function) and sustained attention compared to a body mass index and age matched control group of 25 healthy female participants. We aimed to investigate how cognitive function changed over time and demonstrated that deficits were not permanent. Participants exhibited improvement in several domains including executive function, sustained attention and verbal short-term memory over 12-month follow-up. Improved cognition over time was associated with reduction in intracranial pressure but not body weight. We then evaluated cognition before and after a lumbar puncture with acute reduction in intracranial pressure and noted significant improvement in sustained attention to response task performance. The impact of comorbidities (headache, depression, adiposity and obstructive sleep apnoea) was also explored. We observed that body mass index and the obesity associated cytokine interleukin-6 (serum and cerebrospinal fluid) were not associated with cognitive performance. Headache severity during cognitive testing, co-morbid depression and markers of obstructive sleep apnoea were adversely associated with cognitive performance. Dysregulation of the cortisol generating enzyme 11β hydroxysteroid dehydrogenase type 1 has been observed in idiopathic intracranial hypertension. Elevated cortisol has been associated with impaired cognition. Here, we utilized liquid chromatography-tandem mass spectrometry for multi-steroid profiling in serum and cerebrospinal fluid in idiopathic intracranial hypertension patients. We noted that reduction in the serum cortisol:cortisone ratio in those undergoing bariatric surgery at 12 months was associated with improving verbal working memory. The clinical relevance of cognitive deficits was noted in their significant association with impaired reliability to perform visual field tests, the cornerstone of monitoring vision in idiopathic intracranial hypertension. Our findings propose that cognitive impairment should be accepted as a clinical manifestation of idiopathic intracranial hypertension and impairs the ability to perform visual field testing reliably. Importantly, cognitive deficits can improve over time and with reduction of intracranial pressure. Treating comorbid depression, obstructive sleep apnoea and headache could improve cognitive performance in idiopathic intracranial hypertension., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The prospect of a foot-and-mouth disease (FMD) outbreak in U.S. livestock populations has motivated the development of the Secure Beef Supply (SBS) Plan, which includes a comprehensive list of enhanced biosecurity practices that aim to prevent FMD transmission and facilitate continuity of business during an outbreak. While FMD poses a serious threat to livestock production in the United States, little is known about producers' uptake of the enhanced biosecurity practices included in the SBS Plan. In this study, we benchmark adoption and feasibility-of-adoption perceptions for U.S. cattle producers. Our results show adoption of the 13 enhanced biosecurity practices is generally low. Especially concerning is the low adoption of the three strongly-recommended pre-outbreak practices-having a biosecurity manager, having a written operation-specific enhanced biosecurity plan, and having a line of separation. Adoption of the pre-outbreak practices is likely low because the benefits of adopting the practices depend on a low probability, uncertain event. That said, producers who have adopted the pre-outbreak practices are more likely to have higher feasibility ratings for the remaining enhanced biosecurity practices, suggesting that adoption of the strongly recommended practices is associated with adoption of all enhanced biosecurity during an FMD outbreak. Complementarity is examined and shows that adoption of the pre-outbreak practices coincides with adoption of the outbreak-specific practices. Taken together, our results suggest that adoption of the strongly recommended pre-outbreak practices could help facilitate a quicker and more effective U.S. cattle industry response to an FMD outbreak in the United States., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pudenz, Mitchell, Schulz and Tonsor.)

