Development and Validation of HAS (Hajibandeh Index, ASA Status, Sarcopenia) - A Novel Model for Predicting Mortality After Emergency Laparotomy.

OBJECTIVES: To develop and validate a predictive model to predict the risk of postoperative mortality after emergency laparotomy taking into account the following variables: age, age ≥ 80, ASA status, clinical frailty score, sarcopenia, Hajibandeh Index (HI), bowel resection, and intraperitoneal contamination. SUMMARY BACKGROUND DATA: The discriminative powers of the currently available predictive tools range between adequate and strong; none has demonstrated excellent discrimination yet. METHODS: The TRIPOD and STROCSS statement standards were followed to protocol and conduct a retrospective cohort study of adult patients who underwent emergency laparotomy due to non-traumatic acute abdominal pathology between 2017 and 2022. Multivariable binary logistic regression analysis was used to develop and validate the model via two protocols (Protocol A and B). The model performance was evaluated in terms of discrimination (ROC curve analysis), calibration (calibration diagram and Hosmer-Lemeshow test), and classification (classification table). RESULTS: One thousand forty-three patients were included (statistical power = 94%). Multivariable analysis kept HI (Protocol-A: P =0.0004; Protocol-B: P =0.0017), ASA status (Protocol-A: P =0.0068; Protocol-B: P =0.0007), and sarcopenia (Protocol-A: P <0.0001; Protocol-B: P <0.0001) as final predictors of 30-day postoperative mortality in both protocols; hence the model was called HAS (HI, ASA status, sarcopenia). The HAS demonstrated excellent discrimination (AUC: 0.96, P <0.0001), excellent calibration ( P <0.0001), and excellent classification (95%) via both protocols. CONCLUSIONS: The HAS is the first model demonstrating excellent discrimination, calibration, and classification in predicting the risk of 30-day mortality following emergency laparotomy. The HAS model seems promising and is worth attention for external validation using the calculator provided. HAS mortality risk calculator https://app.airrange.io/#/element/xr3b_E6yLor9R2c8KXViSAeOSK .

Quality of life in women with early-stage and metastatic hormone receptor-positive, HER2-negative breast cancer receiving endocrine therapy.

INTRODUCTION: Early discontinuation of endocrine therapy (ET) is higher among patients with early breast cancer (EBC) compared to patients with metastatic hormone receptor-positive (HR+) breast cancer (MBC). In our clinical experience the reasons for this may include a significant burden of ET side effects impacting quality of life (QOL) in patients with EBC. We hypothesized that QOL is lower in patients with HR + EBC compared to patients with HR + MBC on ET. METHODS: We conducted a cross-sectional observational study to assess QOL utilizing FACT-ES & EORTC QLQ C30 tools among patients with EBC and MBC receiving ET across 5 Irish hospitals. RESULTS: A total of 417 patients were enrolled-EBC (79% n = 331) and MBC 21% (n = 86). Using the FACT-ES, we found no difference in overall QOL by stage (139.2 vs 141, P  = .33). Patients with HR + MBC had a lower symptom burden from ET compared to HR + EBC (61.4 vs 54, P < .01). In adjusted multivariate linear regression models, there was no difference in QOL for patients with EBC and MBC receiving ET. CONCLUSIONS: There was no significant difference in overall QOL for patients with EBC and MBC. However, patients with EBC experienced more endocrine symptoms. In adjusted multivariate linear regression models, the stage did not predict QOL. Our results suggest that endocrine symptoms are significant contributors to impaired QOL for patients with EBC but the role of other determinants of QOL (eg, stage) is less clear. Future work could include the development of stage-specific QOL tools and utilization of electronic patient-reported outcomes (ePROs) to identify and manage emergent toxicities.

Direct Observation of Charge, Energy, and Hydrogen Transfer between the Backbone and Nucleobases in Isolated DNA Oligonucleotides.

Understanding how charge and energy, as well as protons and hydrogen atoms, are transferred in molecular systems as a result of an electronic excitation is fundamental for understanding the interaction between ionizing radiation and biological matter on the molecular level. To localize the excitation at the atomic scale, it was chosen to target phosphorus atoms in the backbone of gas-phase oligonucleotide anions and cations, by means of resonant photoabsorption at the L- and K-edges. The ionic photoproducts of the excitation process were studied by a combination of mass spectrometry and X-ray spectroscopy. The combination of absorption site selectivity and photoproduct sensitivity allowed the identification of X-ray spectral signatures of specific processes. Moreover, charge and/or energy as well as H transfer from the backbone to nucleobases has been directly observed. Although the probability of one versus two H transfer following valence ionization depends on the nucleobase, ionization of sugar or phosphate groups at the carbon K-edge or the phosphorus L-edge mainly leads to single H transfer to protonated adenine. Moreover, our results indicate a surprising proton-transfer process to specifically form protonated guanine after excitation or ionization of P 2p electrons.

