The impact of rising NHS waiting list times on elective surgery for Dupuytren's disease.

Waiting lists for elective surgery are increasing in the United Kingdom. We report a single-centre experience of disease progression of Dupuytren's disease while on the waiting list for surgery and its effect on the type of operative treatment required.

Modified endoluminal ureteral stenting for the management of proximal ureteral obstruction in two cats.

Case series summary: Two cases of placement of modified endoluminal ureteral stents are described, for revision of a subcutaneous ureteral bypass (SUB) and for primary treatment of obstructive ureterolithiasis. Modified endoluminal stents were inserted through the ureterotomy, anchored in the renal pelvis with a single pigtail and shortened to a length sufficient to span the proximal ureter and ureterotomy site. Relevance and novel information: The advantages of this approach as a surgical option for feline obstructive ureterolithiasis are demonstrated, including the avoidance of disruption, or bypass, of the ureterovesicular junction, minimisation of implanted foreign material and avoidance of intravesicular stent mass, maintenance of the physiological route of urine flow, including preservation of active distal ureteral function, and limitation of the potential complications of ureterotomy. The clinical efficacy of this adaptation of the previously published endoluminal stenting technique is demonstrated with its applicability de novo and in the revision of other stenting procedures.

The incidence and cost implications of surgical site infection following lymph node surgery for skin malignancy.

BACKGROUND: Lymph node surgery is commonly performed in the staging and treatment of metastatic skin cancer. Previous studies have demonstrated sentinel lymph node biopsy (SLNB) and, particularly, lymph node dissection (LND) to be plagued by high rates of wound complications, including surgical site infection (SSI) and seroma formation. This study evaluated the incidence of wound complications following lymph node surgery and provided the first published cost estimate of SSI associated with lymph node surgery in the UK. PATIENTS AND METHODS: A retrospective cohort study of 169 patients with a histological diagnosis of primary skin malignancy who underwent SLNB or LND of the axilla and/or inguinal region at a single tertiary centre over a 2 year period was conducted. Demographic, patient risk factor, and operation characteristics data were collected and effect on SSI and seroma formation was analysed. Cost-per-infection was estimated using National Health Service (NHS) reference and antibiotic costs. RESULTS: A total of 146 patients underwent SLNB with a SSI rate of 4.1% and a seroma incidence of 12.3%. Twenty-three patients underwent LND with a SSI rate of 39.1% and a seroma incidence of 39.1%. Seroma formation was strongly associated with the development of SSI in both the SLNB (odds ratio (OR) = 18.0, p < 0.001) and LND (OR = 21.0, p = 0.007) group. The median additional cost of care events and treatment of SSI in the SLNB and LND groups was £199.46 and £5187.04, respectively. CONCLUSION: SSI remains a troublesome and costly event following SLNB and LND. Further research into perioperative care protocols and methods of reducing lymph node surgery morbidity is required and could result in significant cost savings to the NHS.

Electrochemotherapy vs radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases from primary solid organ malignancies: A systematic review and narrative synthesis.

BACKGROUND: Electrochemotherapy has gained international traction and commendation in national guidelines as an effective tool in the management of cutaneous malignancies not amenable to surgical resection. Despite this, no level 5 evidence exists comparing it to radiotherapy in the treatment of cutaneous malignancies. This systematic review aimed to examine the literature directly and indirectly comparing electrochemotherapy and radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases from primary solid organ malignancies. MATERIALS & METHODS: The protocol for this review was registered on the PROSPERO International Prospective Register of Systematic Reviews with the protocol ID CRD42021285415. Searches of MEDLINE, Embase, CINAHL, CENTRAL and ClinicalTrials.gov databases were undertaken from database inception to 28 December 2021. Studies in humans comparing treatment with electrochemotherapy to radiotherapy and reporting tumour response with a minimum four week follow-up were eligible. Risk of bias was assessed using the ROBINS-I tool. Results are provided as a narrative synthesis. RESULTS: Two case series with a total of 92 patients were identified as relevant to this study. Both case series examined patients with cutaneous squamous cell carcinoma. One case series examined elderly patients with predominantly head/neck lesions. The other examined younger patients with predominantly limb lesions who had cutaneous squamous cell carcinoma directly attributable to a rare skin condition. CONCLUSION: There is little literature presenting comparative data for electrochemotherapy and radiotherapy in the treatment of primary cutaneous malignancies or cutaneous metastases. Included studies were marred by serious risk of bias particularly due to confounding. The inherent bias and heterogeneity of the included studies precluded synthesis of a consolidated comparison of clinical outcomes between the two therapies. Further research is required in this domain in the form of clinical trials and observational studies to inform guidelines for electrochemotherapy treatment.

