Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms1-5. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers.

A 13.2 mg epinephrine intranasal spray demonstrates comparable pharmacokinetics, pharmacodynamics, and safety to a 0.3 mg epinephrine autoinjector.

Background: Recent acute anaphylaxis guideline updates have identified remaining unmet needs based on currently available therapeutic options as a critical focus. Objective: We compared the pharmacokinetic, pharmacodynamic, safety, and tolerability profiles of intranasal epinephrine with intramuscular epinephrine administered by autoinjector and manual syringe. Methods: An open-label, 3-period crossover study was conducted in 116 healthy adult volunteers to assess the bioavailability of a single 13.2 mg intranasal dose of epinephrine compared to a 0.3 mg intramuscular autoinjector and a 0.5 mg manual syringe. Patients with epinephrine concentrations of 50, 100, and 200 pg/mL at 10, 20, 30, and 60 minutes after dosing were also evaluated. Results: Pharmacokinetic parameters for the 13.2 mg intranasal dose exceeded those of the 0.3 mg autoinjector with a rapid and higher maximum observed concentration (intranasal, 429.4 pg/mL; autoinjector, 328.6 pg/mL) and greater systemic exposure (AUC0-360; intranasal, 39,060 pg∙min/mL; autoinjector, 17,440 pg∙min/mL). Similar results were observed compared to the 0.5 mg manual syringe. Pharmacokinetic parameters for opposite-nostril and same-nostril dosing were higher than both intramuscular doses, except time to reach maximum observed concentration, which was bracketed between the 2 intramuscular doses (intranasal opposite and same nostril, 20 minutes; autoinjector, 14.9 minutes; manual syringe, 45 minutes). Similar effects on blood pressure and heart rate were observed for intranasal and autoinjector administration. Intranasal epinephrine was safe and well tolerated. No serious or unexpected adverse events were reported, confirming results from earlier clinical studies. Conclusions: Bidose epinephrine spray addresses the unmet medical and patient needs for a needle-free, convenient, and effective dose-delivery system for self-administration of epinephrine that is as good as or better than the 0.3 mg autoinjector.

The transition from cranial surgery to neurosurgery in East London, 1760-1960.

The emergence of neurosurgery from the practice of cranial surgery between the eighteenth and the twentieth centuries in London, UK, is well documented, including the role of Sir Victor Horsley, the first neurosurgical appointee at the National Hospital Queen Square in 1886. The process of this transition elsewhere in London and the subsequent foundation of other neurosurgical units are less well described. In East London, the status of St. Bartholomew's Hospital (Barts) as the oldest London hospital still active on its original site and its comprehensive archives allow an unusually long history of surgical practice in the specialty to be studied. Using these archives and other primary and secondary sources, this article describes the transition of cranial surgery in East London from the general surgeons, limited to the treatment of brain and skull injury, to the specialized discipline of neurosurgery. We discuss the culmination of this process in the foundation of three neurosurgical units at London Hospital, Whitechapel, by Sir Hugh B. Cairns from 1927; at Barts Hospital, Smithfield, by John E. A. O'Connell from 1937; and at Oldchurch Hospital, Romford, by Leslie C. Oliver from 1945. Two modern neurosurgical units, in Whitechapel and Romford, have taken forward the work begun by this group.

Craniectomy with soft tissue reconstruction for locally advanced non-melanoma skin cancer of scalp with calvarial invasion: The Nottingham experience.

