Strain Typing Mycobacterium marinum from Outbreaks at Zebrafish Research Facilities

Zebrafish (Danio rerio) are used as model organisms for biological research due to their rapid and transparent development and high fecundity amongst other reasons. Research has expanded beyond embryonic studies, with adult fish used for longer-term studies such as human disease and senescence. Zebrafish are often housed at high density in large colonies. As with any similar husbandry situation, diseases can occur, with impacts that range from morbidity to premature mortality costing researchers time and money. Understanding the impact of underlying diseases in zebrafish is crucial, particularly for long-term studies where chronic infections may confound results. One such disease problem is mycobacteriosis, caused by numerous Mycobacterium species. Mycobacteria likely spread when fish are exchanged between facilities with no precautions for biosecurity. Bacteria can also persist in the water and live on surface biofilms, making control more difficult. Mycobacterium marinum is one species that is of interest because it is highly virulent, contributing to serious outbreaks. It is also a concern for occupational health because it can cause skin infections in humans. To better understand the spread of mycobacteriosis caused specifically by M. marinum, strain typing was conducted to categorize isolates from seven different zebrafish facilities throughout the United States. For strain typing a variable number of tandem repeat assay was used. This technique was adapted using fluorescently labeled primers followed by fragment analysis in order to increase throughput and repeatability. These results were then used to determine if any epidemiological linkages exist between facilities experiencing outbreaks

Density of Common Complex Ocular Traits in the Aging Eye: Analysis of Secondary Traits in Genome-Wide Association Studies

Genetic association studies are identifying genetic risks for common complex ocular traits such as age-related macular degeneration (AMD). The subjects used for discovery of these loci have been largely from clinic-based, case-control studies. Typically, only the primary phenotype (e.g., AMD) being studied is systematically documented and other complex traits (e.g., affecting the eye) are largely ignored. The purpose of this study was to characterize these other or secondary complex ocular traits present in the cases and controls of clinic-based studies being used for genetic study of AMD. The records of 100 consecutive new patients (of any diagnosis) age 60 or older for which all traits affecting the eye had been recorded systematically were reviewed. The average patient had 3.5 distinct diagnoses. A subset of 10 complex traits was selected for further study because they were common and could be reliably diagnosed. The density of these 10 complex ocular traits increased by 0.017 log-traits/year (P = 0.03), ranging from a predicted 2.74 at age 60 to 4.45 at age 90. Trait-trait association was observed only between AMD and primary vitreomacular traction (P = 0.0009). Only 1% of subjects age 60 or older had no common complex traits affecting the eye. Extrapolations suggested that a study of 2000 similar subjects would have sufficient power to detect genetic association with an odds ratio of 2.0 or less for 4 of these 10 traits. In conclusion, the high prevalence of complex traits affecting the aging eye and the inherent biases in referral patterns leads to the potential for confounding by undocumented secondary traits within case-control studies. In addition to the primary trait, other common ocular phenotypes should be systematically documented in genetic association studies so that adjustments for potential trait-trait associations and other bias can be made and genetic risk variants identified in secondary analyses

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Health state utilities for skeletal-related events secondary to bone metastases.

INTRODUCTION: Patients with bone metastases often experience skeletal-related events (SREs). Although cost-utility models are used to examine treatments for metastatic cancer, limited information is available on utilities of SREs. The purpose of this study was to estimate the disutility of four SREs: spinal cord compression, pathological fracture, radiation to bone, and surgery performed to stabilize a bone. METHODS: General population participants from the UK and Canada completed time trade-off (TTO) interviews to assess the utility of health states drafted based on literature review, clinician interviews, and patient interviews. Respondents first rated a health state describing cancer with bone metastases. Then, the SREs were added to this health state. RESULTS: Interviews were completed with 187 participants (50.8 % male, 80.2 % white). Cancer with bone metastases without an SRE had a mean utility of 0.47 (SD = 0.43) on a standard utility scale (1 = full health, 0 = death). Of the SREs, spinal cord compression was associated with the greatest disutility (i.e. the utility decrease): -0.32 with paralysis and -0.22 without paralysis. Surgery had a disutility of -0.07. Leg, arm, and rib fractures had disutilities of -0.06, -0.04, and -0.03. Two weeks of daily radiation treatment had a disutility of -0.06, while two radiation appointments had the smallest impact on utility (-0.02). CONCLUSION: All SREs were associated with statistically significant utility decreases, suggesting a perceived impact on quality of life beyond the impact of cancer with bone metastases. The resulting disutilities may be used in cost-utility models examining treatments to prevent SREs secondary to bone metastases.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/inPres

Patient-reported outcome instruments used to assess pain and functioning in studies of bisphosphonate treatment for bone metastases

PURPOSE: When treating metastatic bone disease, relief of bone pain is often a key outcome. Because pain cannot be quantified with objective clinical measures, patient-reported outcome (PRO) measures are required to assess patients' subjective experience. The goal of the current review was to examine measures used to assess pain, as well as the impact of pain on functional status and health-related quality of life (HRQL), in trials of bisphosphonates for the treatment of bone metastases. METHODS: A literature search focused on articles published from January 1999 to April 2009. RESULTS: A total of 49 articles were located that used PROs to assess pain-related outcomes of bisphosphonate treatment for bone metastases. The Brief Pain Inventory was the most commonly used multi-item instrument. However, the most common approach for assessing pain was to administer a single-item scale such as a visual analog scale, numerical rating scale, or verbal rating scale. Of the 49 studies, 19 included a PRO assessing functional status or HRQL. CONCLUSIONS: Although pain is an important outcome of trials examining treatment for bone metastases, the current review suggests that there is little consistency in PRO measurement across studies. Furthermore, presentation of measures often lacked clear description, information on measurement properties, citations, clarity regarding method of administration, and consistent instrument names. Recommendations are provided for instrument validation within the target population, assessment of content validity, use of PRO instruments recently developed for patients with bone metastases, clear description of instruments, and implementation of measures consistent with recommendations from instrument developers