A vending machine for drug-like molecules - automated synthesis of virtual screening hits.

As a result of high false positive rates in virtual screening campaigns, prospective hits must be synthesised for validation. When done manually, this is a time consuming and laborious process. Large "on-demand" virtual libraries (>7 × 1012 members), suitable for preparation using capsule-based automated synthesis and commercial building blocks, were evaluated to determine their structural novelty. One sub-library, constructed from iSnAP capsules, aldehydes and amines, contains unique scaffolds with drug-like physicochemical properties. Virtual screening hits from this iSnAP library were prepared in an automated fashion for evaluation against Aedes aegypti and Phytophthora infestans. In comparison to manual workflows, this approach provided a 10-fold improvement in user efficiency. A streamlined method of relative stereochemical assignment was also devised to augment the rapid synthesis. User efficiency was further improved to 100-fold by downscaling and parallelising capsule-based chemistry on 96-well plates equipped with filter bases. This work demonstrates that automated synthesis consoles can enable the rapid and reliable preparation of attractive virtual screening hits from large virtual libraries.

Reagent-Based Scaffold Diversity for DNA-Encoded Library Design: Solid Phase Synthesis of DNA-Tagged sp3-Rich Heterocycles by SnAP Chemistry.

Reactions that require strictly dry conditions are challenging to translate to a DNA-encoded library format. Controlled pore glass solid support-connected DNA oligonucleotide-aldehyde conjugates could be condensed with SnAP reagents and cyclized to various sp3-rich heterocycles. The Boc-group of products provided a handle for product purification, and its facile removal under acidic conditions was tolerated by a chemically stabilized barcode. The reaction provides reagent-based scaffold diversity with functionalities for further library synthesis.

An integrated console for capsule-based, automated organic synthesis.

The current laboratory practices of organic synthesis are labor intensive, impose safety and environmental hazards, and hamper the implementation of artificial intelligence guided drug discovery. Using a combination of reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions with prepacked capsules. The machine conducts coupling reactions and delivers the purified products with minimal user involvement. Two desirable reaction classes - the synthesis of saturated N-heterocycles and reductive amination - were implemented, along with multi-step sequences that provide drug-like organic molecules in a fully automated manner. We envision that this system will serve as a console for developers to provide synthetic methods as integrated, user-friendly packages for conducting organic synthesis in a safe and convenient fashion.

Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome.

Programmed ribosomal frameshifting is a key event during translation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome that allows synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. Here, we present the cryo-electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal messenger RNA (mRNA) channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, we compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention.

Stereoretentive Etherification of an α-Aryl-ß-amino Alcohol Using a Selective Aziridinium Ring Opening for the Synthesis of AZD7594.

A selective aziridinium ring-opening was used to etherify an α-aryl-ß-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-ß-amino alcohol in this system. Process analytical techniques were used to establish reaction understanding, and mixing on large scale was modeled in silico. The process provided a selective and efficient method of preparing the nonsteroidal, inhaled selective glucocorticoid receptor modulator AZD7594.

Structural diversification of the aminobicyclo[4.3.0]nonane skeleton using alkynylsilyl-derived allylic trichloroacetimidates.

The amino substituted bicyclo[4.3.0]nonane is a molecular scaffold found in a wide range of natural products and medicinal agents. Despite this, synthetic methods for the general preparation of this structural motif are sparse. Here we evaluate a diastereoselective approach for the preparation of vinylsilyl derived aminobicyclo[4.3.0]nonanes using a one-pot multi-bond forming process involving a Pd(ii)-catalysed Overman rearrangement, a Ru(ii)-catalysed ring closing enyne metathesis reaction, followed by a hydrogen bonding directed Diels-Alder reaction. We show that a benzyldimethylsilyl-substituted alkene analogue is amenable to further functionalisation and the late stage generation of diverse sp3-rich, drug-like aminobicyclo[4.3.0]nonane scaffolds with up to six stereogenic centres.