In the Eye of the Storm: Bioethics in the Time of COVID-19

HSS Journal ® -     

Extracellular Vesicles Released From Articular Chondrocytes Play a Major Role in Cell–Cell Communication

The purpose of this investigation was to determine the role of extracellular vesicles (EVs), released from articular chondrocytes in a physiological or pathological state, in cell–cell communication with other articular chondrocytes or chondrocyte precursor cells. The conditioned medium from interleukin-1β (IL-1β)-treated human articular chondrocytes stimulated catabolic events and inhibited type II collagen expression in articular chondrocytes to a much greater degree than medium from IL-1β-treated chondrocytes after complete removal of EVs. The vehicle-treated and IL-1β-treated human articular chondrocytes released EVs of similar size; however, the number of EVs released by IL-1β-treated chondrocytes was markedly higher than the number of EVs released from the vehicle-treated cells. Furthermore, our findings demonstrate that similar to medium from IL-1β-treated chondrocytes containing EVs, EVs isolated from medium of IL-1β-treated chondrocytes stimulated catabolic events in articular chondrocytes, whereas EVs isolated from the medium of vehicle-treated chondrocytes inhibited catabolic events and increased messenger RNA levels of aggrecan and type II collagen in IL-1β-treated chondrocytes. Furthermore, the medium containing EVs from vehicle-treated articular chondrocytes or EVs isolated from this medium stimulated chondrogenesis of C3H10T1/2 cells, whereas medium containing EVs from IL-1β-treated chondrocytes or EVs isolated from this medium inhibited chondrogenesis. Our findings suggest that EVs released by articular chondrocytes play a key role in the communication between joint cells and ultimately in joint homeostasis, maintenance, pathology, and repair. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:731-739, 2020     

Blocking CTGF/CCN2 reverses neural fibrosis and sensorimotor declines in a rat model of overuse-induced median mononeuropathy

Encapsulation of median nerves is a hallmark of overuse-induced median mononeuropathy and contributes to functional declines. We tested if an antibody against CTGF/CCN2 (termed FG-3019 or Pamrevlumab) reduces established neural fibrosis and sensorimotor declines in a clinically relevant rodent model of overuse in which median mononeuropathy develops. Young adult female rats performed a high repetition high force (HRHF) lever-pulling task for 18 weeks. Rats were then euthanised at 18 weeks (HRHF untreated), or rested and systemically treated for 6 weeks with either an anti-CCN2 monoclonal antibody (HRHF-Rest/FG-3019) or IgG (HRHF-Rest/IgG), with results compared with nontask control rats. Neuropathology was evident in HRHF-untreated and HRHF-Rest/IgG rats as increased perineural collagen deposition and degraded myelin basic protein (dMBP) in median nerves, and increased substance P in lower cervical dorsal root ganglia (DRG), compared with controls. Both groups showed functional declines, specifically, decreased sensory conduction velocity in median nerves, noxious cold temperature hypersensitivity, and grip strength declines, compared with controls. There were also increases of ATF3-immunopositive nuclei in ventral horn neurons in HRHF-untreated rats, compared with controls (which showed none). FG-3019-treated rats showed no increase above control levels of perineural collagen or dMBP in median nerves, Substance P in lower cervical DRGs, or ATF3-immunopositive nuclei in ventral horns, and similar median nerve conduction velocities and thermal sensitivity, compared with controls. We hypothesize that neural fibrotic processes underpin the sensorimotor declines by compressing or impeding median nerves during movement, and that inhibiting fibrosis using an anti-CCN2 treatment reverses these effects.     

Human Remains Identification,Grief, and Posttraumatic Stress in Bereaved Family Members 14 Years After the September 11, 2001, Terrorist Attacks

Returning human remains to family members after a loved one's death is thought to support grief adaptation. However, no known research has examined the effects that notifications of fragmented remains have on bereaved family members. We examined the number of notifications received, continuing questions about the death, grief severity, and posttraumatic stress (PTS) in family members bereaved by the September 11, 2001 attacks (N = 454). One notification was associated with fewer continuing questions compared to zero notifications, p = .037, or two or more notifications, p = .009. A model using notifications and continuing questions to predict grief severity showed there was no difference between receiving one and zero notifications, p = .244; however, receipt of two or more notifications was associated with higher grief severity compared to zero notifications, p = .032. A similar model demonstrated that receipt of any notifications was associated with PTS, ɳ_p² = .026, p = .006. Having continuing questions was associated with grief severity, ɳ_p² = .170, p < .001; and PTS, ɳ_p² = .086, p < .001. Additionally, participants who received one notification and chose not to receive more had fewer continuing questions compared to all other participants, and participants who received two or more notifications and chose no future notifications had higher PTS levels compared to all other participants. The results indicate that human remains notification is not associated with reduced grief severity but is associated with PTS. These findings should inform notification policy and guide families’ notification choice after traumatic deaths.     

