Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator.

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

A National Cancer Grid pooled procurement initiative, India.

In health systems with little public funding and decentralized procurement processes, the pricing and quality of anti-cancer medicines directly affects access to effective anti-cancer therapy. Factors such as differential pricing, volume-dependent negotiation and reliance on low-priced generics without any evaluation of their quality can lead to supply and demand lags, high out-of-pocket expenditures for patients and poor treatment outcomes. While pooled procurement of medicines can help address some of these challenges, monitoring of the procurement process requires considerable administrative investment. Group negotiation to fix prices, issuing of uniform contracts with standardized terms and conditions, and procurement by individual hospitals also reduce costs and improve quality without significant investment. The National Cancer Grid, a network of more than 250 cancer centres in India, piloted pooled procurement to improve negotiability of high-value oncology and supportive care medicines. A total of 40 drugs were included in this pilot. The pooled demand for the drugs from 23 centres was equivalent to 15.6 billion Indian rupees (197 million United States dollars (US$)) based on maximum retail prices. The process included technical and financial evaluation followed by contracts between individual centres and the selected vendors. Savings of 13.2 billion Indian Rupees (US$ 166.7million) were made compared to the maximum retail prices. The savings ranged from 23% to 99% (median: 82%) and were more with generics than innovator and newly patented medicines. This study reveals the advantages of group negotiation in pooled procurement for high-value medicines, an approach that can be applied to other health systems.

Lorsque les systèmes de santé reçoivent peu de fonds publics et que leurs processus d'achat sont décentralisés, le prix et la qualité des médicaments contre le cancer ont un impact direct sur l'accès aux traitements efficaces contre la maladie. Des facteurs tels que l'application de prix différenciés, les négociations en fonction des volumes ainsi que la confiance placée dans des génériques bon marché dont la qualité n'a pas été évaluée peuvent entraîner des décalages entre l'offre et la demande, d'énormes dépenses non remboursables pour les patients et de piètres résultats thérapeutiques. Bien que les acquisitions groupées de médicaments puissent contribuer à résoudre certains de ces problèmes, le suivi du processus d'achat requiert un engagement considérable au niveau administratif. Les négociations collectives en vue de fixer les tarifs, l'établissement de contrats types assortis de conditions générales standardisées, mais aussi les achats effectués par des hôpitaux en particulier peuvent également faire baisser les coûts et améliorer la qualité sans nécessiter d'importants investissements. Le National Cancer Grid, un réseau réunissant plus de 250 centres d'oncologie en Inde, a testé un dispositif d'achat groupé visant à assurer une meilleure négociabilité pour des médicaments et soins de soutien essentiels contre le cancer. Au total, 40 substances ont été prises en compte dans ce projet pilote. La demande groupée en médicaments émise par 23 centres équivalait à 15,6 milliards de roupies indiennes (197 millions de dollars américains) d'après le prix maximal de vente au détail. Ce processus prévoyait une évaluation technique et financière, puis des contrats entre chaque centre et les distributeurs sélectionnés. Des économies de 13,2 milliards de roupies indiennes (166,7 millions de dollars américains) ont pu être réalisées par rapport au prix maximal de vente au détail. Ces économies étaient comprises entre 23 et 99% (médiane: 82%) et concernaient davantage les médicaments génériques que les marques et les médicaments récemment brevetés. La présente étude révèle les avantages que représentent les négociations collectives lors des achats groupés de médicaments essentiels, une approche applicable à d'autres systèmes de santé.

En los sistemas sanitarios con escasa financiación pública y procesos de adquisición descentralizados, el sistema de fijación de precios y la calidad de los medicamentos contra el cáncer afectan directamente al acceso a una terapia eficaz contra dicha enfermedad. Factores como los diferentes sistemas de determinación de precios, la negociación en función del volumen y la dependencia de genéricos de bajo precio sin evaluación de su calidad pueden generar retrasos en la oferta y la demanda, elevados gastos para los pacientes y malos resultados en el tratamiento. Aunque la adquisición conjunta de medicamentos puede ayudar a abordar algunos de estos retos, el seguimiento del proceso de adquisición requiere una inversión administrativa considerable. La negociación colectiva a la hora de determinar los precios, la emisión de contratos unificados con términos y condiciones estandarizados y la adquisición por parte de algunos hospitales también reducen los costes y mejoran la calidad sin necesidad de realizar una gran inversión. La Red Nacional de Cáncer, una red que cuenta con más de 250 centros oncológicos en la India, puso a prueba la adquisición conjunta con el fin de mejorar la negociabilidad de medicamentos oncológicos y de tratamiento complementario que resultaban costosos. En esta prueba piloto se incluyó un total de 40 medicamentos. La demanda conjunta de medicamentos por parte de 23 centros fue equivalente a 15 600 millones de rupias indias (197 millones USD) según los precios minoristas máximos. El proceso incluyó una evaluación técnica y financiera, así como contratos entre centros independientes y proveedores seleccionados. Se logró un ahorro de 13 200 millones de rupias indias (166,7 millones USD) en comparación con los precios minoristas máximos. El ahorro osciló entre el 23 y el 99% (media: 82%) y fue más alto con los medicamentos genéricos que con los de marca y los recién patentados. Este estudio pone de manifiesto las ventajas de la negociación colectiva en lo que respecta a la adquisición conjunta de medicamentos costosos, un enfoque que se puede aplicar a otros sistemas sanitarios.

