MANTA and MANTA-RAy: Rationale and Design of Trials Evaluating Effects of Filgotinib on Semen Parameters in Patients with Inflammatory Diseases.

INTRODUCTION: The phase 2 MANTA and MANTA-RAy studies were developed in consultation with global regulatory authorities to investigate potential impacts of filgotinib, a Janus kinase 1 preferential inhibitor, on semen parameters in men with active inflammatory diseases. Here we describe the methods and rationale for these studies. METHODS AND RATIONALE: The MANTA and MANTA-RAy studies included men (aged 21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases, respectively. Participants had no history of reproductive health issues, and the following semen parameter values (≥ 5th percentile of World Health Organization reference values) at baseline: semen volume ≥ 1.5 mL, total sperm/ejaculate ≥ 39 million, sperm concentration ≥ 15 million/mL, sperm total motility ≥ 40% and normal sperm morphology ≥ 30%. Each trial included a 13-week, randomized, double-blind, placebo-controlled period (filgotinib 200 mg vs placebo, up to N = 125 per arm), for pooled analysis of the week-13 primary endpoint (proportion of participants with ≥ 50% decrease from baseline in sperm concentration). All semen assessments were based on two samples (≤ 14 days apart) to minimize effects of physiological variation; stringent standardization processes were applied across assessment sites. From week 13, MANTA and MANTA-RAy study designs deviated owing to disease-specific considerations. All subjects with a ≥ 50% decrease in sperm parameters continued the study in the monitoring phase until reversibility, or up to a maximum of 52 weeks, with standard of care as treatment. Overall conclusions from MANTA and MANTA-RAy will be based on the totality of the data, including secondary/exploratory measures (e.g. sperm motility/morphology, sex hormones, reversibility of any effects on semen parameters). CONCLUSIONS: Despite the complexities, the MANTA and MANTA-RAy studies form a robust trial programme that is the first large-scale, placebo-controlled evaluation of potential impacts of an advanced IBD and rheumatic disease therapy on semen parameters. TRIAL REGISTRATION: EudraCT numbers 2017-000402-38 and 2018-003933-14; ClinicalTrials.gov identifiers NCT03201445 and NCT03926195.

Filgotinib is a treatment for patients with ulcerative colitis and rheumatoid arthritis, and is being studied in other inflammatory diseases. Filgotinib works by blocking Janus kinase 1, an intracellular protein involved in inflammatory signalling processes. We designed the MANTA and MANTA-RAy trials with global health agencies to find out if filgotinib decreases the quality of semen in men with active inflammatory bowel disease (ulcerative colitis or Crohn's disease) (MANTA) or rheumatic disease (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or non-radiographic axial spondylitis) (MANTA-RAy). This paper describes the design of the two trials.Patients had normal sperm measurements and could not have had previous reproductive health issues. Nearly 250 patients were included in each trial. In both MANTA and MANTA-RAy, half of the patients were treated with 200 mg of filgotinib once a day for 13 weeks, and the other half with placebo. We determined if any patients had a decrease in number of sperm cells per millilitre (sperm concentration) by at least half after 13 weeks of treatment. We then monitored any patients who had such a decrease in sperm concentration for up to 52 weeks (while they received standard of care treatment) or until the decrease was reversed.The conclusions from the trials will be in a different paper and will be based on all the final data, including changes in sex hormones. This is the first large-scale clinical trial programme to measure the effect of a treatment on sperm in men with inflammatory bowel disease or rheumatic diseases.

Diverse integrated ecosystem approach overcomes pandemic-related fisheries monitoring challenges.

The COVID-19 pandemic caused unprecedented cancellations of fisheries and ecosystem-assessment surveys, resulting in a recession of observations needed for management and conservation globally. This unavoidable reduction of survey data poses challenges for informing biodiversity and ecosystem functioning, developing future stock assessments of harvested species, and providing strategic advice for ecosystem-based management. We present a diversified framework involving integration of monitoring data with empirical models and simulations to inform ecosystem status within the California Current Large Marine Ecosystem. We augment trawl observations collected from a limited fisheries survey with survey effort reduction simulations, use of seabird diets as indicators of fish abundance, and krill species distribution modeling trained on past observations. This diversified approach allows for evaluation of ecosystem status during data-poor situations, especially during the COVID-19 era. The challenges to ecosystem monitoring imposed by the pandemic may be overcome by preparing for unexpected effort reduction, linking disparate ecosystem indicators, and applying new species modeling techniques.

