Children's Anaesthesia and perioperative care challenges, and innovations.

The 2015 Sustainable Development Goals emphasise good health to all with reduced inequalities, and surgical and anaesthesia care is essential to achieve these. https://sdgs.un.org/goals. However, it has been estimated that 1.7 billion children do not have access to safe anaesthesia and surgery when needed and this disproportionately affects children in low- and middle-income countries (1). It is alarming that 1 in 10 individuals in LMICs do not have access to safe surgical care. Both safe surgery and anaesthesia are essential for ensuring that individuals receive proper medical attention. Economically viable public health initiatives that can avert many disability-adjusted years are needed. (2-4) Morbidity and mortality from surgical disease and anaesthesia care remain high in low-income countries, unlike in high-income countries. The incidence of severe anaesthesia-related critical events and perioperative cardiac arrest is between three and ten times more in LMICs than in HICs (5-7) A baseline POMR that is 100 times higher in LMICs compared to HICs is reported. (8) This perioperative morbidity and mortality gap is more evident in neonates and younger age groups, especially in children with congenital abnormalities. The challenges facing providers of anaesthesia and perioperative care are multifactorial and include but are not limited to the inadequate workforce, inadequate and inappropriate infrastructure, lack of adequate and appropriately sized equipment, including monitors, and safe monitoring capacity, supply chain challenges for medicines and reusable consumables, unreliable supply of oxygen and blood products, lack of data and research for policy formulation, inadequate resource allocation from governments and lack of safety culture among other things. In paediatrics, this is further multiplied by the variability in the sizes of the patients, from neonates to older children (9).

Unpaid caregiving for people following hip fracture: longitudinal analysis from the English Longitudinal Study of Ageing.

PURPOSE: To determine the provision and its change over time in unpaid care for people following hip fracture. METHODS: Data were sought from the English Longitudinal Study of Ageing (ELSA) cohort. We identified participants who self-reported experiencing a hip fracture, who had clinical and caregiving data in the previous and subsequent two data collection waves. Demographic and clinical data were collected in addition to data on provision of unpaid care, who provided care and the frequency of needs being met. RESULTS: The analysed cohort consisted of 246 participants [150 females (61%), mean age 78.9 years (standard deviation: 8.6)]. There was an increase in the number of participants requiring unpaid care between the Pre-Fracture and Fracture Wave (29% vs. 59%), which plateaued in the subsequent two waves (56%; 51%). Although both spouse and daughters provided the most unpaid care to participants over this study period, there was an increase in support provided during the Fracture Wave by both sons and daughters. This increased support offered by spouses continued until Post-Fracture Wave 2 when this plateaued. Support provided by friends increased from 3 to 8% and brothers and sisters increased from 0 and 1% Pre-Fracture to 8% by Post-Fracture Wave 2. CONCLUSION: These findings provide insights into who, what and how unpaid carers support people following hip fracture over time. Given the level of support unpaid carers offer, and previously reported carer stress and burden, undertaking clinical trials to assess the effectiveness of carer-patient support interventions would be valuable.

Recurrent chondromyxoid fibroma of the distal femur treated with percutaneous cryoablation.

Chondromyxoid fibroma is a rare, benign tumor of the bone with excellent prognosis but a high rate of recurrence. We report a patient presenting with pain and a history of chondromyxoid fibroma of the distal left femur previously treated with multiple prior curettage and bone graft procedures. Magnetic resonance imaging and histopathology indicated a recurrence of tumor. Due to the small size of the tumor recurrence and challenges associated with prior open surgery, the patient underwent cryoablation of the lesion with computed tomography guidance. Follow-up 18 months later indicated a resolution of pain and improvement on magnetic resonance imaging, and no concerns after 20 months. To our knowledge, this is the first reported case of chondromyxoid fibroma treated with cryoablation. This case suggests cryoablation could be considered in the setting of recurrent chondromyxoid fibroma for local tumor control.

MCB-613 exploits a collateral sensitivity in drug resistant EGFR-mutant non-small cell lung cancer through covalent inhibition of KEAP1.

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets EGFR-mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms. Subsequent proteomic and functional genomic screens involving MCB-613 identified its target in this context to be KEAP1, revealing that this gene is selectively essential in the setting of EGFR inhibitor resistance. In-depth molecular characterization demonstrated that (1) MCB-613 binds KEAP1 covalently; (2) a single molecule of MCB-613 is capable of bridging two KEAP1 monomers together; and, (3) this modification interferes with the degradation of canonical KEAP1 substrates such as NRF2. Surprisingly, NRF2 knockout sensitizes cells to MCB-613, suggesting that the drug functions through modulation of an alternative KEAP1 substrate. Together, these findings advance MCB-613 as a new tool for exploiting the selective essentiality of KEAP1 in drug-resistant, EGFR-mutant NSCLC cells.