Background: Early antiretroviral therapy (ART) restricts the size of the human immunodeficiency virus (HIV) reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown., Methods: We measured total and integrated HIV DNA, as well as the frequency of CD4 T cells producing multiply spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically infected Thai infants. Eighty-five infants were followed longitudinally for up to 3 years. We compared the size of the reservoir in children who received continuous ARV prophylaxis since birth vs those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings., Results: Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous ARV prophylaxis since birth compared to those in whom ARV prophylaxis was discontinued or never initiated (P < .020 and P < .001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (P < .01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during 3 years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARVs before starting ART and those who delayed ART initiation without receiving prior prophylaxis., Conclusions: Neonatal ARV prophylaxis with direct transition to ART durably limits the size of the HIV reservoir., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The aim of this study was to evaluate the sensitivity and specificity of the interferon-gamma release assay (IGRA) for diagnosing infections with members of the Mycobacterium (M.) tuberculosis-complex (MTBC) and non-tuberculous mycobacteria (NTM) in domestic cats, and to generate defined feline-specific cut-off values using receiver operating characteristic (ROC) curve analysis to improve test performance. Records of 594 cats that had been tested by IGRA were explored to identify individuals that had a culture and/or polymerase chain reaction (PCR)-confirmed case of mycobacterial disease, and those that had a final diagnosis of non-mycobacterial disease. A total of 117 cats - 80 with mycobacterial disease and 37 diagnosed with a condition other than mycobacteriosis - were identified for further detailed analysis. This population was used to estimate test sensitivity and specificity, as well as likelihood ratios for the IGRA to correctly identify a cat with or without mycobacterial disease. Agreement between IGRA results and culture/PCR using current and proposed new cut-off values was also determined. ROC analysis of defined confirmed infected and non-mycobacterial disease control cats allowed an adjustment of current test cut-offs that increased the overall test sensitivity for MTBC infections from 83.1 % (95 % confidence interval [CI]: 71.5-90.5 %) to 90.2 % (95 % CI: 80.2-95.4%), and M. bovis infection from 43 % (95 % CI: 28.2-60.7%) to 68 % (95 % CI: 51.4-82.1%) while maintaining high test specificity (100 % in both cases). Overall agreement between IGRA results and culture/PCR, while recognising that neither culture nor PCR tests have perfect sensitivity, improved from weak (κ = 0.57) to moderate (κ = 0.71) using new proposed IGRA test cut-off values. Application of these results, based upon the statistical analysis of accumulated test data, can improve the diagnostic performance of the feline IGRA, particularly for identifying infections with M. bovis, without compromising specificity., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Background: Idiopathic intracranial hypertension (IIH) is associated with significant morbidity, predominantly affecting women of childbearing age living with obesity. Weight loss has demonstrated successful disease-modifying effects; however, the long-term cost-effectiveness of weight loss interventions for the treatment of IIH has not yet been established., Objectives: To estimate the cost-effectiveness of weight-loss treatments for IIH., Setting: Single-payer healthcare system (National Health Service, England)., Methods: A Markov model was developed comparing bariatric surgery with a community weight management intervention over 5-, 10-, and 20-year time horizons. Transition probabilities, utilities, and resource use were informed by the IIH Weight Trial (IIH:WT), alongside the published literature. A probabilistic sensitivity analysis was conducted to characterize uncertainty within the model., Results: In the base case analysis, over a 20-year time horizon, bariatric surgery was "dominant," led to cost savings of £49,500, and generated an additional 1.16 quality-adjusted life years in comparison to the community weight management intervention. The probabilistic sensitivity analysis indicated a probability of 98% that bariatric surgery is the dominant option in terms of cost-effectiveness., Conclusion: This economic modeling study has shown that when compared to community weight management, bariatric surgery is a highly cost-effective treatment option for IIH in women living with obesity. The model shows that surgery leads to long-term cost savings and health benefits, but that these do not occur until after 5 years post surgery, and then gradually increase over time., (Copyright © 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Importance: Idiopathic intracranial hypertension (IIH) causes headaches, vision loss, and reduced quality of life. Sustained weight loss among patients with IIH is necessary to modify the disease and prevent relapse., Objective: To compare the effectiveness of bariatric surgery with that of a community weight management (CWM) intervention for the treatment of patients with active IIH., Design, Setting, and Participants: This 5-year randomized clinical trial (Idiopathic Intracranial Hypertension Weight Trial) enrolled women with active IIH and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or higher at 5 National Health Service hospitals in the UK between March 1, 2014, and May 25, 2017. Of 74 women assessed for eligibility, 6 did not meet study criteria and 2 declined to participate; 66 women were randomized. Data were analyzed from November 1, 2018, to May 14, 2020., Interventions: Bariatric surgery (n = 33) or CWM intervention (Weight Watchers) (n = 33)., Main Outcomes and Measures: The primary outcome was change in intracranial pressure measured by lumbar puncture opening pressure at 12 months, as assessed in an intention-to-treat analysis. Secondary outcomes included lumbar puncture opening pressure at 24 months as well as visual acuity, contrast sensitivity, perimetric mean deviation, and quality of life (measured by the 36-item Short Form Health Survey) at 12 and 24 months. Because the difference in continuous outcomes between groups is presented, the null effect was at 0., Results: Of the 66 female participants (mean [SD] age, 32.0 [7.8] years), 64 (97.0%) remained in the clinical trial at 12 months and 54 women (81.8%) were included in the primary outcome analysis. Intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, -6.0 [1.8] cm cerebrospinal fluid [CSF]; 95% CI, -9.5 to -2.4 cm CSF; P = .001) and at 24 months (adjusted mean [SE] difference, -8.2 [2.0] cm CSF; 95% CI, -12.2 to -4.2 cm CSF; P < .001) compared with the CWM arm. In the per protocol analysis, intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, -7.2 [1.8] cm CSF; 95% CI, -10.6 to -3.7 cm CSF; P < .001) and at 24 months (adjusted mean [SE] difference, -8.7 [2.0] cm CSF; 95% CI, -12.7 to -4.8 cm CSF; P < .001). Weight was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, -21.4 [5.4] kg; 95% CI, -32.1 to -10.7 kg; P < .001) and at 24 months (adjusted mean [SE] difference, -26.6 [5.6] kg; 95% CI, -37.5 to -15.7 kg; P < .001). Quality of life was significantly improved at 12 months (adjusted mean [SE] difference, 7.3 [3.6]; 95% CI, 0.2-14.4; P = .04) and 24 months (adjusted mean [SE] difference, 10.4 [3.8]; 95% CI, 3.0-17.9; P = .006) in the bariatric surgery arm., Conclusions and Relevance: In this randomized clinical trial, bariatric surgery was superior to a CWM intervention in lowering intracranial pressure. The continued improvement over the course of 2 years shows the impact of this intervention with regard to sustained disease remission., Trial Registration: ClinicalTrials.gov Identifier: NCT02124486.