A Team-Based Approach to Introduce and Sustain the Use of the WHO Surgical Safety Checklist in Tanzania

Introduction

Millions of patients worldwide suffer disability and death due to complications related to surgery. Many of these complications can be reduced by the use of the World Health Organization (WHO) Surgical Safety Checklist (SSC), a simple tool that can enhance teamwork and communication and improve patient safety. Despite the evidence on benefits of its use, introducing and sustaining the use of the checklist are challenging. We present a team-based approach employed in a low-resource setting in Tanzania, which resulted in high checklist utilization and compliance rates.

Methods

We reviewed reported data from facility registers supplemented by direct observation data by mentors to evaluate the use of the WHO SSC across 40 health facilities in two regions of Tanzania between January and December 2018. We analyzed the self-reported monthly data on total number of major surgeries performed and proportion of surgeries where the checklist was used. We also analyzed the use of the SSC during direct observation by external mentors and completion rates of the SSC in a random selection of patient files during two mentorship visits between June and December 2018.

Results

During the review period, the average self-reported checklist utilization rate was 79.3% (11,564 out of 14,580 major surgeries). SSC utilization increased from 0% at baseline in January 2018 to 98% in December 2018. The proportion of checklists that were completely and correctly filled out increased between the two mentor visits from 82.1 to 92.8%, but the gain was significantly greater at health centers than at hospitals (p < 0.05). Health centers (which had one or two surgical teams) self-reported a higher checklist utilization rate than hospitals (which had multiple surgical teams), i.e., 99.4% vs 68.8% (p < 0.05).

Conclusion and recommendations

Our findings suggest that Surgical Safety Checklist implementation is feasible even in lower-resource settings. The self-reported SSC utilization rate is higher than reported in other similar settings. We attribute this finding to the team-based approach employed and the ongoing regular mentorship. We recommend use of this approach to scale-up checklist use in other regions in the country as recommended in the Ministry of Health of Tanzania’s National Surgical, Obstetric, and Anesthesia Plan (NSOAP).

     

Correlation Between Trough Plasma Dabigatran Concentrations and Estimates of Glomerular Filtration Rate Based on Creatinine and Cystatin C

Aims

Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft–Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys).

Methods

A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations.

Results

The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38–94 years) taking dabigatran etexilate was 60 µg/L (range 9–279). The dose-corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R², 95 % CI) 32 % (9–55), 37 % (12–60), 41 % (16–64) and 47 % (20–69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R² values for each equation was not statistically significant (p = 0.74).

Discussion

Estimates of renal function using the four equations accounted for 32–47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-014-0045-9) contains supplementary material, which is available to authorized users.     

Development of an inter-professional clinical practice guideline for vocational evaluation following severe burn

Purpose

To develop an inter-professional clinical practice guideline for vocational evaluation following severe burn.

Methods

The Canadian Medical Association's (CMA) handbook on clinical practice guideline and the appraisal of guidelines for research and evaluation (AGREE) were used to develop the guideline. The following steps from the CMA handbook were followed: (1) identifying the guideline's objective and questions; (2) systematic literature review; (3) study selection and quality appraisal and (4) development of clear recommendations by key stakeholders. The international classification of function and disability was used as a guiding theoretical framework.

Results

The guideline includes recommendations within seven domains: (1) establishing evaluation purpose and consent; (2) history taking and information gathering; (3) assessment of functional systems: body systems and structures; (4) assessment of functional systems: activity limitations and participation restrictions; (5) identification of key personal and environmental factors; (6) analysis and synthesis; (7) development of evaluation recommendations.

Conclusions

This guideline insures that vocational evaluators use an evidence-based approach to systematically assess elements within the individual, the work, workplace, personal and environmental facilitators and barriers to work participation. The guideline may be useful to clinicians, healthcare teams, employers and individuals with severe burns. Future steps will include guideline pilot testing and endorsement.