The risk of recurrent pancreatitis after first episode of acute pancreatitis in relation to etiology and severity of disease: A systematic review, meta-analysis and meta-regression analysis.

BACKGROUND AND AIM: The study aims to determine and quantify the stratified risk of recurrent pancreatitis (RP) after the first episode of acute pancreatitis in relation to etiology and severity of disease. METHODS: A systematic review and meta-analysis in compliance with PRISMA statement standards was conducted. A search of electronic information sources was conducted to identify all studies investigating the risk of RP after the first episode of acute pancreatitis. Proportion meta-analysis models using random effects were constructed to calculate the weighted summary risks of RP. Meta-regression was performed to evaluate the effect of different variables on the pooled outcomes. RESULTS: Analysis of 57,815 patients from 42 studies showed that the risk of RP after first episode was 19.8% (95% confidence interval [CI] 17.5-22.1%). The risk of RP was 11.9% (10.2-13.5%) after gallstone pancreatitis, 28.7% (23.5-33.9%) after alcohol-induced pancreatitis, 30.3% (15.5-45.0%) after hyperlipidemia-induced pancreatitis, 38.1% (28.9-47.3%) after autoimmune pancreatitis, 15.1% (11.6-18.6%) after idiopathic pancreatitis, 22.0% (16.9-27.1%) after mild pancreatitis, 23.9% (12.9-34.8%) after moderate pancreatitis, 21.6% (14.6-28.7%) after severe pancreatitis, and 6.6% (4.1-9.2%) after cholecystectomy following gallstone pancreatitis. Meta-regression confirmed that the results were not affected by the year of study (P = 0.541), sample size (P = 0.064), length of follow-up (P = 0.348), and age of patients (P = 0.138) in the included studies. CONCLUSIONS: The risk of RP after the first episode of acute pancreatitis seems to be affected by the etiology of pancreatitis but not the severity of disease. The risks seem to be higher in patients with autoimmune pancreatitis, hyperlipidemia-induced pancreatitis, and alcohol-induced pancreatitis and lower in patients with gallstone pancreatitis and idiopathic pancreatitis.

The risk of hepatic pseudoaneurysm after liver trauma in relation to the severity of liver injury: a meta-analysis and meta-regression analysis.

AIM: To determine the risk of hepatic pseudoaneurysm after liver trauma in relation to the severity of liver injury. METHODS: We performed a systematic review and meta-analysis in compliance with PRISMA statement standards (Registration Number: CRD42022328834). A search of electronic information sources was conducted to identify all studies reporting the risk of hepatic pseudoaneurysm after liver trauma. The JBI assessment tool was used to assess the risk of bias of the included studies. Random-effects models were applied to calculate pooled outcome data. RESULTS: A total of 2030 patients from six studies were included. Based on the American Association for the Surgery of Trauma classification system, 21% had grade I injury; 33% grade II injury; 28% grade III injury; 12% grade IV injury and 5% grade V injury. The pooled risk of hepatic pseudoaneurysm was 1.8% (95% CI 1.1-2.5%). The risk was 0.4% (0-1.2%) in patients with grade I injury, 0.7% (0-1.7%) in patients with grade II injury; 1.5% (0.4-2.7%) in patients with grade III injury; 4.6% (1.4-7.7%) in patients with grade IV injury and 10.6% (1.8-22.9%) in patients with grade V injury. The average time between liver injury and detection of hepatic pseudoaneurysm was 6 days (95% CI 1-10) CONCLUSIONS: The risk of hepatic pseudoaneurysm after liver trauma increases as the severity of liver injury increases. Hepatic pseudoaneurysms are rare after grade I or grade II injuries, and increasingly common after grades III, IV and V injuries. We recommend routine surveillance imaging in patients with grade III to V injuries.

Cohort study of long-term survival and recurrence patterns following operative management of colorectal liver metastasis - is follow-up beyond 5 years warranted?