The interferon-gamma release assay (IGRA) is used to diagnose cases of feline mycobacteriosis, but the use of serial testing to monitor treatment responses has not been evaluated in this species. From a population of cats that underwent IGRA testing for diagnostic investigation, individuals were identified with a pre- and end-of-treatment IGRA that passed control thresholds. The number of cats which reverted to negative at the end-of-treatment IGRA, changes in paired antigen-specific optical density (OD) values and differences in the pre-treatment antigen-specific OD values for those which underwent reversion were compared. Factors to explain reversion or recurrence of disease post-treatment were explored. Four of 18 cats (22%) reverted to negativity at the point of clinical resolution ( p = 0.33), there was no difference in paired antigen-specific OD values ( p ≥ 0.12), and cats that reverted did not have a lower baseline OD value ( p = 0.63). No statistically significant factors were identified to predict reversion ( p ≥ 0.08). Remaining positive at the end of treatment IGRA was not associated with recurrence of disease post-treatment ( p = 0.34). Overall, these data suggest there is limited value in the use of the IGRA to monitor treatment responses in cats.

BACKGROUNDIdiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess, and an increased risk of cardiovascular morbidity. Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype.METHODSIn fasted, matched IIH (n = 97) and control (n = 43) patients, we assessed glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case-control study.RESULTSWe demonstrate an insulin- and leptin-resistant phenotype in IIH in excess of that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed toward depot-specific lipogenesis.CONCLUSIONThese data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improve cardiovascular outcomes.FUNDINGThis study was supported by the UK NIHR (NIHR-CS-011-028), the UK Medical Research Council (MR/K015184/1), Diabetes UK, Wellcome Trust (104612/Z/14/Z), the Sir Jules Thorn Award, and the Midlands Neuroscience Teaching and Research Fund.

Background: The Idiopathic Intracranial Hypertension Weight Trial (IIH:WT) established the efficacy of bariatric surgery as compared to a community weight management intervention in reducing intracranial pressure in active IIH. The aim of this cost-effectiveness analysis was to evaluate the economic impact of these weight loss treatments for IIH., Methods: IIH:WT was a five-year randomised, controlled, parallel group, multicentre trial in the United Kingdom, where participants with active IIH and a body mass index ≥35 kg/m 2 were randomly assigned (1:1) to receive access to bariatric surgery or a community weight management intervention. All clinical and quality of life data was recorded at baseline, 12 and 24 months. Economic evaluation was performed to assess health-care costs and cost-effectiveness. Evaluations were established on an intention to treat principle, followed by a sensitivity analysis using a per protocol analysis., Results: The mean total health care costs were GBP 1353 for the community weight management arm and GBP 5400 for the bariatric surgery arm over 24 months. The majority of costs for the bariatric surgery arm relate to the surgical procedure itself. The 85% who underwent bariatric surgery achieved a 12.5% reduction in intracranial pressure at 24 months as compared to 39% in the community weight management arm; a mean difference of 45% in favour of bariatric surgery. The cost effectiveness of bariatric surgery improved over time., Conclusions: The IIH:WT was the first to compare the efficacy and cost-effectiveness of bariatric surgery with community weight management interventions in the setting of a randomised control trial. The cost-effectiveness of bariatric surgery improved over time and therefore the incremental cost of surgery when offset against the incremental reduction of intracranial pressure improved after 24 months, as compared with 12 months follow up.

Objective: Anxiety symptoms are common among cancer survivors. This study evaluated whether an acceptance-based group intervention delivered by social workers in community oncology clinics improved anxiety and related symptoms, and healthcare use, relative to enhanced usual care (EUC)., Method: This multi-site trial included 135 survivors of various cancers with moderate to high anxiety about cancer/survivorship, 1.5-24 months after treatment. Participants were randomized 1:1 to a 7-session acceptance and commitment therapy (ACT)-based group (Valued Living) or EUC (access to onsite supportive care plus resource list). Questionnaires were administered at baseline, 1, 2, 5, and 8 months post-randomization, diagnostic interviews at baseline, 2, and 8 months, and healthcare use tracked throughout. Outcomes included anxiety symptoms (primary), related symptoms, and healthcare use. Putative moderators included age, anxiety, and avoidance., Results: In intent-to-treat comparisons to EUC, Valued Living (VL) showed a nonsignificant pattern of greater improvement on anxiety symptoms (p = .08), improved significantly more on cancer-related post-traumatic stress (p = .002), fear of recurrence (p = .003), and energy/fatigue (p = .02), and missed significantly fewer medical appointments (p < .05). Conditions improved similarly on depressive symptoms, sense of meaning, and most severe anxiety or depressive disorder. Effects were moderated: VL participants with higher baseline anxiety or avoidance (+1SD) improved more on anxiety, meaning (p s ≤ .01), and disorder severity (p = .05) than their EUC counterparts., Conclusions: An acceptance-based group intervention delivered in community oncology clinics enhanced psychological recovery and energy levels, and reduced missed medical appointments for anxious cancer survivors, with stronger effects for more distressed participants. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The understanding of raised intracranial pressure (ICP) is increasing with the directed use of intracranial telemetric ICP monitors. This case uniquely observed ICP changes by telemetric monitoring in a patient with idiopathic intracranial hypertension (IIH), who developed rapid sight-threatening disease. A lumbar drain was inserted, as a temporising measure, and was clamped prior to surgery. This resulted in a rapid rise in ICP, which normalised after insertion of a ventriculoperitoneal shunt. This case highlighted the utility of the ICP monitor and the lumbar drain as a temporising measure to control ICP prior to a definitive procedure as recommended by the IIH consensus guidelines.