How reconfiguration of a minor injuries unit has affected service delivery during the COVID-19 pandemic: a retrospective analysis.

INTRODUCTION: Redeployment of orthopaedic consultants to a minor injuries unit (MIU) during the COVID-19 pandemic provided a unique opportunity to assess the impact of early senior specialist input on patient management. METHODS: Patient demographics, diagnosis, location of injury and disposal method were compared between three 7-day periods: during the April 2020 COVID-19 lockdown (period A), one month prior to period A (period B) and one year prior to period A (period C). Orthopaedic consultants staffed the MIU during period A, and emergency nurse practitioners staffed the MIU during periods B and C. RESULTS: Period A witnessed higher injury severity either due to modified activities or altered healthcare-seeking behaviour during lockdown. For fractures, compared with periods B and C, period A saw a lower rate of referral to fracture clinic (41% vs 100% vs 86%, p<0.001) and higher rate of discharge (38% vs 0% vs 9%, p<0.001). The median time to fracture clinic was also longer (15 days vs 6 days vs 10 days, p<0.001), indicating earlier institution of definitive care. There were no other significant differences between periods with radiology alerts and complaints received remaining largely unchanged. CONCLUSION: Early senior orthopaedic input in the patient journey from MIU had clear benefits, this being most true for fracture diagnoses. Earlier definitive management planning was observed as lower rates of fracture clinic referral, higher rates of discharge and deferred first fracture clinic reviews. This study highlights the benefits of greater partnership between MIU and orthopaedics. As the pandemic subsides and redeployed staff return to normal duties, a modification of this model could be utilised to ensure this partnership is sustainable.

Overexpressed Gα13 activates serum response factor through stoichiometric imbalance with Gßγ and mislocalization to the cytoplasm.

Gα13, a heterotrimeric G protein α subunit of the G12/13 subfamily, is an oncogenic driver in multiple cancer types. Unlike other G protein subfamilies that contribute to cancer progression via amino acid substitutions that abolish their deactivating, intrinsic GTPase activity, Gα13 rarely harbors such mutations in tumors and instead appears to stimulate aberrant cell growth via overexpression as a wildtype form. It is not known why this effect is exclusive to the G12/13 subfamily, nor has a mechanism been elucidated for overexpressed Gα13 promoting tumor progression. Using a reporter gene assay for serum response factor (SRF)-mediated transcription in HEK293 cells, we found that transiently expressed, wildtype Gα13 generates a robust SRF signal, approximately half the amplitude observed for GTPase-defective Gα13. When epitope-tagged, wildtype Gα13 was titrated upward in cells, a sharp increase in SRF stimulation was observed coincident with a "spillover" of Gα13 from membrane-associated to a soluble fraction. Overexpressing G protein ß and γ subunits caused both a decrease in this signal and a shift of wildtype Gα13 back to the membranous fraction, suggesting that stoichiometric imbalance in the αßγ heterotrimer results in aberrant subcellular localization and signalling by overexpressed Gα13. We also examined the acylation requirements of wildtype Gα13 for signalling to SRF. Similar to GTPase-defective Gα13, S-palmitoylation of the wildtype α subunit was necessary for SRF activation but could be replaced functionally by an engineered site for N-terminal myristoylation. However, a key difference was observed between wildtype and GTPase-defective Gα13: whereas the latter protein lacking palmitoylation sites was rescued in its SRF signalling by either an engineered polybasic sequence or a C-terminal isoprenylation site, these motifs failed to restore signalling by wildtype, non-palmitoylated Gα13. These findings illuminate several components of the mechanism in which overexpressed, wildtype Gα13 contributes to growth and tumorigenic signalling, and reveal greater stringency in its requirements for post-translational modification in comparison to GTPase-defective Gα13.

Clinical Outcomes following Percutaneous Urinary Diversion for Hemorrhagic Cystitis.

Hemorrhagic cystitis (HC) can lead to severe morbidity in treatment-refractory cases. Percutaneous nephrostomy (PCN) drainage was first described in 1993 as a safe, nonoperative procedure to achieve supravesical urinary diversion and treat severe HC. Despite its early success, subsequent studies in the adult population have been limited. This retrospective case series describes long-term outcomes following PCN placement in 24 patients with refractory HC. The overall technical success of the procedure was 100%. Seventeen of 24 (71%) patients experienced resolution of hematuria. The median time for hematuria resolution after the procedure was 12 days (interquartile range, 7-28 days). Postprocedural HC severity grade significantly decreased from a median Grade 3 to Grade 1 (P < .01). The complications included catheter obstruction, dislodgement, and associated urinary tract infections occurring at rates of 1.0, 1.6, and 1.7 per 1,000 catheter days, respectively. This study of PCN placement demonstrated and further confirmed the effectiveness of urinary diversion in treating refractory HC.