Reproductive hyperallometry and managing the world's fisheries.

Marine fisheries are an essential component of global food security, but many are close to their limits and some are overfished. The models that guide the management of these fisheries almost always assume reproduction is proportional to mass (isometry), when fecundity generally increases disproportionately to mass (hyperallometry). Judged against several management reference points, we show that assuming isometry overestimates the replenishment potential of exploited fish stocks by 22% (range: 2% to 78%) for 32 of the world's largest fisheries, risking systematic overharvesting. We calculate that target catches based on assumptions of isometry are more than double those based on assumptions of hyperallometry for most species, such that common reference points are set twice as high as they should be to maintain the target level of replenishment. We also show that hyperallometric reproduction provides opportunities for increasing the efficacy of tools that are underused in standard fisheries management, such as protected areas or harvest slot limits. Adopting management strategies that conserve large, hyperfecund fish may, in some instances, result in higher yields relative to traditional approaches. We recommend that future assessment of reference points and quotas include reproductive hyperallometry unless there is clear evidence that it does not occur in that species.

Spatiotemporal patterns of variability in the abundance and distribution of winter-spawned pelagic juvenile rockfish in the California Current.

Rockfish are an important component of West Coast fisheries and California Current food webs, and recruitment (cohort strength) for rockfish populations has long been characterized as highly variable for most studied populations. Research efforts and fisheries surveys have long sought to provide greater insights on both the environmental drivers, and the fisheries and ecosystem consequences, of this variability. Here, variability in the temporal and spatial abundance and distribution patterns of young-of-the-year (YOY) rockfishes are described based on midwater trawl surveys conducted throughout the coastal waters of California Current between 2001 and 2019. Results confirm that the abundance of winter-spawning rockfish taxa in particular is highly variable over space and time. Although there is considerable spatial coherence in these relative abundance patterns, there are many years in which abundance patterns are very heterogeneous over the scale of the California Current. Results also confirm that the high abundance levels of YOY rockfish observed during the 2014-2016 large marine heatwave were largely coastwide events. Species association patterns of pelagic YOY for over 20 rockfish taxa in space and time are also described. The overall results will help inform future fisheries-independent surveys, and will improve future indices of recruitment strength used to inform stock assessment models and marine ecosystem status reports.

Remote reporting in the COVID-19 era: from pilot study to practice.

AIM: To assess the benefits and challenges of remote reporting using an intra-departmental teleradiology system. MATERIALS AND METHODS: A pilot of an in-hospital Trust radiologist reporting on in-hospital Trust patients via a remote login was undertaken. Reporting output, training impact, and quality improvement were measured. RESULTS: Reporting output increased by 140%. Trainee satisfaction was high in a qualitative survey, particularly for out-of-hours support and teaching. Clinicians found the service to be similar to the same service provided by a locally based radiologist. CONCLUSION: In the COVID-19 era, remote working has developed rapidly. This study shows that radiology departments can provide remote reporting that is equal in standard to reporting from within the hospital, and in addition, that there are advantages to output and training.

Phylogenetic analysis of Histoplasma capsulatum var duboisii in baboons from archived formalin-fixed, paraffin embedded tissues.

Histoplasma capsulatum var. duboisii (Hcd) infections have been well documented to cause chronic granulomatous disease, mainly involving the skin of baboons and humans in African countries primarily. This retrospective study classified the subspecies of Histoplasma and developed a phylogenetic tree utilizing DNA sequences extracted from formalin-fixed, paraffin embedded (FFPE) tissues from 9 baboons from a research colony in Texas histologically diagnosed with Hcd. Based on sequence analysis of ITS-2, Tub-1, and ARF, Hcd isolated from the archived samples closely aligns with the African clade and has 88% sequence homology with a sample isolated from an individual in Senegal.

Bomb blast imaging: bringing order to chaos.