Background: Platelets release platelet-derived extracellular vesicles (PDEVs) upon activation - in a process that is regulated by generation of reactive oxygen species (ROS). Platelet NADPH oxidase-1 (Nox-1) contributes to ROS generation and thrombus formation downstream of the collagen receptor GPVI., Objectives: We aimed to investigate whether PDEVs contain Nox-1 and whether this is relevant for PDEV-induced platelet activation., Methods: PDEVs were isolated through serial centrifugation after platelet activation with thrombin receptor agonist TRAP-6 (activated PDEVs) or in the absence of agonist (resting PDEVs). The physical properties of PDEVs were analyzed through nanoparticle tracking analysis. Nox-1 levels, fibrinogen binding and P-selectin exposure were measured using flow cytometry, and protein levels quantified by immunoblot analysis. ROS were quantified using DCF fluorescence and electron paramagnetic resonance., Results: Nox-1 was found to be increased on the platelet outer membrane upon activation and was present in PDEVs. PDEVs induced platelet activation, while co-addition of GPVI agonist collagen-related peptide (CRP) did not potentiate this response. PDEVs were shown to be able to generate superoxide in a process at least partially mediated by Nox-1, while Nox-1 inhibition with ML171 (also known as 2-APT) did not influence PDEV production. Finally, inhibition of Nox-1 abrogated PDEV-mediated platelet activation., Conclusions: PDEVs are able to generate superoxide, bind to and activate platelets in a process mediated by Nox-1. These data provide novel mechanisms by which Nox-1 potentiates platelet responses, thus proposing Nox-1 inhibition as a feasible strategy to treat and prevent thrombotic diseases., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Nanoliposomal irinotecan (Nal-IRI) is a preferred second-line treatment for metastatic pancreas cancer. It is unclear, however, whether patients who had received irinotecan derive benefit., Methods: Medical records of metastatic pancreas cancer patients who had received irinotecan and then Nal-IRI were reviewed. The primary endpoint was overall survival after the initiation of Nal-IRI (an a priori threshold of >4 months defined success); adverse events and quotes from the medical record on decision-making were also recorded., Results: Sixty four patients met eligibility criteria with a median age of 65 years (range: 36, 80 years). The median overall survival from initiation of Nal-IRI was 5.1 months (95% confidence interval (CI): 4.3, 5.6 months). An exploratory comparison, based on no cancer progression with irinotecan versus progression, showed improved survival with Nal-IRI in the former group: 6.1 months (95% CI: 5.1, 9.3 months) versus 4.3 months (95% CI: 2.3, 4.8 months); p = 0.0006. Nal-IRI adverse events occurred as expected. Qualitative data illustrate several themes, including "limited treatment options," which appeared to drive the decision to prescribe Nal-IRI., Conclusion: Nal-IRI might be considered in pancreas cancer patients who had received irinotecan, particularly in the absence of disease progression with the latter., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To determine the effectiveness of erenumab in treating headaches in idiopathic intracranial hypertension (IIH) in whom papilledema had resolved., Background: Disability in IIH is predominantly driven by debilitating headaches with no evidence for the use of preventative therapies. Headache therapy in IIH is an urgent unmet need., Methods: A prospective, open-label study in the United Kingdom was conducted. Adult females with confirmed diagnosis of IIH now in ocular remission (papilledema resolved) with chronic headaches (≥15 days a month) and failure of ≥3 preventative medications received erenumab 4-weekly (assessments were 3-monthly). The primary end point was change in monthly moderate/severe headache days (MmsHD) from baseline (30-day pretreatment period) compared to 12 months., Results: Fifty-five patients, mean (SD) age 35.3 (9) years and mean duration of