Medical Student Perspectives on Undergraduate Oncology Education in the UK.

AIMS: The British Oncology Network for Undergraduate Societies (BONUS) surveyed students who attended an oncology revision day to determine their views on the current quantity, quality and type of curriculum-based oncology teaching they have experienced. MATERIALS AND METHODS: Students attending two BONUS revision days received a questionnaire assessing their experience of oncology teaching within the medical curriculum and interest in pursuing a future career in oncology using a 10-point Likert scale. Data were collected with informed consent to be anonymised and used for research. Student demographics and qualitative and quantitative data about experiences of oncology education were analysed. RESULTS: In total, 451 students registered to attend the revision days. After removal of duplicates, non-responders and non-UK participants, responses from 153 students studying across years 1-6 at 22 UK medical schools were analysed. The mean quantity of oncology lectures students reported receiving was 8.9 hours and the mean quantity of clinic/ward-based oncology teaching was 7.5 hours. Ninety (62.1%) of the 145 students who responded to the relevant question reported that they had received dedicated teaching in oncology. Students who had received dedicated oncology teaching reported a statistically significantly higher mean quality 6.1 (95% confidence interval 5.6-6.5) versus 5.0 (95% confidence interval 4.3-5.5; P = 0.003) and quantity 5.2 (95% confidence interval 4.7-5.6) versus 4.3 (95% confidence interval 3.7-4.9; P = 0.03) of oncology teaching compared with those who had not received this. CONCLUSION: Appropriate oncology education is essential for all medical students due to the high prevalence of cancer. All future doctors need the appropriate knowledge and communication skills to care for cancer patients. Our analysis provides quantitative evidence to support the value of specialist oncology teaching within the medical school curriculum in improving student-reported experience. National student-led revision days and events may widen interest in a future career in oncology and aid collaboration between oncology societies. It is important for the general undergraduate medical curriculum to integrate specialty content. An integrated curriculum should facilitate a holistic approach that spans prevention, screening, treatment and palliation rather than being split by subspeciality.

Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence.

Cannabidiol (CBD) is a constituent of the cannabis plant with a diverse array of pharmacological activities as well as potential therapeutic uses. An oral formulation of CBD (Epidiolex in the US; Epidyolex in Europe) is approved for treating seizures associated with rare and severe forms of epilepsy. These studies, which supported the approval of the medication, investigated abuse-related effects of CBD in rats and nonhuman primates (NHPs) using drug self-administration, drug discrimination, and physical dependence procedures and characterized its pharmacokinetics. In NHPs (n = 5) that self-administered midazolam (0.01 or 0.032 mg/kg/infusion), CBD (0.1-3.2 mg/kg/infusion) failed to maintain responding above vehicle levels. CBD maintained very modest levels of self-administration in rats (n = 7-8) that self-administered heroin (0.015 mg/kg/infusion) and did not increase drug-lever responding, up to a dose of 150 mg/kg (by mouth), in rats (n = 6) trained to discriminate 0.5 mg/kg (i.p.) midazolam. In juvenile (5-6 weeks old) and adult (10-11 weeks old) male and female rats, discontinuation of chronic treatment (twice daily for 20 days) with an oral formulation of CBD (20 or 100 mg/kg, by mouth) did not reliably produce signs of withdrawal. Pharmacokinetic studies confirmed that the dosing regimens used in these studies resulted in therapeutically relevant plasma levels. Taken together, the lack of reliable self-administration, the failure to increase drug-lever responding in rats trained to discriminate midazolam, and the absence of withdrawal signs upon discontinuation of chronic treatment indicate that CBD has very low abuse potential and is unlikely to produce physical dependence. SIGNIFICANCE STATEMENT: Legalization of cannabis across the United States and elsewhere has led to intense investigation into the safety and therapeutic potential of cannabis and its constituent materials, including cannabidiol (CBD). Results of these preclinical abuse potential studies on CBD indicate no rewarding properties, physical dependence potential, or similarity to a benzodiazepine. Together with data from in vitro pharmacology and human abuse potential studies, the abuse potential of Epidiolex in humans is likely to be negligible.