Blast injuries are complex, severe, and outside of our everyday clinical practice, but every radiologist needs to understand them. By their nature, bomb blasts are unpredictable and affect multiple victims, yet require an immediate, coordinated, and whole-hearted response from all members of the clinical team, including all radiology staff. This article will help you gain the requisite expertise in blast imaging including recognising primary, secondary, and tertiary blast injuries. It will also help you understand the fundamental role that imaging plays during mass casualty attacks and how to avoid radiology becoming a bottleneck to the forward flow of severely injured patients as they are triaged and treated.

Parturition in baboons (PAPIO SPP.).

The Old World non-human primates (NHP) - baboons (Papio spp.) share similarities with humans regarding fetal and placental development and some pregnancy-related complications. Information about the mechanism of birth and complications arising during parturition in these species is relatively sparse. In this manuscript, we add information from a series of pathological and observational cases to highlight insights and selected complications of birth in Papio spp, based on video-recording of the delivery process, X-ray, MRI, and ultrasound evaluations in pregnant baboons. Additionally, we abstracted pathology records obtained from perinatal loss in a large baboon colony during a 17 year period. The presented cases provide important information for the management of pregnancy and delivery in Papio spp.

Microflow imaging: New Doppler technology to detect low-grade inflammation in patients with arthritis.

AIM: To assess the efficacy of microvascular imaging in detecting low-grade inflammation in arthritis compared with Power Doppler ultrasound (PDUS). METHOD AND MATERIALS: Patients presenting for ultrasound with arthralgia were assessed with grey-scale, PDUS and Superb Microvascular Imaging (SMI). Videoclips were stored for analysis at a later date. Three musculoskeletal radiologists scored grey-scale changes, signal on PDUS and/or SMI within these joints. If a signal was detected on both PDUS and SMI, the readers graded the conspicuity of vascular signal from the two Doppler techniques using a visual analogue scale. RESULTS: Eighty-three patients were recruited with 134 small joints assessed. Eighty-nine of these demonstrated vascular flow with both PD and SMI, whilst in five no flow was detected. In 40 joints, vascularity was detected with SMI but not with PDUS (p = 0.007). Out of the 89 joints with vascularity on both SMI and PDUS, 23 were rated as being equal; while SMI scored moderately or markedly better in 45 cases (p <0.001). CONCLUSION: SMI is a new Doppler technique that increases conspicuity of Doppler vascularity in symptomatic joints when compared to PDUS. This allows detection of low grade inflammation not visualised with Power Doppler in patients with arthritis. KEY POINTS: • SMI detects vascularity with improved resolution and sensitivity compared to Power Doppler. • SMI can detect low-grade inflammation not seen with Power Doppler. • Earlier detection of active inflammation could have significant impact on treatment paradigms.

Subspecialisation in Emergency Radiology: Proposal for a harmonised European curriculum.

Introduction: Radiology plays a crucial role in the emergency care setting by delivering early and precise diagnoses under pressure of time, right at the beginning of patient treatment. Although there is a need for postgraduate education in emergency radiology, most of the national bodies responsible do not offer it in a uniform fashion and a general proof of qualification is missing in Europe. Therefore, the European Society of Radiology (ESR) has founded the (Sub-)Society of Emergency Radiology (ESER), prompting them to develop a European curriculum. This trend, which is currently also encouraged in many other non-radiological specialties which demand the highest professional qualifications, often lacks expertise in medical education. Goals: The goal of this article is the general description of the curricular planning process for a European postgraduate subspecialisation programme, using the example of Emergency Radiology (European Diploma in Emergency Radiology, EDER), including the utilisation of TOOLS and recommendations derived from comparable projects. Project description: The project was divided into partial steps: the timeline displayed in a GANTT chart, and tasks and responsibilities assigned in a RASCI matrix. The curriculum was iteratively developed using the KERN approach and steps were prioritised using the PARETO principle. Furthermore, the following TOOLS were used: limitations and needs assessment, SWOT analysis, formulating learning objectives and categorising them after MILLER and SCLO, and using BLOOM's taxonomy for cognitive learning objectives and operationalising them according to MAGER. Psychomotoric and affective learning objectives were assigned to CANMEDS roles, grouped by topic using CLUSTERING, and then mapped by MATRIX analysis to appropriate learning and evaluation methods. Striving for continuous improvement, the curriculum was finally embedded in curricular quality management. Results: The standardisation of the EDER access, considering the different national conditions, the minimisation of European learners' attendance phases, restricting expenses by best possible use of existing structures, respecting the requirements and retaining the support of the European umbrella society ESR, finishing the project by a specific deadline and the demands of continuous improvement were particular challenges. A curriculum with the eligibility of five years' speciality training in general radiology has evolved on schedule. The subspeciality training lasts at least one year and is divided into webinars, workshops during congresses (e.g. the annual ESR and ESER congresses) and one year practical training at the individual learner's corresponding local hospitals, which adhere to a catalogue of requirements, comparable to national educational policies. The curriculum is completed by passing a written and oral exam (diploma) and re-accreditation every five years. Conclusions: Despite complex requirements, the TOOLS utilised allowed an almost seamless, resource-minimised, professional, location-independent distributed development of a European subspeciality curriculum within one year. The definitive implementation is still due. If any deviations from the draft presented should become necessary in the future, the embedment in the curricular quality management will lead to a redirection in the right way and, furthermore, secure a continuous improvement in the best way possible.