INTRODUCTION: Locally advanced non-melanoma skin cancer (NMSC) involving the periosteum or calvarium poses a clinical challenge for patients who are unfit for immunotherapy due to medical comorbidities and/or frailty. This case series aims to investigate outcomes for patients undergoing craniectomy and soft tissue reconstruction. METHOD: Patients who underwent craniectomy and soft tissue reconstruction for invasive NMSC with calvarium or periosteal invasion between 2016 and 2022 were included. Data, including demographics, operative details, and clinical outcomes, were gathered from Nottingham University Hospitals' digital health record and the histopathology electronic database. RESULT: Eight patients (average age: 78.4 years, 3 females 5 males) with significant comorbidities and varying degrees of periosteal or bone invasion fulfilled the inclusion criteria. Diagnoses included four squamous cell carcinomas, two basal cell carcinomas, and two pleomorphic dermal sarcomas. Five patients had a history of prior incomplete deep margin excision. The median sizes for soft tissue defect, tumor and bone defect size were 51.83 cm2, 34.63 cm2 and 42.25 cm2, respectively. Intraoperative complications included one dural tear. Four patients underwent local flap reconstruction and with split-thickness skin grafting, four patients underwent free flap reconstruction. Adjuvant radiotherapy was administered to three patients. Complications comprised partial graft loss in two and complete graft loss in one. There was partial flap loss in one case. One patient required subsequent parotidectomy due to regional progression before achieving disease control. All patients achieved lasting locoregional disease control (average follow-up 29.7 months). CONCLUSION: Craniectomy with soft tissue reconstruction proves to be a safe and effective treatment option in advanced NMSC of the scalp in patients unsuitable for immunotherapy due to frailty or medical co-morbidity.

The Use of the Suboccipital Transtentorial Approach to the Posterior Inferior Incisural Space.

Objective To describe our experience with the microsurgical technique of the suboccipital transtentorial (SOTT) approach in the removal of posterior fossa lesions located in the posterior incisural space. Method Between 2002 and 2020 we reviewed all patients who underwent microsurgical resection of lesions of the posterior incisural space at the Department of Neurosurgery, Essex Neuroscience Centre, London, England (eight patients, male to female 3:5, mean age: 51, range 35-69). We describe the preoperative symptoms, radiological findings, surgical techniques, histology and postoperative outcomes in this cohort of patients. Results Eight patients with tumours located in the posterior incisural space underwent surgery during the study period including four meningiomas (50%), two haemangioblastomas (25%), one metastasis (13%) and one giant prolactinoma (13%). Gross or near total resection was achieved in six patients (75%): the giant prolactinoma could not be radically removed and one of the meningiomas required a small fragment to be left in place to protect the Vein of Galen. No patient developed a visual field deficit due to occipital lobe retraction. One patient developed a temporary trochlear nerve palsy (13%). Five patients had mild disability (Glasgow Outcome Scale (GOS) = 5), and four had moderate disability (GOS = 4). Conclusion In our series, the SOTT approach provided excellent access for all cases of tumours in the posterior incisural space. The tumour's size and relationship to the deep venous system contributed to the choice of approach and in one patient who had previously undergone surgery via the supracerebellar route, the SOTT approach enabled the avoidance of gliotic scar tissue. Success is dependent on careful case selection, though from our series of 8 patients, we conclude that this approach allows safe access to the posterior incisural space, with acceptable outcomes with regard to postoperative disability and cranial nerve palsy. As such, the approach should be in the armamentarium of any neurosurgeon who regularly deals with posterior fossa pathology.

Hydrocephalus in patients with vestibular schwannoma.

BACKGROUND: Hydrocephalus (HC) is common in patients with vestibular schwannoma (VS). This can be managed with a cerebrospinal fluid (CSF) diversion procedure prior to VS resection or with VS resection, keeping CSF diversion in reserve unless required postoperatively. No clear consensus exists as to which approach is superior. This study identifies factors predictive of the development of HC, and analyses outcomes for those managed with primary CSF resection versus tumour resection. METHODS: Single-centre retrospective cohort study of 204 consecutive adult patients with a unilateral VS from May 2009 to June 2021. Data was collected on patient and tumour demographics, management, and outcome. RESULTS: 204 patients, with a mean age at presentation of 59.5 (21-83), with 50% female, and a mean follow-up of 7.5 years (1.8-13.9) were included. 119 were managed conservatively, 36 with stereotactic radiosurgery only, and 49 with surgery. 30 (15%) patients had radiological HC, of which 23 (77%) were obstructive, and 7 (23%) were communicating. Maximum intracranial tumour diameter and Koos grade were higher in patients with HC. Of the patients with HC the majority (20, 67%) were managed initially with CSF diversion, with 12 patients undergoing subsequent tumour resection, and three patients avoiding primary resection. Nine (30%) were managed with primary surgical resection, of whom three required subsequent CSF diversion. Complication rates and Modified Rankin Scale (MRS) were comparable or lower in the CSF diversion group (8%, MRS ≤2 = 83%), versus the primary resection group (67%, MRS ≤2 = 67%), and the primary surgical resection without HC group (25%, MRS ≤2 = 86%). CONCLUSIONS: CSF diversion prior to tumour resection is a safe and acceptable strategy compared to primary VS resection, with improved outcomes and reduced surgical complications. Randomized studies and national databases are needed to determine the long-term outcomes of patients treated with CSF diversion versus primary resection.