headaches 10.4 (8.4) years with 3.7 (0.9) preventative treatment failures, were enrolled. Mean baseline MmsHD was 16.1 (4.7) and total monthly headache days (MHD) was (29) 2.3. MmsHD reduced substantially at 12 months by mean (SD) [95% CI] 10.8 (4.0) [9.5, 11.9], p < 0.001 and MHD reduced by 13.0 (9.5) [10.2, 15.7], p < 0.001. Crystal clear days (days without any head pain) increased by 13.1 (9.5) [9.6, 15.3], p < 0.001, headache severity (scale 0-10) fell by 1.3 (1.7) [0.9, 1.9], p < 0.001, and monthly analgesic days reduced by 4.3 (9.2) [1.6, 6.9], p = 0.002. All these measures had improved significantly by 3 months, with a consistent significant response to 12 months. Headache impact test-6 score and quality of life Short Form-36 Health Survey significantly improved at 12 months. Sensitivity analysis revealed similar results for patients with and without a prior migraine diagnosis (28/55 (52%) patients) or those with or without medication overuse (27/55 (48%) patients)., Conclusions: This study provides evidence for the effectiveness of erenumab to treat headaches in IIH patients with resolution of papilledema. It provides mechanistic insights suggesting that calcitonin gene-related peptide is likely a modulator driving headache and a useful therapeutic target., (© 2020 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background: The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH)., Methods: We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry., Results: Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass., Conclusions: These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Importance: There is an unmet need for noninvasive biomarkers of intracranial pressure (ICP), which manifests as papilledema that can be quantified by optical coherence tomography (OCT) imaging., Objective: To determine whether OCT of the optic nerve head in papilledema could act as a surrogate measure of ICP., Design, Setting, and Participants: This longitudinal cohort study used data collected from 3 randomized clinical trials that were conducted between April 1, 2014, and August 1, 2019. Participants who were female and had active idiopathic intracranial hypertension were enrolled from 5 National Health Service hospitals in the UK. Automated perimetry and OCT imaging were followed immediately by ICP measurement on the same day. Cohort 1 used continuous sitting telemetric ICP monitoring (Raumedic Neurovent P-tel device) on 1 visit. Cohort 2 was evaluated at baseline and after 3, 12, and 24 months and underwent lumbar puncture assessment of ICP., Main Outcomes and Measures: Optical coherence tomography measures of the optic nerve head and macula were correlated with ICP levels, Frisén grading, and perimetric mean deviation. The OCT protocol included peripapillary retinal nerve fiber layer, optic nerve head, and macular volume scans (Spectralis [Heidelberg Engineering]). All scans were validated for quality and resegmented manually when required., Results: A total of 104 women were recruited. Among cohort 1 (n = 15; mean [SD] age, 28.2 [9.4] years), the range of OCT protocols was evaluated, and optic nerve head central thickness was found to be most closely associated with ICP (right eye: r = 0.60; P = .02; left eye: r = 0.73; P = .002). Subsequently, findings from cohort 2 (n = 89; mean [SD] age, 31.8 [7.5] years) confirmed the correlation between central thickness and ICP longitudinally (12 and 24 months). Finally, bootstrap surrogacy analysis noted a positive association between central thickness and change in ICP at all points (eg, at 12 months, a decrease in central thickness of 50 μm was associated with a decrease in ICP of 5 cm H2O)., Conclusions and Relevance: In this study, optic nerve head volume measures on OCT (particularly central thickness) reproducibly correlated with ICP and surrogacy analysis demonstrated its ability to inform ICP changes. These data suggest that OCT has the utility to not only monitor papilledema but also noninvasively prognosticate ICP levels in idiopathic intracranial hypertension.

