Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening.

The emergence of several zoonotic viruses in the last twenty years, especially the pandemic outbreak of SARS-CoV-2, has exposed a dearth of antiviral drug therapies for viruses with pandemic potential. Developing a diverse drug portfolio will be critical to rapidly respond to novel coronaviruses (CoVs) and other viruses with pandemic potential. Here we focus on the SARS-CoV-2 conserved macrodomain (Mac1), a small domain of non-structural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that cleaves mono-ADP-ribose (MAR) from target proteins, protects the virus from the anti-viral effects of host ADP-ribosyltransferases, and is critical for the replication and pathogenesis of CoVs. In this study, a luminescent-based high-throughput assay was used to screen ∼38,000 small molecules for those that could inhibit Mac1-ADP-ribose binding. We identified 5 compounds amongst 3 chemotypes that inhibit SARS-CoV-2 Mac1-ADP-ribose binding in multiple assays with IC50 values less than 100 µM, inhibit ADP-ribosylhydrolase activity, and have evidence of direct Mac1 binding. These chemotypes are strong candidates for further derivatization into highly effective Mac1 inhibitors.

Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening.

The emergence of several zoonotic viruses in the last twenty years, especially the pandemic outbreak of SARS-CoV-2, has exposed a dearth of antiviral drug therapies for viruses with pandemic potential. Developing a diverse drug portfolio will be critical for our ability to rapidly respond to novel coronaviruses (CoVs) and other viruses with pandemic potential. Here we focus on the SARS-CoV-2 conserved macrodomain (Mac1), a small domain of non-structural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that cleaves mono-ADP-ribose (MAR) from target proteins, protects the virus from the anti-viral effects of host ADP-ribosyltransferases, and is critical for the replication and pathogenesis of CoVs. In this study, a luminescent-based high-throughput assay was used to screen ∼38,000 small molecules for those that could inhibit Mac1-ADP-ribose binding. We identified 5 compounds amongst 3 chemotypes that inhibit SARS-CoV-2 Mac1-ADP-ribose binding in multiple assays with IC 50 values less than 100 µ M, inhibit ADP-ribosylhydrolase activity, and have evidence of direct Mac1 binding. These chemotypes are strong candidates for further derivatization into highly effective Mac1 inhibitors.

The PINS Trial: a prospective randomized clinical trial comparing a traditional versus an emollient skincare regimen for the care of pin-sites in patients with circular frames.

AIMS: Pin-site infection remains a significant problem for patients treated by external fixation. A randomized trial was undertaken to compare the weekly use of alcoholic chlorhexidine (CHX) for pin-site care with an emollient skin preparation in patients with a tibial fracture treated with a circular frame. METHODS: Patients were randomized to use either 0.5% CHX or Dermol (DML) 500 emollient pin-site care. A skin biopsy was taken from the tibia during surgery to measure the dermal and epidermal thickness and capillary, macrophage, and T-cell counts per high-powered field. The pH and hydration of the skin were measured preoperatively, at follow-up, and if pin-site infection occurred. Pin-site infection was defined using a validated clinical system. RESULTS: Out of 116 patients who were enrolled in the study, 23 patients (40%) in the CHX group and 26 (44%) in the DML group had at least one bad or ugly pin-site infection. This difference was not statistically significant (p = 0.71). There was no significant relationship between pH or hydration of the skin and pin-site infection. The epidermal thickness was found to be significantly greater in patients who had a pin-site infection compared with those who did not (p = 0.01). Skin irritation requiring a change of treatment occurred in four patients (7%) using CHX, and none using DML. CONCLUSION: We found no significant difference in the incidence of pin-site infection between the CHX and DML treatment groups. Dermol appeared to offer a small but significant advantage in terms of tolerability. We did not find a significant association between patient or treatment related factors and pin-site infection. It is therefore difficult to make specific recommendations based upon these results. The use of either cleaning agent appears to be appropriate. Cite this article: Bone Joint J 2021;103-B(2):279-285.

Dutiful daughters: HIV/AIDS, moral pragmatics, female citizenship and structural violence among Devadasis in northern Karnataka, India.

Decades of research have documented how sex workers worldwide, particularly female sex workers (FSWs), shoulder a disproportionate burden of the HIV epidemic. In India, although a substantial progress has been made in controlling the epidemic, its prevalence among FSWs and the Devadasis (also called traditional sex workers) in northern Karnataka is still significantly high. On the other hand, much of the HIV prevention research has focused on their mapping and size estimation, typologies, bio-behavioural surveillance, condom use and other prevention technologies. In this article, drawing on critical theoretical perspectives, secondary historical sources and in-depth interviews, we unravel wider social, cultural and political economic complexities surrounding the lives of Devadasis, and specifically illuminate the moral pragmatics that shed light on their entry into sex trade and vulnerability to HIV. Findings from this research are extremely important since while much is known about Devadasis in social sciences and humanities, relatively little is known about the complexities of their lives within public health discourses related to HIV. Our work has direct implications for ongoing HIV prevention and health promotion efforts in the region and beyond.