AIMS: To evaluate the patterns of overall survival (OS) and recurrence following surgical resection of colorectal liver metastases (CRLM). METHODS: In compliance with STROCSS guideline, a single-centre retrospective cohort study was conducted. All consecutive patients undergoing resection of CRLM between 2003 and 2019 were considered eligible for inclusion. The outcome measures included OS, recurrence-free survival (RFS), recurrence rate, time to recurrence (TTR) and longest TTR. Statistical analyses included simple descriptive statistics and Kaplan-Meier survival statistics. RESULTS: We included 486 liver resections in 472 patients. The estimated median OS and RFS were 5.1 years and 3.1 years, respectively. The probability of 1-year, 3-year, 5-year and 10-year OS was 93%, 69%, 50% and 34%, respectively. The probability of 1-year, 3-year, 5-year and 10-year RFS was 81%, 50%, 34% and 33%, respectively. Recurrence occurred in 56% (271/486) of patients, and the median TTR was 1.6 years (IQR: 0.8-2.7) with longest TTR of 4.8 years. Although there were no recurrences in the 66 patients that entered the 6th year, the 95% CI for true rate of recurrence in the population given these data is 0-5.4%. CONCLUSIONS: Our results suggest that recurrences that occur after operative management of CRLM are almost certain to occur within the first 5 years even for patients surviving longer than 5 years. This does not disprove the requirement for follow up beyond 5 years. However, based on this data, we have altered our follow up from 10 to 6 years. The need for the 6th year of follow up will be reassessed in light of further observations.

Oligometastatic breast cancer: Are we there yet?

Patients with metastatic breast cancer are usually considered incurable. Recent advances have resulted in significant improvements in survival for patients with metastatic breast cancer. Due to the lack of randomised trials and heterogeneous disease biology, treatment decisions for patients with oligometastatic breast cancer vary widely. Some patients are treated similar to those with widespread disease while others are treated more aggressively. We conducted a review of the evidence for treatment options in oligometastatic breast cancer and consulted ClinicalTrials.gov to explore currently accruing or studies in development aimed at investigating oligometastatic disease in breast cancer. Surgery to the primary tumour in patients with metastatic breast cancer has failed to show any advantage over systemic therapy. However, there may be a benefit in women with controlled systemic disease who are hormone receptor positive with bone-predominant metastasis. Stereotactic radiotherapy has gained increased interest in this setting due to its excellent efficacy and lower rates of associated toxicity. A significant challenge remains in identifying the patient population who would benefit from such an approach, and to do so, we need to understand the distinct biology of oligometastatic breast cancer. Unique miRNA expression and low levels of tumour infiltrating lymphocytes in the immune micro-environment have been described in tumour tissues in patients with oligometastatic breast cancer. There is ongoing research aimed to better characterise these tumours, thus, allowing the selection of patients who would truly benefit from multi-modality treatment in an attempt for long-term survival and cure.

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. METHODS: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. RESULTS: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Roadmap on quantum nanotechnologies.

Quantum phenomena are typically observable at length and time scales smaller than those of our everyday experience, often involving individual particles or excitations. The past few decades have seen a revolution in the ability to structure matter at the nanoscale, and experiments at the single particle level have become commonplace. This has opened wide new avenues for exploring and harnessing quantum mechanical effects in condensed matter. These quantum phenomena, in turn, have the potential to revolutionize the way we communicate, compute and probe the nanoscale world. Here, we review developments in key areas of quantum research in light of the nanotechnologies that enable them, with a view to what the future holds. Materials and devices with nanoscale features are used for quantum metrology and sensing, as building blocks for quantum computing, and as sources and detectors for quantum communication. They enable explorations of quantum behaviour and unconventional states in nano- and opto-mechanical systems, low-dimensional systems, molecular devices, nano-plasmonics, quantum electrodynamics, scanning tunnelling microscopy, and more. This rapidly expanding intersection of nanotechnology and quantum science/technology is mutually beneficial to both fields, laying claim to some of the most exciting scientific leaps of the last decade, with more on the horizon.

Patient-reported experiences of consultation with an advanced nurse practitioner: Factor structure and reliability analysis of the patient enablement and satisfaction survey.

