Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Quantifying displacement of urogenital organs after abdominoperineal resection for rectal cancer.

AIM: This study aimed to quantify displacement of urogenital organs after abdominoperineal resection (APR), and to explore patient and treatment characteristics associated with displacement. METHOD: Patients from 16 centres who underwent APR for primary or recurrent rectal cancer (2001-2018) with evaluable preoperative and 6-18 months postoperative radiological imaging were included in the study. Anatomical landmarks on sagittal images were related to a coordinate system based on reference lines between fixed bony structures and absolute displacements were calculated using the Pythagorean theorem. Rotation of landmarks was measured relative to a pubic-S5 reference line. RESULTS: There were 248 patients included of which 171 were men and 77 women. The median displacement of the internal urethral orifice was 25 mm in men (maximum 65), and 17 mm in women (maximum 50). Rotation of the internal urethral orifice was in a caudal direction in 160/170 (94%) of men and 65/73 (89%) of women, with a median of 32 degrees (maximum 85) and 33 degrees (maximum 83), respectively. Displacements of the posterior bladder wall, distal end of prostatic urethra and cervix were significantly correlated with the internal urethral orifice. In linear regression analysis, biological mesh reconstruction of the pelvic floor and visceral interposition were significantly associated with increased displacement of the internal urethral orifice, and female gender and any filling of the presacral space with decreased displacement. CONCLUSIONS: Substantial absolute displacement and rotation of urogenital organs after APR for rectal cancer were observed, but with high variability among both men and women, and being significantly associated with reconstructive interventions.

CT assessment of the quality of omentoplasty and its implications for perineal wound healing.

PURPOSE: This study was designed to examine the impact of an omentoplasty and its quality on pelviperineal morbidity after abdominoperineal resection (APR) for rectal cancer. METHODS: This was a retrospective single-centre study of consecutive patients undergoing APR for primary or recurrent rectal cancer between 2000 and 2018. Quality of omentoplasty was categorised (sufficient vs insufficient) based on postoperative CT scans. Main study endpoints were perineal wound healing and perineal hernia. RESULTS: This study included 100 patients: 16 with a sufficient omentoplasty, 16 with an insufficient omentoplasty, and 68 without omentoplasty. Rate of pelviperineal complications within 30 days was 44%, 69% and 64% (P = 0.283), and delayed wound healing at 3 months was 19%, 54% and 27%, respectively (P = 0.109). Sufficient omentoplasty was not significantly associated with less delayed healing in multivariable analysis (OR 0.597; 95% CI 0.149-2.397). An insufficient omentoplasty demonstrated significantly higher rates of delayed healing at 6 months (46% vs 14%; P = 0.016) and chronic perineal sinus at 12 months (31% vs 3%; P = 0.008) compared with no omentoplasty. CONCLUSION: This relatively small series suggest that even a sufficient omentoplasty, as determined by postoperative imaging, does not reduce pelviperineal morbidity after APR for rectal cancer. The methodology of CT-based assessment of an omentoplasty as well as the correlation with postoperative outcomes has to be validated in future studies.

Spontaneous haemothorax from an extramedullary haematopoietic mass.

We report the presentation of a 43-year-old female with an unusual acute complication from an inherited blood dyscrasia. After a provisional working diagnosis of pulmonary embolus, the patient was finally diagnosed with spontaneous haemorrhage from extramedullary haematopoietic foci within the thorax.

Secondary spontaneous pneumothorax: a rare complication of pulmonary embolism.

An 85-year-old lady presented with a left middle cerebral artery territory infarct. Several days into her admission she became hypoxic and haemodynamically unstable. A CT pulmonary angiogram showed bilateral pulmonary emboli, right-sided parenchymal cavitation due to infarction and an associated large pneumothorax. She was treated successfully with an intercostal drain and anticoagulation. This case describes the rare phenomenon of secondary spontaneous pneumothorax due to pulmonary infarction from pulmonary embolism. The factors associated with the development of infarcts from pulmonary thromboemboli are poorly understood although a number of predisposing conditions and pathological features have been suggested. Pulmonary infarction occurs in around 10% of cases of pulmonary emboli but the complication of secondary spontaneous pneumothorax would appear to be much less common. One should consider pulmonary embolism as the cause of pneumothorax where there is significant clinical suspicion.

A case-control study of colorectal cancer detection by quantification of DNA isolated from directly collected exfoliated colonocytes.