Soft tissue sarcoma - A review of presentation, management and outcomes in 110 patients.

UNLABELLED: Soft tissue sarcomas are a rare group of mesenchymal tumours the treatment of which poses oncological and reconstructive challenges. Limb-salvage surgery aims to balance adequate excision margins for disease control and preservation of important structures to retain function. Reported here is the review of the Hull Plastic surgery sarcoma service over a twelve year period. METHOD: We performed a review of the Hull sarcoma database over a twelve year period between 1997 and 2009. Demographic data, tumour grade, operative details complications and outcomes were recorded. RESULTS: The database contained a total of 435 patients with a diagnosis of sarcoma. 110 were treated at the Plastic Surgery department over a period of 12 years between 1997 and 2009. The patients treated in our department consisted of 67 males and 43 females (median age 70 years). The most common histological type was leiomyosarcoma (n = 23). Distribution of anatomical sites affected were head and neck (n = 15), upper limb (n = 17), lower limb (n = 56), trunk (n = 22). Large tumours (greater than 8 cm) n = 30, deep tumours n = 48, and high grade (Trojani 3) n = 33. Patients were treated with surgical excision and postoperative radiotherapy in the high grade groups (2 and 3). A range of reconstructive procedures were required from skin grafting, functional muscle transfer and free flap reconstruction. Nine patients developed regional recurrence, six patients had grade 3 tumours. Three were not resectable. Fourteen patients developed distant metastases, seven had grade 3 tumours, six underwent chemotherapy, two were treated palliatively. There were twenty deaths in this group, of which sixteen were sarcoma related. Deaths in the high risk groups was seven (high grade), nine (deep tumours) and eight (tumour size >8 cm). There were six survivors from eleven in the group with all three of these risk factors. CONCLUSION: This study summarises the management of sarcoma form one unit over a twelve year period and lends further evidence to the fact that the principles of limb-salvage surgery are applicable to a wide range of tumour-types and grades, to all patient age groups and anatomical sites with good functional results and that local and free flap reconstruction provides wound cover robust enough to withstand courses of radiotherapy. Early recurrence of high-grade disease and the development of metastasis carry a worse prognosis, especially if adjuvant therapy cannot be given. LEVEL OF EVIDENCE: 4.

Osteonecrosis of the jaw after a single bisphosphonate infusion in a patient with metastatic renal cancer treated with sunitinib.

BACKGROUND: Osteonecrosis of the jaw (ONJ) is recognised as an important adverse effect of intravenous bisphosphonates. Recent reports have suggested that antiangiogenic agents may promote the development of this condition. CASE REPORT: We report a case of ONJ occurring within days after the first infusion of zoledronic acid in a patient being treated with sunitinib for metastatic renal cancer. No dental procedure contributed to the occurrence of ONJ. The patient had previously experienced oral mucositis caused by sunitinib. ONJ improved with conventional oral hygiene measures, zoledronic acid discontinuation, and hyperbaric oxygen treatment. CONCLUSIONS: Sunitinib-induced mucosal injury and inhibition of angiogenic signalling pathways, also involved in bone repair and remodelling, may have precipitated the phenomenon. A possible synergistic effect may need to be increasingly addressed in the clinical setting since the concomitant use of sunitinib with bisphosphonates is becoming common.

Bilateral renal hemorrhage due to polyarteritis nodosa wrongly attributed to blunt trauma.

BACKGROUND: A 36-year-old, previously healthy man presented to an accident and emergency department with right-sided abdominal pain 7 days after he sustained a trauma to his right flank. He was using no medication other than over-the-counter analgesics since his injury. INVESTIGATIONS: Complete blood count, serum creatinine measurement, liver function tests, hepatitis B and C screening, abdominal CT, renal angiography, surgical exploration and histology of kidney samples. DIAGNOSIS: Polyarteritis nodosa with Page kidney causing bilateral perirenal hematoma, severe hypertension and renal failure. MANAGEMENT: The patient was severely anemic, and his bleeding was investigated. A 15 x 13 x 12 cm retroperitoneal hematoma was found in the region of the right kidney and the patient underwent unilateral right nephrectomy. 3 weeks after discharge the patient was readmitted with a left-sided perirenal hematoma. Steel-coil embolization of the kidney stopped the bleeding but the patient developed hypertension and renal failure, and antihypertensive agents and dialysis were started. Microaneurysms and vessel-wall necrosis were discovered on re-examination of the angiogram and histology, respectively, so immunosuppressive therapy was started, comprising intravenous methylprednisolone daily for 3 days and oral prednisolone and intravenous cyclophosphamide for 4 weeks. Page kidney, resulting from the bleeding into the solitary kidney, caused stretching of the renal artery and deterioration of renal function, which required hemodialysis treatment.