Quality improvement in hospitals: barriers and facilitators.

Purpose The purpose of this paper is to examine quality improvement (QI) initiatives in acute care hospitals, the factors associated with success, and the impacts on patient care and safety. Design/methodology/approach An extensive online survey was completed by senior managers responsible for QI. The survey assessed QI project types, QI methods, staff engagement, and barriers and factors in the success of QI initiatives. Findings The response rate was 37 percent, 46 surveys were completed from 125 acute care hospitals. QI initiatives had positive impacts on patient safety and care. Staff in all hospitals reported conducting past or present hand-hygiene QI projects and C. difficile and surgical site infection were the next most frequent foci. Hospital staff not having time and problems with staff prioritizing QI with other duties were identified as important QI barriers. All respondents reported hospital leadership support, data utilization and internal champions as important QI facilitators. Multiple regression models identified nurses' active involvement and medical staff engagement in QI with improved patient care and physicians' active involvement and medical staff engagement with greater patient safety. Practical implications There is the need to study how best to support and encourage physicians and nurses to become more engaged in QI. Originality/value QI initiatives were shown to have positive impacts on patient safety and patient care and barriers and facilitating factors were identified. The results indicated patient care and safety would benefit from increased physician and nurse engagement in QI initiatives.

Pregnancy-driven cardiovascular maternal miR-29 plasticity in obesity.

BACKGROUND: Obesity in pregnancy (MO) is a risk factor for maternal and/or fetal cardiovascular system disorders. This study evaluated maternal CVS expression of microRNA-29 family and its target molecules in MO to test the hypotheses: CVS miR-29 concentrations are increased in pregnancy and decreased in MO. METHODS: Non-pregnant (n=4), pregnant obese (POb, n=4), and pregnant non-obese (PnOb, n=4) baboons (Papio spp.) were studied. Maternal left ventricle (LV), left atrium (LA), and aortic arch (AA) were collected at the end of gestation. Expression of MiR-29 and elastin (ELN) mRNA were quantified. RESULTS: LA miR-29 (a, c) expression was highest in PnOb. In the LV, miR-29b expression trended lower (P=.059) for PnOb animals. ELN mRNA expression correlated positively with miR-29b expression in AA (r=.76, P=.03). CONCLUSION: Maternal obesity diminishes miR-29 adaptation to pregnancy. Pharmacologic, tissue-specific targeting of miRNA-29 may represent a strategy for prevention and treatment of MO complications.

Pancreatic neuroendocrine tumors in twelve baboons (Papio spp.).

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are rare in nonhuman primates and in humans. METHODS: Twenty-one PNETs from twelve female baboons (Papio spp.) from the Southwest National Primate Research Center were evaluated using histopathology and immunohistochemistry. RESULTS: Histologically, all tumors were benign and had neuroendocrine packeting. Immunohistochemical staining for synaptophysin and chromogranin was positive in all tumors evaluated (17/17). Insulin was positive in 16 of 21 tumors. Somatostatin was positive in 9 of 20 tumors. Multifocal staining for glucagon and pancreatic polypeptide was evident in a minority of tumors (6/20 and 2/17, respectively). Gastrin and vasoactive intestinal peptide were negative in all tumors evaluated. Nine tumors expressed more than one hormone marker. CONCLUSIONS: This is the first detailed pathologic study of pancreatic endocrine tumors in the baboon. The findings suggest that these tumors are generally benign and have similar morphologic and immunohistochemical features as those described in people, including the ability to express multiple hormones.