Mycobacterial infections are a major concern in veterinary medicine because of the difficulty achieving an etiological diagnosis, the challenges and concerns of treatment, and the potential zoonotic risk. Mycobacterium kansasii , a slow-growing non-tuberculous mycobacteria, causes disease in both humans and animals. While infections have been well described in humans, where it may be misdiagnosed as tuberculosis, there are fewer reports in animals. Only four cases have been reported in the domestic cat. This case report describes systemic M. kansasii infection in two sibling indoor-only cats that presented two and half years apart with cutaneous disease that was found to be associated with osteolytic and pulmonary pathology. Infection with M. kansasii was confirmed in both cats by polymerase chain reaction on fine-needle aspirate of a lumbosacral soft tissue mass in one cat and on a tissue punch biopsy of a skin lesion in the other; interferon-gamma release assay inferred M. avium -complex and M. tuberculosis -complex infection in the two cats, respectively. Both patients made a full recovery following antimicrobial therapy with rifampicin, azithromycin, and pradofloxacin (plus N-acetyl cysteine in cat 2). This report highlights successful treatment of systemic M. kansasii mycobacteriosis in the cat and the challenge of accurately diagnosing this infection.

Background: Adults with metastatic cancer frequently report anxiety and depression symptoms, which may impact health behaviors such as advance care planning (ACP). Objective: The study leveraged acceptance and commitment therapy (ACT), an evidence-based approach for reducing distress and improving health behaviors, and adapted it into a multimodal intervention (M-ACT) designed to address the psychosocial and ACP needs of anxious and depressed adults with metastatic cancer. The study evaluated M-ACT's acceptability, feasibility, and efficacy potential. Design: The study was designed as a single-arm intervention development and pilot trial. Setting/Subjects: The trial enrolled 35 anxious or depressed adults with stage IV cancer in community oncology clinics, with a referred-to-enrolled rate of 69% and eligible-to-enrolled rate of 95%. Measurements: M-ACT alternated four in-person group sessions with three self-paced online sessions. Acceptability and feasibility were assessed through enrollment, attendance, and satisfaction ratings. Outcomes and theorized intervention mechanisms were evaluated at baseline, midintervention, postintervention, and two-month follow-up. Results: Participant feedback was used to refine the intervention. Of participants starting the intervention, 92% completed, reporting high satisfaction. One-quarter did not begin M-ACT due to health declines, moving, or death. Completers showed significant reductions in anxiety, depression, and fear of dying and increases in ACP and sense of life meaning. In this pilot, M-ACT showed no significant impact on pain interference. Increases in two of three mechanism measures predicted improvement on 80% of significant outcomes. Conclusions: The M-ACT intervention is feasible, acceptable, and shows potential for efficacy in community oncology settings; a randomized trial is warranted.

Background: Headache is the dominant factor for quality of life related disability in idiopathic intracranial hypertension (IIH) and typically has migraine-like characteristics. There are currently no evidence-based therapeutics for headache in IIH, and consequently this is an important unmet clinical need., Case Series: We report a series of seven patients in whom headaches were the presenting feature of IIH and the headaches had migraine-like characteristics, as is typical in many IIH patients. Papilloedema settled (ocular remission) but headaches continued. These headaches responded markedly to erenumab, a monoclonal antibody targeted against the calcitonin gene related peptide (CGRP) receptor. Of note, there was a recurrence of raised ICP, as evidenced by a return of the papilloedema, however the headaches did not recur whilst treated with erenumab., Conclusions: Those with prior IIH who have their headaches successfully treated with CGRP therapy, should remain under close ocular surveillance (particularly when weight gain is evident) as papilloedema can re-occur in the absence of headache. These cases may suggest that CGRP could be a mechanistic driver for headache in patients with active IIH.

Objective and Design: A randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI)., Methods: Fifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n ​= ​10) or ART alone (n ​= ​5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) ​> ​1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM ​+ ​ART versus ART only with VL ​< ​50 copies/mL for 24 weeks after TI., Results: Fifteen participants on ART (median: 178 weeks: range 79-295) enrolled. Two on VHM ​+ ​ART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM ​+ ​ART (n ​= ​9) median: 4 weeks and ART only (n ​= ​5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p ​= ​0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation., Conclusions: Administration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies., Competing Interests: NC has served on the scientific advisory board of Theravectys. JA has participated in advisory meetings for ViiV Healthcare, Merck, AbbVie, Gilead, and Roche. All other authors declare no competing interests., (© 2020 The Author(s).)

The global pandemic of coronavirus disease 2019 (COVID-19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID-19 patients show elevated D-dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI-1) from lung epithelium and endothelial cells create a hypofibrinolytic state. Prophylaxis treatment of COVID-19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre-existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue-type plasminogen activator (tPA), to treat COVID-19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID-19 patients to degrade fibrin and improving oxygenation in critically ill patients., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Plasmacytoid dendritic cells (pDCs) are robust producers of IFNα and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-κB. The levels of phosphorylated IRF7 and NF-κB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with the time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data from a limited cohort provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.

Background: Responding to an epidemic of opioid-related deaths, guidelines and laws have been implemented to promote safe opioid prescribing practices. Objective: This study evaluates differences in screening practices and knowledge of laws between oncologists and cardiologists who prescribe opiates. Design: Surveys regarding screening practices and knowledge of opioid prescribing laws were distributed in March 2017 to oncology and congestive heart failure (CHF) clinicians at the University of Virginia. Chi-square and Wilcoxon rank sum tests were used. Results: Forty-six of 129 (35.6%) oncology providers and 7 of 14 (50%) CHF providers reported prescribing opiates in their clinic with usable survey results. The majority of oncology (65.22%) and cardiology (85.71%) providers report screening for substance abuse "when indicated" ( p  = 0.053). Only 19.6% of oncologists reported always using the prescription monitoring program (PMP), while 71.43% of cardiologists reported using it always ( p  = 0.014). Of the oncology providers, 66.67% report never using the urine drug screen (UDS), while 86.7% of cardiologists reported using it "when indicated" ( p  = 0.0086). Up to 34.78% of the oncologists and 57.14% of the cardiologists reported of never screening the family members for misuse ( p  = 0.317). Knowledge of laws was similar between groups, with 14.29% of cardiology and 17.39% of oncology providers reporting no knowledge of opioid prescribing laws ( p  = 0.2869). Conclusions: Routine screening for substance misuse risk was uncommon for both groups, but cardiology providers were more likely to use the PMP or UDS. Knowledge gaps regarding Virginia laws were noted in both groups. Improved education regarding best practices and laws, as well as programs to promote screening, is needed for all providers.