AIM: The aim was to analyse the psychometric properties of a patient-reported-experience measure, the Patient Enablement and Satisfaction Survey (PESS), when used to evaluate the care provided by Advanced Nurse Practitioners (ANPs) in terms of factor structure and internal consistency. The PESS is a 20-item, patient-completed data collection tool that was originally developed to measure patient experience and enablement following consultation with nurses in general practice. DESIGN: Cross-sectional survey; validity and reliability analysis. METHODS: The sample in this study consisted of 178 patients who consulted with 26 ANPs working in four different specialities. Data were collected between June and December 2019. An exploratory factor analysis of the PESS was conducted to determine convergent validity which was supported by parallel analysis and the traditional Kaiser criterion. The internal consistency of individual PESS items was determined via Cronbach's alpha, McDonald's omega, the Average Variance Extracted tests and item-subscale/total score correlations. RESULTS: A three-factor structure (PESS-ANP) was found through exploratory factor analysis and this was supported by parallel analysis, the traditional Kaiser criterion and the percentage of variance explained criterion. A high degree of internal consistency was reported across all factors. One question was omitted from the analysis ('Overall Satisfaction') following the identification of problematic cross-loadings. The three factor solution was identified as: patient satisfaction, quality of care provision and patient enablement. CONCLUSION: The findings of this study propose a three-factor model that is sufficiently reliable for analysing the experience and enablement of patients following consultation with an ANP. IMPACT: Increasingly, patient-reported experience measures are being used to evaluate patients' experience of receiving care from a healthcare professional. The PESS was identified to be reliable in evaluating the experience of patients who receive care from an ANP while a three-factor structure was proposed that can capture specific attributes of this care.

Hyperpolarized Nanodiamond Surfaces.

The widespread use of nanodiamond as a biomedical platform for drug-delivery, imaging, and subcellular tracking applications stems from its nontoxicity and unique quantum mechanical properties. Here, we extend this functionality to the domain of magnetic resonance, by demonstrating that the intrinsic electron spins on the nanodiamond surface can be used to hyperpolarize adsorbed liquid compounds at low fields and room temperature. By combining relaxation measurements with hyperpolarization, spins on the surface of the nanodiamond can be distinguished from those in the bulk liquid. These results are likely of use in signaling the controlled release of pharmaceutical payloads.

Imaging Surveillance in Patients After a Benign Fine-Needle Aspiration Biopsy of the Thyroid: Associated Cost and Incidence of Subsequent Cancer.

OBJECTIVE: The objective of our study was to determine patterns and cost of imaging tumor surveillance in patients after a benign fine-needle aspiration (FNA) biopsy of the thyroid in a large teaching hospital as well as the rate of subsequent cancer detection. MATERIALS AND METHODS: This cohort study was approved by the appropriate institutional review board and complied with HIPAA. All patients who had a benign thyroid FNA biopsy between January 1, 1999, and December 31, 2003, were identified from an institutional pathology database. We gathered information from electronic medical records on imaging tumor surveillance and subsequent cancer detection. Cost was determined using the facility total relative value unit and the 2014 Hospital Outpatient Prospective Payment System conversion factor. RESULTS: Between January 1, 1999, and December 31, 2003, 1685 patients had a benign thyroid FNA biopsy, 800 (47.5%) of whom underwent follow-up imaging. These patients underwent 2223 thyroid ultrasound examinations, 606 ultrasound-guided thyroid FNA biopsies, 78 thyroid scintigraphy examinations, 168 neck CTs, and 53 neck MRIs at a cost of $529,874, $176,157, $39,622, $80,580, and $53,114, respectively, for a total cost of $879,347 or $1099 per patient. The mean length of follow-up was 7.3 years, during which time 19 (2.4%) patients were diagnosed with thyroid cancer at a cost of $46,281 per cancer. Seventeen (89.5%) were diagnosed with papillary carcinoma and two (10.5%) with Hurthle cell carcinoma. CONCLUSION: Over a 5-year period, about half of the patients who had a benign thyroid FNA biopsy underwent follow-up imaging at considerable cost with a small rate of subsequent malignancy.

Maintaining surgical skills for military general surgery: the potential role for multivisceral organ retrieval in military general surgery training and practice.

The closure of the Medical Treatment facility in Camp BASTION and the return to contingency operations presents a new challenge in training and maintaining the skills of military surgeons. Multivisceral organ retrieval presents a unique opportunity to practice some of the more unusual techniques required in military surgery in the National Health Service. This article details the experience that organ retrieval offers and matches this to the needs of military surgeons. National Organ Retrieval Service teams need skilled surgeons, and a mutually beneficial partnership is in prospect.

Dissecting muscle synergies in the task space.