The problem of over-medicalisation: How AOD disease models perpetuate inequity for young people with multiple disadvantage.

Young people who experience multiple disadvantage have been identified as some of the most marginalised and under-serviced people in the alcohol and other drug (AOD) system. In this paper, we draw on a range of research evidence to argue that one of the challenges in responding appropriately to the needs of these young people are models of care which seek to ameliorate 'illness' rather than promote wellness. While disease approaches have some important benefits, overly-medicalised AOD treatment responses also have negative impacts. We argue that disease models rest on understandings of substance use as an individual enterprise and thereby pay insufficient attention to the material disadvantage that shape young people's substance use, creating feelings of shame, failure and a reluctance to return to care if they continue to use. Additionally we draw on literature that shows how disease models construe young people's substance use as compulsive, perpetuating deficit views of them as irrational and failing to account for the specific meanings that young people themselves give to their substance use. By focusing on clinical solutions rather than material and relational ones, medicalised treatment responses perpetuate inequity: they benefit young people whose resources and normative values align with the treatments offered by disease models, but are much less helpful to those who are under-resourced,. We suggest that alternative approaches can be found in First Nations models of care and youth programs that attend to social, cultural, and material wellbeing, making living well the focus of treatment rather than illness amelioration.

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Influence of spatial-intensity contrast in ultraintense laser-plasma interactions.

Increasing the intensity to which high power laser pulses are focused has opened up new research possibilities, including promising new approaches to particle acceleration and phenomena such as high field quantum electrodynamics. Whilst the intensity achievable with a laser pulse of a given power can be increased via tighter focusing, the focal spot profile also plays an important role in the interaction physics. Here we show that the spatial-intensity distribution, and specifically the ratio of the intensity in the peak of the laser focal spot to the halo surrounding it, is important in the interaction of ultraintense laser pulses with solid targets. By comparing proton acceleration measurements from foil targets irradiated with by a near-diffraction-limited wavelength scale focal spot and larger F-number focusing, we find that this spatial-intensity contrast parameter strongly influences laser energy coupling to fast electrons. We find that for multi-petawatt pulses, spatial-intensity contrast is potentially as important as temporal-intensity contrast.

Deconvolution of multi-Boltzmann x-ray distribution from linear absorption spectrometer via analytical parameter reduction.

Accurate characterization of incident radiation is a fundamental challenge for diagnostic design. Herein, we present an efficient spectral analysis routine that is able to characterize multiple components within the spectral emission by analytically reducing the number of parameters. The technique is presented alongside the design of a hard x-ray linear absorption spectrometer using the example of multiple Boltzmann-like spectral distributions; however, it is generally applicable to all absorption based spectrometer designs and can be adapted to any incident spectral shape. This routine is demonstrated to be tolerable to experimental noise and suitable for real-time data processing at multi-Hz repetition rates.

Distribution of mortality patterns in cats with naturally occurring trauma: A Veterinary Committee on Trauma registry study.

A greater understanding of the prognostic variables that affect the timing of death for cats with trauma may help clinicians select treatments and monitoring plans. This study investigated the mortality rate and its distribution pattern in a large population of cats to identify variables associated with the timing of trauma-related deaths. Clinical data was retrieved from the Veterinary Committee on Trauma database to determine mortality rates and timing of deaths, defined as early death (ED; <1 day post-presentation) or delayed death (DD; ≥1 day post-presentation). Multivariable logistic regression analyses were performed to identify characteristics and interventions that best predicted timing of death. Overall mortality rate for 6703 feline trauma patients with complete records was 17.2%, with 7.6% due to natural death and 92.3% due to euthanasia. Among the subset of 543 cats with trauma that died after presentation or required euthanasia due to a grave prognosis (representing an 8.1% mortality rate), EDs were more common (71.7%) than DD and the cause of death was not significantly associated with the timing of death. Clinical pathology parameters were unable to identify animals more likely to die or to require euthanasia due to a poor prognosis during hospitalisation. Factors that were significantly different for cats with ED vs. DD included the median cumulative results for the Modified Glasgow Coma Scale (MGCS) score and the Animal Trauma Triage (ATT) score, the presence of spinal trauma, administration of blood products and undertaking surgical procedures. An increased likelihood of DD rather than ED was associated with the administration of blood products (odds ratio [OR], 3.959; P = 0.019) vs. not, performing a surgical procedure (OR, 6.055; P < 0.001) vs. not, and a cumulative MGCS of 15-17 or 18 (OR, 1.947 and 3.115; P = 0.031 and P = 0.01, respectively) vs. a cumulative MGCS ≤ 11.