The management of symptomatic hyperostotic bilateral spheno-orbital meningiomas: patient series.

BACKGROUND: The occurrence of hyperostotic bilateral spheno-orbital meningiomas (BSOMs) is very rare. Patients present with bilateral symptoms and require bilateral treatment. This series describes 6 patients presenting to 2 UK neurosurgical units and includes a literature review. To the best of the authors' knowledge, this is the largest series documented. OBSERVATIONS: This is a retrospective review of patients with BSOMs presenting between 2006 and 2023. Six females, whose mean age was 43 (range: 36-64) years, presented with features of visual disturbance. Bilateral sphen-oorbital meningiomas were identified. All patients underwent bilateral staged resections. The patients had an initial improvement in their symptoms. Extensive genetic testing was performed in 4 patients, with no variants in the NF2, LZTR1, SMARCB1, SMARCE1, and SMARCA4 genes or other variants detected. The mean follow-up was 100.3 (range: 64-186) months. Sixty-seven percent of patients had good long-term visual acuity. The progression rate was 75% and was particularly aggressive in 1 patient. Four patients required radiation therapy, and 2 needed further surgery. LESSONS: Hyperostotic BSOMs are extensive, challenging tumors causing significant disability. They can recur, with significant patient impact. Multidisciplinary management and indefinite long-term follow-up are essential. The biology of these tumors remains unclear. As molecular testing expands, the understanding of BSOM oncogenesis and potential therapeutic targets is likely to improve.

Aberrant Arterial Anatomy at the Floor of the Third Ventricle: Video Case Report.

A 65-year-old woman presented with a 2-month progressive history of forgetfulness, headaches, and decline in mobility. Imaging showed a large, enhancing pineal region tumor with triventricular hydrocephalus. She underwent an endoscopic third ventriculostomy and biopsy after appropriate consent was gained. Video 1 demonstrates the endoscopic procedure during which 2 aberrant arteries were identified at the floor of the third ventricle. The endoscopic third ventriculostomy was performed between these 2 arteries with great care to preserve them. The patient improved postoperatively with resolution of the hydrocephalus. Histology showed a metastatic malignant melanoma. To the best of our knowledge, no similar anatomy has been shown in an endoscopic procedure. We speculate that these are perforating arteries from the posterior communicating artery (premamillary artery) or a branch from the first part of the posterior cerebral artery P1 (thalamoperforators). Other options include perforators from the ophthalmic segment of the internal carotid artery, the communicating segment of the internal carotid artery, the superior hypophyseal artery, or a branch of the medial posterior choroidal arteries. We look at each in turn.

The NIDA Avenir award in genetics or epigenetics of substance use disorders.

NIDA's Avenir Program in the Genetics or Epigenetics of Substance Use Disorders (SUDs) was launched to support early stage investigators who propose innovative, high risk, but potentially high impact research and who show promise of being tomorrow's leaders in this scientific field. Since 2015, NIDA has supported 30 Avenir Investigators with unique expertise and creative ideas. This special issue showcases how some of these ideas have germinated, flourished, and borne fruit. In this perspective article we briefly describe the purpose and implementation of the Avenir award and provide a high altitude overview of the awardees and their scientific projects to date.

Advancing Biomarkers for Treatment of Smoking and Nicotine Dependence: An Overview.

The special issue on Biomarkers of Nicotine and Tobacco Dependence reviews the science for precision treatment of nicotine dependence and future opportunities for research on biomarkers for inclusion in tobacco product cessation and switching clinical trials to advance translation. This overview summarizes the articles contributed to the special issue by leading researcher in field of addiction.