This pilot study aimed to assess an original test based on the analysis of exfoliated colonocytes as a new approach to colorectal cancer (CRC) detection. DNA was isolated from exfoliated cells collected from the surface of the rectal mucosa by a standardized minimally invasive procedure in a case-control trial involving 66 patients with CRC diagnosis and 110 healthy volunteers (age 50-70). PicoGreen staining and quantitative real-time PCR (QRTPCR) were used for DNA quantification. Mean DNA scores in microg/ml obtained for the control and cancer groups were 2.1 (95% CI 1.7-2.5) and 9.0 (CI 6.7-11.2) respectively (p < 0.001) for PicoGreen and 0.8 (CI 0.6-0.9) and 3.8 (CI 1.9-5.7) respectively (p = 0.003) for QRTPCR. The PicoGreen assay better detected CRC presence. At DNA score cut-off point of 2.5 microg/ml this assay gave sensitivities of 77.8% (CI 52.4-93.6) for proximal tumours, 91.4% (CI 76.9-98.2) for distal CRC and 86.8% (CI 74.7-94.5) for all CRC with specificity at 74.0% (CI 64.0-82.4). Increasing the cut-off point to 5.0 microg/ml resulted in sensitivities of 38.9% (CI 17.3-64.3) for proximal tumours, 71.4% (CI 53.7-85.4) for distal CRC and 60.4% (CI 46.0-73.5) for all CRC. Specificity for this cut-off point increased to 94.8% (CI 88.3-98.3). The new procedure of exfoliated cell collection from the surface of the rectal mucosa is a simple, safe and well-tolerated technique providing high quality cells. These early results suggest that exfoliated cell collection in combination with DNA quantification can potentially be employed as a tool for CRC early detection.

The coronary sinus conduit function: anatomical study (relationship to adjacent structures).

BACKGROUND: The mitral valve annulus (MVA) is anchored antero-medially to the aorta. Dilatation of the MVA primarily affects its postero-lateral aspect, which is related to the coronary sinus (CS). The CS and its tributaries have been used for pacing the left ventricle in patients with intractable heart failure. The aim of this study was to determine anatomical relations between the CS and its adjacent structures in 40 adult normal cadaveric heart specimens. METHODS: In 32 specimens, longitudinal sections were made along the free circumference of the MVA in 6 separate regions, 36 degrees between each, with the 0 degree marked by a line joining the centre of the CS ostium and that of the MV. In each section, the relations of the CS to the circumflex artery and the MVA were determined. CS diameter and its distance from the endocardium, just below the MVA, were also measured by a digital calliper. RESULTS: The great cardiac vein (GCV) diameter is 5.6 +/- 1.6 mm. As it leaves the interventricular groove, it curves to the left forming the base of the triangle of "Brocq and Mouchet" with the two branches of the left coronary artery, having a triple relationship with the circumflex artery. It then continues as the CS (diameter 9.3 +/- 5.3 mm) in the inferior atrioventricular groove. The end part of the GCV crosses superficial to the left circumflex artery at the level of the left marginal vein. The shortest distance between the wall of the CS and the endocardium adjacent to the MVA at the level of the anterolateral commissure is 5.2 +/- 1.6 mm, i.e. beyond the Vieussens valve. Thus, together with the CS the great cardiac vein, form a semicircular venous channel at the postero-lateral aspect of the MVA. In 37/40 hearts, this venous channel arches upwards in its middle part to be in direct contact with the left atrium. CONCLUSION: This study demonstrates an intimate proximity between the coronary sinus, at its beginning and end, and the mitral valve annulus. It also highlights the close relationship between the great cardiac vein, the annulus and the left ventricular free wall. Assessing the same relationship using the currently available imaging techniques should aid in the successful cannulation of the coronary sinus for various cardiological interventions.

The osteo-odonto-keratoprosthesis (OOKP).

The osteo-odonto-keratoprosthesis (OOKP), although described over 40 years ago, remains the keratoprosthesis of choice for end-stage corneal blindness not amenable to penetrating keratoplasty. It is particularly resilient to a hostile environment such as the dry keratinized eye resulting from severe Stevens-Johnson syndrome, ocular cicatricial pemphigoid, trachoma, and chemical injury. Its rigid optical cylinder gives excellent image resolution and quality. The desirable properties of the theoretical ideal keratoprosthesis is described. The indications, contraindications, and patient assessment (eye, tooth, buccal mucosa, psychology) for OOKP surgery are described. The surgical and anaesthetic techniques are described. Follow-up is life-long in order to detect and treat complications, which include oral, oculoplastic, glaucoma, vitreo-retinal complications and extrusion of the device. Resorption of the osteo-odonto-lamina is responsible for extrusion, and this is more pronounced in tooth allografts. Regular imaging with spiral-CT or electron beam tomography can help detect bone and dentine loss. The optical cylinder design is discussed. Preliminary work towards the development of a synthetic OOKP analogue is described. Finally, we describe how to set up an OOKP national referral center.