A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex.

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.

Managing Acute Ankle and Hindfoot Fracture in Diabetic Patients.

The management of ankle fractures in the diabetic population requires special attention as the risks of injury or treatment-related complications are high. Thorough review of clinical history and detailed assessment provide the treating surgeons with key information to guide treatment pathway. Vigilance is required when opting for nonoperative treatment in undisplaced stable ankle fractures in patients with peripheral neuropathy. The presence of critical ischemia in injured limb demands vascular consultation and ultimately, an intervention before surgical fixation of ankle fracture. An extended period of immobilization is one of the key principles in the management of ankle fracture patients with diabetes.

A Pan-respiratory Antiviral Chemotype Targeting a Transient Host Multiprotein Complex.

We present a small molecule chemotype, identified by an orthogonal drug screen, exhibiting nanomolar activity against members of all the six viral families causing most human respiratory viral disease, with a demonstrated barrier to resistance development. Antiviral activity is shown in mammalian cells, including human primary bronchial epithelial cells cultured to an air-liquid interface and infected with SARS-CoV-2. In animals, efficacy of early compounds in the lead series is shown by survival (for a coronavirus) and viral load (for a paramyxovirus). The drug target is shown to include a subset of the protein 14-3-3 within a transient host multi-protein complex containing components implicated in viral lifecycles and in innate immunity. This multi-protein complex is modified upon viral infection and largely restored by drug treatment. Our findings suggest a new clinical therapeutic strategy for early treatment upon upper respiratory viral infection to prevent progression to lower respiratory tract or systemic disease. One Sentence Summary: A host-targeted drug to treat all respiratory viruses without viral resistance development.

Medium-term outcomes of multi-disciplinary surgical management of non-ischemic diabetic heel ulcers.

BACKGROUND: Heel ulcers in patients with peripheral neuropathy and diabetes pose a significant challenge to treating physicians. Infection spreading to the os calcis is associated with a poor prognosis. There is no consensus on which method of surgical treatments results in better outcomes. The aim of this study was to assess patients' survival, rate of ulcer healing following surgical treatment, along with limb salvage rate, time taken for healing, ulcer recurrence and patients' functional outcome after healing. METHODS: We studied 29 patients (20 men, 9 women) presenting with diabetic neuropathic heel ulcers (30 feet) and no critical limb ischemia, were managed surgically in our unit and followed-up for a minimum of 12 months. We assessed their clinical and functional outcomes within a mean follow-up period of 28 months (12-83). RESULTS: 11 out of 29 patients died (38%) with mean duration of post op survival being 31months (range 4-70). 14 ulcers (50%) healed fully within a mean of 360 days (131-1676). Limb salvage was achieved in 29 feet (97%). Only 5 out of 17 patients with diabetic nephropathy (p value 0.016) and 9 out of 24 ulcers with calcaneal osteomyelitis (p value 0.044) achieved full ulcer healing. Ulcer recurrence rate was 36% (5/14) within 12 months of achieving ulcer healing. Six patients were able to return to independent walking in surgical shoes while 11 patients were mobilising using either a crutch or frame. CONCLUSION: While excellent limb salvage can be anticipated from the outcome of surgically managed infected heel ulcers in patients with diabetes, complete healing can still be slow and unpredictable. Significant medical co-morbidities in these patients make them vulnerable to medium-term post-operative complication and survival.

The radiological diagnosis of extra-articular posteromedial talocalcaneal coalition.

OBJECTIVES: Extra-articular posteromedial talocalcaneal coalition (EA-PM TCC) accounts for approximately one-third of TCC, but its radiographic features are not well-described. The current study aims to compare the radiographic features of EA-PM TCC with normal ankles and with the commoner forms of TCC. MATERIALS AND METHODS: A retrospective review of cases of TCC over 12 years for whom radiographs, CT, and/or MRI study were available. Radiographs were assessed by 2 radiologists for the presence of the C-sign, talar beak, dysmorphic sustentaculum, absent middle facet, and prominence of the posterior subtalar joint. TCC was classified by a third radiologist based on CT/MRI findings into 3 groups: no TCC, EA-PM TCC, and other TCCs. The radiographic findings for the 3 groups were compared. RESULTS: The study included 50 patients, 28 males and 22 females with a mean age of 21.1 years (range 8-70 years). In 15 patients, both ankles had been imaged, resulting in a total of 65 cases. In 17 ankles, no TCC was identified, while 15 ankles were classified as EA-PM TCC and 33 as having other types of TCC. There were no statistically significant differentiating radiological features between the groups with no TCC and EA-PM TCC apart from prominence of the posterior subtalar joint, while only the C-sign allowed identification of patients with other types of TCC. CONCLUSIONS: The study suggests that EA-PM TCC cannot be diagnosed based on the classical indirect radiological signs of TCC, but can be identified by prominence of the posterior subtalar joint.