Granular cell tumour of the cavernous sinus: A rare cause of secondary trigeminal neuralgia.

BACKGROUND: Cavernous sinus tumours comprise 0.1-0.2% of all intracranial tumours, and are most commonly meningiomas or schwannomas. Central nervous system and cranial nerve granular cell tumours (GCTs) are extremely rare. We report the tenth case of a GCT arising from a cranial nerve, and the second case reported in a cavernous sinus location, and review the literature. CLINICAL PRESENTATION: A 67-year-old man presented with right sided trigeminal neuralgia. Imaging findings suggested a trigeminal schwannoma and he was treated with CyberKnife radiosurgery. Over a period of 41 months follow up, there was a progression in both symptoms and imaging findings, requiring debulking surgery. Histopathology identified a GCT. CONCLUSIONS: This is the first case of a cranial nerve GCT treated with stereotactic radiosurgery. Trigeminal nerve GCTs are a rare differential in cases of presumed schwannomas.

IL-4/IL-13-producing ILC2s are required for timely control of intestinal helminth infection in mice.

Infection of mice with Nippostrongylus brasiliensis (Nb) serves as a model for human hookworm infection affecting about 600 million people world-wide. Expulsion of Nb from the intestine requires IL-13-mediated mucus secretion from goblet cells and activation of smooth muscles cells. Type 2 innate lymphoid cells (ILC2s) are a major cellular source of IL-13 but it remains unclear whether IL-13 secretion from ILC2s is required for Nb expulsion. Here, we compared the immune response to Nb infection in mixed bone marrow chimeras with wild-type or IL-4/IL-13-deficient ILC2s. ILC2-derived IL-4/IL-13 was required for recruitment of eosinophils to the lung but had no influence of systemic eosinophil levels. In the small intestine, goblet cell hyperplasia and tuft cell accumulation was largely dependent on IL-4/IL-13 secretion from ILC2s. This further translated to higher eggs counts and impaired worm expulsion in mice with IL-4/IL-13-deficient ILC2s. Overall, we demonstrate that ILC2s constitute a non-redundant source of IL-4/IL-13 required for protective immunity against primary Nb infection.

Potential Surgical Implications of Internal Jugular Stenosis in a Craniocervical Junction Meningioma.

We report a case of a 61-year-old lady presenting with several weeks of progressive left-sided weakness, and found to have a foramen magnum meningioma. She was counselled on surgical resection of the tumour, and a preoperative computed tomography angiogram (CTA) was obtained for operative planning purposes. CTA demonstrated incidental bilateral internal jugular vein (IJV) stenosis, with enlarged extracranial collateral vessels and elongated styloid processes. The main surgical concern was potential injury of the extracranial collateral vessels during operative exposure, which may compromise her intracranial venous outflow in light of the IJV stenosis. A doppler ultrasound scan of the IJVs was performed, which demonstrated that blood flow was still present through both vessels. Through careful soft tissue dissection during surgery, potential complications and injury to the extracranial collaterals were avoided. We performed a literature review of the incidence of IJV stenosis, its associated conditions, and potential surgical implications. Complications from injury to vital collateral extracranial vessels should be considered during preoperative planning in patients with anatomical variants or risk factors for IJV stenosis, as seen in this case.

Pharmacy-led initiative for improving peri-operative medication reconciliation among bariatric surgical patients: what is the role?