Demographics and management of paediatric dental-facial trauma in the 'lockdown' period: A UK perspective.

BACKGROUND: The United Kingdom entered 'lockdown' on the 23 March 2020 due to the COVID-19 pandemic. This resulted in school closures forcing children to remain at home. Dental-facial trauma was still likely to be common place due to falls and injuries exercising. The aim of this study was to explore the impact of the COVID-19 pandemic on clinical practice in a paediatric population in a tertiary care hospital and a linked Dental Institute. METHOD: A proforma was designed to capture the demographics, presenting complaints, type of dental-facial injury, treatment need and the treatment received for all paediatric patients presenting face to face with dental-facial trauma to King's College Hospital during the 'lockdown' period (23 March- 14 June 2020). RESULTS: Four hundred and twenty calls were triaged, converting to 102 patients seen face-to-face for dental-facial trauma. The remainder were able to be triaged 'virtually'. Injuries seen included 56 (54.9%) dentoalveolar injuries, 37 (36.2%) lacerations, five (4.9%) suspected facial fractures and four (3.9%) dog bites. Males and females were equally affected. The majority of incidents occurred in the home environment (n = 60, 58.8%), with the remainder (n = 42, 41.2%) occurring outside the home environment. The main causes of dental-facial trauma were falls (n = 47, 46.1%) and bicycles/scooters (n = 29, 28.4%). The most common type of dentoalveolar injury was lateral luxation (n = 15, 26.7%), followed by avulsion (n = 12, 21.4%). Only one child required treatment under general anaesthesia (GA). CONCLUSION: The demographic, presenting complaints and treatment needs of patients who presented during the lockdown period with dental-facial trauma were unusual. The overwhelming majority were able to be treated without the use of GA. The attendance protocol in a tertiary care setting and the use of 'teledentistry' ensured only the most severe trauma cases were seen. This highlights how more complex trauma can still occur during 'lockdown' and requires immediate management.

Paediatric dental pain and infection during the COVID period.

BACKGROUND: During the coronavirus pandemic, paediatric patients will still likely present with dental pain and infection. In order to streamline care at King's College Hospital (KCH), Paediatric Dentistry and Oral and Maxillofacial Surgery (OMFS) have developed a collaborative working approach allowing patients to be treated effectively and to streamline patient care in the absence of easy access to general anaesthetic facilities. METHOD: Presenting complaints, treatment need and the treatment received were recorded for all paediatric patients presenting with dental pain and infection in the "lockdown" period (23rd March- 14th June) during "normal" working hours and "out of hours" to either paediatric dentistry or OMFS. RESULTS: 420 calls were triaged which converted to 67 patients seen face-to-face for oro-facial pain and infection. 41% of children were treated successfully under Local anaesthetic alone, only 13% required a general anaesthetic (GA) in the "lockdown" period. The vast majority of patients had antibiotics prescribed prior to attendance (80%). CONCLUSION: We have demonstrated the demographic, presenting complaints and treatment need of patients who presented to KCH during the lockdown period with dental pain and infection. The majority were able to be treated without needing for GA facilities. This paper highlights how a collaborative approach between paediatric dentistry and OMFS can help streamline patient care and is a model which can be adopted by other units in the event of further "lockdowns".

COVID-19 pandemic: the first wave - an audit and guidance for paediatric dentistry.

With the use of newly issued guidelines, King's College Hospital has developed new standard operating procedures specifically for the COVID-19 pandemic. Given the unprecedented nature of the current global pandemic, this paper highlights how paediatric dental emergencies can be managed safely and efficiently, as well as new measures which can help reduce transmission of the virus. Furthermore, an audit of the current paediatric dental emergencies attending the hospital is presented. Seventy-six percent of patients attending met the agreed local criteria for urgent treatment, with the most common presentation being irreversible pulpitis. This highlights the types of cases that practitioners enrolled in urgent dental care centres (UDCs) can expect to encounter and how to effectively manage this challenging group of patients.

Post-operative pain and morbidity in children who have tooth extractions under general anaesthesia: a service evaluation.

Introduction Children find dental extractions under general anaesthesia (GA) painful despite national analgesic guidelines.Aims To report on children's post-operative pain, morbidity, families' satisfaction and analgesic regime during GA dental extractions.Design A prospective service evaluation.Setting King's College Hospital, London.Methods Children (n = 143) self-reported pain using the Faces Pain Scale-Revised (FPS-R) pre- and post-operatively and one week later by telephone as reported by the child's parent/carer. Morbidity was assessed using the Morbidity Checklist & Post Hospital Behaviour Questionnaire and each family's satisfaction using the Treatment Evaluation Inventory.Results Children were a mean age of six years and had seven primary teeth extracted. When given intravenous (IV) fentanyl (n = 69), either alone (n = 11) or in combination with paracetamol (n = 58) the children had 0.17 times odds of not having post-op pain compared to patients who received only paracetamol (logistic regression, p = 0.006). After one week 99% of families were satisfied with the service but 11% reported that their child still had post-operative morbidity.Conclusion Three quarters of children reported pain following extractions of primary teeth under GA. Use of IV paracetamol and fentanyl reduced the immediate post-operative self-reported pain. After a week most families (99%) were satisfied with the treatment their child had received and morbidity was reported by 11% of families.