Background: Legionnaires' disease is under-diagnosed because of inconsistent use of diagnostic tests and uncertainty about whom to test. We assessed the increase in case detection following large-scale introduction of routine PCR testing of respiratory specimens in New Zealand., Methods: LegiNZ was a national surveillance study done over 1-year in which active case-finding was used to maximise the identification of cases of Legionnaires' disease in hospitals. Respiratory specimens from patients of any age with pneumonia, who could provide an eligible lower respiratory specimen, admitted to one of 20 participating hospitals, covering a catchment area of 96% of New Zealand's population, were routinely tested for legionella by PCR. Additional cases of Legionnaires' disease in hospital were identified through mandatory notification., Findings: Between May 21, 2015, and May 20, 2016, 5622 eligible specimens from 4862 patients were tested by PCR. From these, 197 cases of Legionnaires' disease were detected. An additional 41 cases were identified from notification data, giving 238 cases requiring hospitalisation. The overall incidence of Legionnaires' disease cases in hospital in the study area was 5·4 per 100 000 people per year, and Legionella longbeachae was the predominant cause, found in 150 (63%) of 238 cases., Interpretation: The rate of notified disease during the study period was three-times the average over the preceding 3 years. Active case-finding through systematic PCR testing better clarified the regional epidemiology of Legionnaires' disease and uncovered an otherwise hidden burden of disease. These data inform local Legionnaires' disease testing strategies, allow targeted antibiotic therapy, and help identify outbreaks and effective prevention strategies. The same approach might have similar benefits if applied elsewhere in the world., Funding: Health Research Council of New Zealand., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose of Review: The current article appraises the recent developments in idiopathic intracranial hypertension (IIH), with particular attention to novel therapeutic avenues and advanced clinical assessment and monitoring with optical coherence tomography and telemetric intracranial pressure devices., Recent Findings: The incidence of IIH is increasing. The first consensus guidelines for IIH have been published detailing investigation and management algorithms for adult IIH. Improved understanding, clinical assessment and monitoring are emerging with the use of optical coherence tomography. Intracranial pressure telemetry is providing unique insights into the physiology of raised intracranial pressure in IIH. There are now an increasing number of ongoing clinical trials evaluating weight loss methods and novel targeted therapies, such as 11ß-HSD1 inhibition and Glucagon-like peptide 1 (GLP-1) receptor agonists., Summary: Several studies are evaluating new therapies for IIH. Monitoring techniques are advancing, aiding diagnosis and allowing the clinician to accurately evaluate changes in papilloedema and intracranial pressure.

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.

Background: The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats., Methods: We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate., Results: At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999)., Conclusion: Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.

Background: Anxiety is a common concern of cancer survivors during the transition from active cancer treatment to cancer survivorship (the re-entry phase). This paper presents the study protocol for a novel group-based behavioral intervention to improve mental health, well-being, and medical use outcomes among anxious cancer survivors at re-entry., Methods/design: This two-armed, prospective randomized controlled trial will randomize a minimum of 100 re-entry-phase cancer survivors with moderate to high anxiety to the intervention or a usual care control condition. The intervention is delivered in a group format over 7 weeks; content is based on Acceptance and Commitment Therapy (ACT), an acceptance, mindfulness, and values-based intervention. Participants will be recruited from community cancer care centers and the intervention will be led by the onsite clinical social workers. Participants will be assessed at baseline, mid-intervention, post-intervention, and 3- and 6-month follow-up. ACT participants will complete process measures before the beginning of group sessions 2, 4, and 6; all participants will complete the process measures during the regular assessments. The primary outcome is anxiety symptoms; secondary outcomes include anxiety disorder severity, fear of recurrence, depressive symptoms, cancer-related trauma symptoms, sense of life meaning, vitality/fatigue, and medical utilization., Discussion: This clinical trial will provide valuable evidence regarding the efficacy of the group ACT intervention in community oncology settings., Trial Registration: Clinicaltrials.gov NCT02550925 .

Essentials Plasma Factor XIII, a heterodimer of A and B subunits FXIIIA 2 B 2 , is a transglutaminase enzyme with a well-established role in haemostasis. Cells of bone marrow and mesenchymal lineage express the FXIII-A gene (F13A1) that encodes the cellular form of the transglutaminase, a homodimer of the A subunits, FXIII-A. FXIII-A was presumed to function intracellularly, however, several lines of evidence now indicate that FXIII-A is externalised by an as yet unknown mechanism This review describes the mounting evidence that FXIII-A is a diverse transglutaminase with many intracellular and extracellular substrates that can participate in an array of biological processes SUMMARY: Factor XIII is a tranglutaminase enzyme that catalyzes the formation of ε-(γ-glutamyl)lysyl isopeptide bonds in protein substrates. The plasma form, FXIII-A 2 B 2 , has an established function in hemostasis, where its primary substrate is fibrin. A deficiency in FXIII manifests as a severe bleeding diathesis, underscoring its importance in this pathway. The cellular form of the enzyme, a homodimer of the A-subunits, denoted FXIII-A, has not been studied in as extensive detail. FXIII-A was generally perceived to remain intracellular, owing to the lack of a classical signal peptide for its release. In the last decade, emerging evidence has revealed that this diverse transglutaminase can be externalized from cells, by an as yet unknown mechanism, and can cross-link extracellular substrates and participate in a number of diverse pathways. The FXIII-A gene (F13A1) is expressed in cells of bone marrow and mesenchymal lineage, notably megakaryocytes, monocytes/macrophages, dendritic cells, chrondrocytes, osteoblasts, and preadipocytes. The biological processes that FXIII-A is coupled with, such as wound healing, phagocytosis, and bone and matrix remodeling, reflect its expression in these cell types. This review describes the mounting evidence that this cellular transglutaminase can be externalized, usually in response to stimuli, and participate in extracellular cross-linking reactions. A corollary of being involved in these biological pathways is the participation of FXIII-A in pathological processes. In conclusion, the functions of this transglutaminase extend far beyond its role in hemostasis, and our understanding of this enzyme in terms of its secretion, regulation and substrates is in its infancy., (© 2018 International Society on Thrombosis and Haemostasis.)