BACKGROUND: Multiple medication changes are common after bariatric surgery, but pharmacist assistance in this setting is not well described. This study evaluated the feasibility and effectiveness of a pharmacy-led initiative for facilitating discharge medicine reconciliation after bariatric surgery. METHODS: A standardized post-operative pharmacy consult evaluation was conducted on bariatric surgery inpatients at a single academic center starting 1/2/2019. Retrospective chart review evaluated patient characteristics, medication changes, and 30-day outcomes pre-intervention (7/2018-12/2018) and post-intervention (1/2019-12/2019). Two-sample t tests or binomial tests were used for continuous or categorical variables, respectively; a p-value of < 0.05 was deemed statistically significant. RESULTS: A total of 353 patients were identified for study inclusion (n = 158 pre-intervention, n = 195 post-intervention) with a mean age of 45 years, 87% female, and 71% sleeve gastrectomy. Overall pharmacy consultation compliance was 94% with 77.0% of home medication recommendations followed. Non-narcotic pain medication prescription use significantly increased (39% pre- vs. 54% post-intervention; p < 0.001). At discharge, the average number of changed or new medications significantly increased (3.7 ± 1.2 pre- vs. 4.2 ± 1.8 post-intervention; p = 0.003) while the average number of stopped medications was similar (1.2 ± 1.5 pre- vs. 1.5 ± 1.9 post-intervention; p = 0.09). Anti-hypertensive medications were decreased or stopped substantially more often with pharmacist input (44.7% pre- vs. 85.4% post-intervention; p < 0.001). Three medication-related readmissions happened pre-intervention with none post-intervention. Outpatient medication-related phone calls did considerably increase (31% pre- vs. 39% post-intervention; p = 0.04), while overall 30-day readmissions significantly decreased (7.6% pre- vs. 1.5% post-intervention; p = 0.04). CONCLUSIONS: Inpatient pharmacy consultation facilitated rapid alteration to more appropriate therapy for hypertension management and significantly increased use of non-narcotic pain medications upon discharge among bariatric surgery patients. Improved protocol adherence is anticipated with program maturity and patient education interventions will be deployed to address outpatient phone calls.

Differences between Primary and Revision Rhinoplasty: Indications, Techniques, Grafts, and Outcomes.

BACKGROUND: The nose is at the center of the face and has essential functional and aesthetic properties. Over recent years, rhinoplasty has gained increasing popularity through the influence of "selfies" and social media. As a result, a growing demand for secondary correction has also emerged. Revision rhinoplasty is more complex than primary cases and often requires the use of extranasal grafting material. The authors sought to analyze the indications, techniques, and outcomes after primary and revision rhinoplasty. METHODS: A total of 245 patients (153 primary cases and 92 revisions) undergoing surgery at the authors' specialized clinic for facial plastic surgery were included. All patients were treated by an experienced facial plastic surgeon according to the authors' established clinic standards. A retrospective data analysis was performed to evaluate the differences between the groups regarding the indications, intraoperative techniques, and postoperative outcomes. RESULTS: Although more patients sought revision surgery for aesthetic reasons alone than isolated functional issues, almost two-thirds of the revision patients had functional and aesthetic problems in combination. Complex reconstructive techniques, extracorporeal septoplasties, and extranasal grafts were more commonly used in revision cases. The occurrence of another revision during the follow-up period was significantly higher after revision surgery compared to primary rhinoplasty cases (primary rhinoplasty, 10.5 percent; revision surgery, 23.9 percent; p = 0.006). CONCLUSIONS: There are differences between primary and revision rhinoplasty that must be appreciated by the treating surgeon. The patient should be informed about the increased complexity of the secondary procedure, the possible need for extranasal grafts, and the increased risk of a further revision. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Metabolomics reveals biomarkers of opioid use disorder.

Opioid use disorder (OUD) is diagnosed using the qualitative criteria defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Diagnostic biomarkers for OUD do not currently exist. Our study focused on developing objective biological markers to differentiate chronic opiate users with OUD from chronic opiate users without OUD. Using biospecimens from the Golestan Cohort Study, we compared the metabolomics profiles of high opium users who were diagnosed as OUD positive with high opium users who were diagnosed as OUD negative. High opium use was defined as maximum weekly opium usage greater than or equal to the median usage (2.4 g per week), and OUD was defined as having 2 or more DSM-5 criteria in any 12-month period. Among the 218 high opium users in this study, 80 were diagnosed as OUD negative, while 138 were diagnosed as OUD positive. Seven hundred and twelve peaks differentiated high opium users diagnosed as OUD positive from high opium users diagnosed as OUD negative. Stepwise logistic regression modeling of subject characteristics data together with the 712 differentiating peaks revealed a signature that is 95% predictive of an OUD positive diagnosis, a significant (p < 0.0001) improvement over a 63% accurate prediction based on subject characteristic data for these samples. These results suggest that a metabolic profile can be used to predict an OUD positive diagnosis.