Device-Associated Infection Rates in 20 Cities of India, Data Summary for 2004-2013: Findings of the International Nosocomial Infection Control Consortium.

OBJECTIVE: To report the International Nosocomial Infection Control Consortium surveillance data from 40 hospitals (20 cities) in India 2004-2013. METHODS: Surveillance using US National Healthcare Safety Network's criteria and definitions, and International Nosocomial Infection Control Consortium methodology. RESULTS: We collected data from 236,700 ICU patients for 970,713 bed-days Pooled device-associated healthcare-associated infection rates for adult and pediatric ICUs were 5.1 central line-associated bloodstream infections (CLABSIs)/1,000 central line-days, 9.4 cases of ventilator-associated pneumonia (VAPs)/1,000 mechanical ventilator-days, and 2.1 catheter-associated urinary tract infections/1,000 urinary catheter-days In neonatal ICUs (NICUs) pooled rates were 36.2 CLABSIs/1,000 central line-days and 1.9 VAPs/1,000 mechanical ventilator-days Extra length of stay in adult and pediatric ICUs was 9.5 for CLABSI, 9.1 for VAP, and 10.0 for catheter-associated urinary tract infections. Extra length of stay in NICUs was 14.7 for CLABSI and 38.7 for VAP Crude extra mortality was 16.3% for CLABSI, 22.7% for VAP, and 6.6% for catheter-associated urinary tract infections in adult and pediatric ICUs, and 1.2% for CLABSI and 8.3% for VAP in NICUs Pooled device use ratios were 0.21 for mechanical ventilator, 0.39 for central line, and 0.53 for urinary catheter in adult and pediatric ICUs; and 0.07 for mechanical ventilator and 0.06 for central line in NICUs. CONCLUSIONS: Despite a lower device use ratio in our ICUs, our device-associated healthcare-associated infection rates are higher than National Healthcare Safety Network, but lower than International Nosocomial Infection Control Consortium Report.

Surgical site infection rates in six cities of India: findings of the International Nosocomial Infection Control Consortium (INICC).

BACKGROUND: Surgical site infections are a threat to patient safety. However, in India, data on their rates stratified by surgical procedure are not available. METHODS: From January 2005 to December 2011, the International Nosocomial Infection Control Consortium (INICC) conducted a cohort prospective surveillance study on surgical site infections in 10 hospitals in 6 Indian cities. CDC National Healthcare Safety Network (CDC-NHSN) methods were applied and surgical procedures were classified into 11 types, according to the ninth edition of the International Classification of Diseases. RESULTS: We documented 1189 surgical site infections, associated with 28 340 surgical procedures (4.2%; 95% CI: 4.0-4.4). Surgical site infections rates were compared with INICC and CDC-NHSN reports, respectively: 4.3% for coronary bypass with chest and donor incision (4.5% vs 2.9%); 8.3% for breast surgery (1.7% vs 2.3%); 6.5% for cardiac surgery (5.6% vs 1.3%); 6.0% for exploratory abdominal surgery (4.1% vs 2.0%), among others. CONCLUSIONS: In most types of surgical procedures, surgical site infections rates were higher than those reported by the CDC-NHSN, but similar to INICC. This study is an important advancement towards the knowledge of surgical site infections epidemiology in the participating Indian hospitals that will allow us to introduce targeted interventions.

Simplified basic periodontal examination (BPE) in children and adolescents: a guide for general dental practitioners.

UNLABELLED: Dental plaque-induced periodontal diseases are common in children and adults. Guidelines were previously not available for the periodontal screening of under 18s. However, new guidelines have been introduced by the British Society of Periodontology and the British Society of Paediatric Dentistry which set out recommendations for the periodontal screening and management of under 18s in primary dental care. This article provides a practical guide for general dental practitioners on how to use the BPE in children and adolescents, and highlights the importance of early detection and management of periodontal diseases in this age group. A failure to use the modified BPE in a young patient who is later diagnosed with periodontitis may leave a dentist vulnerable to a medico-legal complaint or claim. CLINICAL RELEVANCE: New BPE guidelines for children and adolescents have been introduced by the BSPD and BSP; it is important that all dentists are aware of these guidelines and how to implement them in general practice.

Cytohistological features of rhinoscleroma.

Rhinoscleroma, also known as Mikulicz disease, is a chronic progressive disease caused by Klebsiella rhinoscleromatis. The disease is uncommon in Delhi. There are no cytological references of this disease. We describe the cytological features which should alert the pathologist to rule out this entity, which needs to be treated early. Immunohistochemistry on histopathological material is a useful adjunct to the diagnosis.