Spontaneous Reproductive Tract Lesions in Aged Captive Chimpanzees.

Chimpanzees (Pan troglodytes) have served as an important model for studies of reproductive diseases and aging-related disorders in humans. However, limited information is available about spontaneously occurring reproductive tract lesions in aging chimpanzees. In this article, the authors present histopathologic descriptions of lesions identified in the reproductive tract, including the mammary gland, of 33 female and 34 male aged chimpanzees from 3 captive populations. The most common findings in female chimpanzees were ovarian atrophy, uterine leiomyoma, adenomyosis, and endometrial atrophy. The most common findings in male chimpanzees were seminiferous tubule degeneration and lymphocytic infiltrates in the prostate gland. Other less common lesions included an ovarian granulosa cell tumor, cystic endometrial hyperplasia, an endometrial polyp, uterine artery hypertrophy and mineralization, atrophic vaginitis, mammary gland inflammation, prostatic epithelial hyperplasia, dilated seminal vesicles, a sperm granuloma, and lymphocytic infiltrates in the epididymis. The findings in this study closely mimic changes described in the reproductive tract of aged humans, with the exception of a lack of malignant changes observed in the mammary gland and prostate gland.

Evaluation of disease-mediated therapeutic protein-drug interactions between an anti-interleukin-6 monoclonal antibody (sirukumab) and cytochrome P450 activities in a phase 1 study in patients with rheumatoid arthritis using a cocktail approach.

This therapeutic protein-drug interaction study evaluated the disease-mediated effect of sirukumab (anti-interleukin 6 [anti-IL-6] monoclonal antibody) on the pharmacokinetics of the cytochrome P450 (CYP) probe substrates midazolam (CYP3A), omeprazole (CYP2C19), warfarin (CYP2C9), and caffeine (CYP1A2) in patients with active rheumatoid arthritis (RA). Twelve patients with C-reactive protein (CRP) ≥ 8.0 mg/L at screening received oral administration of a CYP probe cocktail consisting of 0.03 mg/kg midazolam, 10 mg warfarin + 10 mg vitamin K (equivalent to 5 mg S-warfarin), 20 mg omeprazole, and 100 mg caffeine 1 week before and 1, 3, and 6 weeks after a single subcutaneous dose of 300 mg sirukumab. The results showed that the pharmacokinetics of midazolam, omeprazole, and S-warfarin were nonequivalent before and after the administration of a single dose of 300 mg sirukumab. Area under the plasma concentration-time curve (AUC0- ∞ ) for midazolam, omeprazole, and S-warfarin was reduced by 30%-35%, 37%-45%, and 18%-19%, respectively, after sirukumab administration. Caffeine AUC0-∞ was increased by 20%-34% after sirukumab administration. The effect of sirukumab on CYP substrates was sustained for at least 6 weeks. No new adverse drug reactions related to the administration of sirukumab were observed in this study. These results suggest that sirukumab may reverse IL-6-mediated suppression of CYP3A, CYP2C9, and CYP2C19 activities in patients with active RA.

Herpes simplex virus lymphadenitis: the elusive doppelganger in immunocompromised patients.

Herpes simplex virus has protean manifestations and is an important cause of morbidity in the immunocompromised host. We report a case of recurrent lymphadenopathy and rash in a patient with chronic lymphocytic leukemia. The elusive clinical diagnosis eventually required core biopsy of a lymph node with immunohistochemistry and confirmation by polymerase chain reaction. This case illustrates the challenging clinical and laboratory diagnosis of herpes simplex virus lymphadenitis and the need to maintain a high index of suspicion for infection when treating an immunocompromised patient with unusual and/or persistent symptoms.

Working relationships of infection prevention and control programs and environmental services and associations with antibiotic-resistant organisms in Canadian acute care hospitals.