Objective: A growing number of cancer antineoplastic agents can cause life-threatening acute infusion reactions. Because previous studies have not studied these reactions from the perspective of patients, this study was undertaken with that objective in mind., Methods: Patients who had an acute infusion reaction were interviewed based on the Leventhal model. Once saturation of content was achieved, interviews were transcribed and analyzed with qualitative methodology., Results: Twenty-one patients were enrolled. Most were women (n = 15); the median age was 58 years, and paclitaxel was the most common inciting agent. Three themes emerged. First, these reactions are frightening; patients made remarks such as "I was just thinking oh my God, I am dying." Second, prior education about these reactions seemed to mitigate this fear, "Basically everything the nurses told me potentially could happen, like happened. So, I was prepared." Third, when health-care providers were prompt and attentive during the reaction, patients described less fear with future chemotherapy, "So no, I'm really not fearful about going in tomorrow because I know they'll be there and they'll be watching me.", Conclusion: These reactions evoke fear which can be mitigated with education prior to and with prompt responsiveness during the acute infusion reaction.

Background: Optical Coherence Tomography (OCT) imaging is being increasingly used in clinical practice for the monitoring of papilloedema. The aim is to characterise the extent and location of the Retinal Nerve Fibre Layer (RNFL) Thickness automated segmentation error (SegE) by manual refinement, in a cohort of Idiopathic Intracranial Hypertension (IIH) patients with papilloedema and compare this to controls., Methods: Baseline Spectral Domain OCT (SDOCT) scans from patients with IIH, and controls with no retinal or optic nerve pathology, were examined. The internal limiting membrane and RNFL thickness of the most severely affected eye was examined for SegE and re-segmented. Using ImageJ, the total area of the RNFL thickness was calculated pre and post re-segmentation and the percentage change was determined. The distribution of RNFL thickness error was qualitatively assessed., Results: Significantly greater SegE (p = 0.009) was present in RNFL thickness total area, assessed using ImageJ, in IIH patients (n = 46, 5% ± 0-58%) compared to controls (n = 14, 1% ± 0-6%). This was particularly evident in moderate to severe optic disc swelling (n = 23, 10% ± 0-58%, p < 0.001). RNFL thickness was unable to be quantified using SDOCT in patients with severe papilloedema., Conclusions: SegE remain a concern for clinicians using SDOCT to monitor papilloedema in IIH, particularly in the assessment of eyes with moderate to severe oedema. Systematic assessment and manual refinement of SegE is therefore important to ensure the accuracy in longitudinal monitoring of patients.

Background: Idiopathic intracranial hypertension (IIH) is a condition with few effective management options. So far, there have been no randomized controlled trials evaluating new treatments in IIH., Objectives: The purpose of this paper is to outline the trial design for the Idiopathic Intracranial Hypertension Drug Trial (IIH:DT), assessing an innovative medical treatment in IIH and the rationale for the chosen trial methodology., Methods: IIH:DT is a phase II double-blind randomized placebo-controlled trial recruiting 30 female participants with active IIH (intracranial pressure >25cm H 2 O and papilledema). Participants are randomized in a 1:1 ratio to 12 weeks of either AZD4017, an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, or a matching placebo. They receive either 400 mg of AZD4017 or placebo twice daily. Participants are followed up at Weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16 postrandomization. The primary outcome is to examine the effect of AZD4017 on intracranial pressure, measured by lumbar puncture, over 12 weeks. Secondary outcome measures include IIH symptoms, visual function, papilledema, headache measures, safety, and tolerability. Cerebrospinal fluid, serum, plasma, urine, and adipose tissue are also taken for exploratory outcomes., Results: All participants were recruited between April 2014 and August 2016., Conclusions: IIH:DT is the first phase II double-blind randomized placebo-controlled trial assessing the efficacy and safety of the novel pharmacological intervention, AZD4017, for the treatment of IIH., Trial Registration: Clinicaltrials.gov NCT02017444; https://clinicaltrials.gov/ct2/show/NCT02017444 (Archived by WebCite at http://www.webcitation.org/6tVHesN6s)., (©Keira Annie Markey, Ryan Ottridge, James L Mitchell, Caroline Rick, Rebecca Woolley, Natalie Ives, Peter Nightingale, Alexandra J Sinclair. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 18.09.2017.)