BACKGROUND: Environmental contamination in hospitals with antibiotic-resistant organisms (AROs) is associated with patient contraction of AROs. This study examined the working relationship of Infection Prevention and Control (IPAC) and Environmental Services and the impact of that relationship on ARO rates. METHODS: Lead infection control professionals completed an online survey that assessed the IPAC and Environmental Services working relationship in their acute care hospital in 2011. The survey assessed cleaning collaborations, staff training, hospital cleanliness, and nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection, vancomycin-resistant Enterococcus (VRE) infection, and Clostridium difficile infection (CDI). RESULTS: The survey was completed by 58.3% of hospitals (119 of 204). Two-thirds (65.8%; 77 of 117) of the respondents reported that their cleaners were adequately trained, and 62.4% (73 of 117) reported that their hospital was sufficiently clean. Greater cooperation between IPAC and Environmental Services was associated with lower rates of MRSA infection (r = -0.22; P = .02), and frequent collaboration regarding cleaning protocols was associated with lower rates of VRE infection (r = -0.20; P = .03) and CDI (r = -0.31; P < .001). CONCLUSIONS: Canadian IPAC programs generally had collaborative working relationships with Environmental Services, and this was associated with lower rates of ARO. Deficits in the adequacy of cleaning staff training and hospital cleanliness were identified. The promotion of collaborative working relationships and additional training for Environmental Services workers would be expected to lower ARO rates.

Environmental cleaning resources and activities in Canadian acute care hospitals.

BACKGROUND: Environmental cleaning interventions have increased cleaning effectiveness and reduced antibiotic-resistant organisms in hospitals. This study examined cleaning in Canadian acute care hospitals with the goal of developing strategies to improve cleaning and reduce antibiotic-resistant organism rates. METHODS: Managers most responsible for environmental services (EVS) completed an extensive online survey that assessed EVS resources and cleaning practices. RESULTS: The response rate was 50.5%; 96 surveys were completed, representing 103 of 204 hospitals. Whereas 86.3% (82/95) of managers responsible for EVS reported their staff was adequately trained and 76.0% (73/96) that supplies and equipment budgets were sufficient, only 46.9% (45/96) reported that EVS had enough personnel to satisfactorily clean their hospital. A substantial minority (36.8%, 35/95) of EVS departments did not audit the cleaning of medical surgical patient rooms on at least a monthly basis. Cleaning audits of medical surgical patient rooms frequently included environmental marking methods in only one third (33.3%, 31/93) of hospitals and frequently included the measurement of residual bioburden in only 13.8% (13/94). CONCLUSION: There was a general need for increased and improved auditing of environmental cleaning in Canadian hospitals, and there were perceived EVS staffing deficits in the majority of hospitals.

Reovirus-associated meningoencephalomyelitis in baboons.

Baboon orthoreovirus (BRV) is associated with meningoencephalomyelitis (MEM) among captive baboons. Sporadic cases of suspected BRV-induced MEM have been observed at Southwest National Primate Research Center (SNPRC) for the past 20 years but could not be confirmed due to lack of diagnostic assays. An immunohistochemistry (IHC)-based assay using an antibody against BRV fusion-associated small transmembrane protein p15 and a conventional polymerase chain reaction (PCR)-based assay using primers specific for BRV were developed to detect BRV in archived tissues. Sixty-eight cases of suspected BRV-induced MEM from 1989 through 2010 were tested for BRV, alphavirus, and flavivirus by IHC. Fifty-nine of 68 cases (87%) were positive for BRV by immunohistochemistry; 1 tested positive for flavivirus (but was negative for West Nile virus and St Louis encephalitis virus by real-time PCR), and 1 virus isolation (VI) positive control tested negative for BRV. Sixteen cases (9 BRV-negative and 7 BRV-positive cases, by IHC), along with VI-positive and VI-negative controls, were tested by PCR for BRV. Three (of 9) IHC-negative cases tested positive, and 3 (of 7) IHC-positive cases tested negative by PCR for BRV. Both IHC and PCR assays tested 1 VI-positive control as negative (sensitivity: 75%). This study shows that most cases of viral MEM among baboons at SNPRC are associated with BRV infection, and the BRV should be considered a differential diagnosis for nonsuppurative MEM in baboons.