The muscle synergy is a guiding concept in motor control research that relies on the general notion of muscles 'working together' towards task performance. However, although the synergy concept has provided valuable insights into motor coordination, muscle interactions have not been fully characterised with respect to task performance. Here, we address this research gap by proposing a novel perspective to the muscle synergy that assigns specific functional roles to muscle couplings by characterising their task-relevance. Our novel perspective provides nuance to the muscle synergy concept, demonstrating how muscular interactions can 'work together' in different ways: (1) irrespective of the task at hand but also (2) redundantly or (3) complementarily towards common task-goals. To establish this perspective, we leverage information- and network-theory and dimensionality reduction methods to include discrete and continuous task parameters directly during muscle synergy extraction. Specifically, we introduce co-information as a measure of the task-relevance of muscle interactions and use it to categorise such interactions as task-irrelevant (present across tasks), redundant (shared task information), or synergistic (different task information). To demonstrate these types of interactions in real data, we firstly apply the framework in a simple way, revealing its added functional and physiological relevance with respect to current approaches. We then apply the framework to large-scale datasets and extract generalizable and scale-invariant representations consisting of subnetworks of synchronised muscle couplings and distinct temporal patterns. The representations effectively capture the functional interplay between task end-goals and biomechanical affordances and the concurrent processing of functionally similar and complementary task information. The proposed framework unifies the capabilities of current approaches in capturing distinct motor features while providing novel insights and research opportunities through a nuanced perspective to the muscle synergy.

A Clinical Trial Shows Improvement in Skin Collagen, Hydration, Elasticity, Wrinkles, Scalp, and Hair Condition following 12-Week Oral Intake of a Supplement Containing Hydrolysed Collagen.

Background: Hydrolysed collagen supplements are reported to fight the signs of aging and improve skin appearance, but more authoritative clinical evidence is needed to support efficacy. Aim: This randomised, double-blind, placebo-controlled study evaluated the efficacy of a supplement containing hydrolysed collagen and vitamin C (Absolute Collagen, AC) on biophysical parameters and visible signs of aging for skin, scalp, and hair, when taken daily or every 48 hours. Methods: We measured dermal collagen using confocal microscopy and high-resolution ultrasound. Hydration, elasticity, wrinkles, and clinical trichoscopy were measured in parallel to expert visual grading. Efficacy measures were recorded at baseline, week 6, and week 12. Results: Following 12 weeks daily use of the AC supplement, using confocal microscopy, we observed a significant 44.6% decrease in fragmentation vs. placebo (p < 0.01). We also measured a change in the ultrasound LEP (low echogenic pixel) ratio comparing upper and lower dermis (-9.24 vs. -7.83, respectively, p=0.05), suggesting collagen improvements occurred more in the upper dermal compartment. After 12 weeks vs. placebo, skin hydration was increased by 13.8% (p < 0.01), R2 elasticity index was increased by 22.7% (p<0.01), and Rz profilometry index was decreased by 19.6% (p < 0.01). Trichoscopy showed an average 11.0% improvement in scalp scaling and a 27.6% increase in the total number of hairs counted vs. placebo (p=n.s.). This was associated with a 31.9% increase in clinical grading score for hair healthy appearance (p < 0.01). Conclusion: The AC supplement has shown clinical benefits for skin, scalp, and hair, when used either daily or every 48 hours, over a 12-week period.

The Governance of Traffic Noise Impacting Pedestrian Amenities in Melbourne Australia: A Critical Policy Review.

By identifying a unified aim of Federal, State, and Local government authorities to deliver healthier, more liveable urban spaces and enable walkable neighbourhoods in Melbourne, Australia, questions emerge regarding noise data collection methods and the policies that aim to protect pedestrian areas from potential increases in urban traffic noise. It highlights a missed opportunity to develop strategies that provide explicit guidance for designing more compact urban forms without diminishing pedestrian amenities. This study investigates the governance of traffic-induced noise pollution and its impact on pedestrian amenities in Melbourne, Australia. It aims to identify the government bodies best positioned to protect pedestrians from noise pollution and evaluate the strategic justification for reducing traffic noise to enhance urban walkability. This research employs a semi-systematic policy selection method and a hybrid critique and review method to evaluate the multidisciplinary governance frameworks engaged in the management and mitigation of traffic noise in Melbourne. Key findings reveal that while traffic noise poses significant health risks, current policies overlook its impact on pedestrian amenities in urban areas. This study emphasises the benefits of qualitative and subjective noise data collection to inform policy-makers of the pedestrian aural experience and impacts. Discussion points include noise management strategies and the value of implementing metropolitan-scale noise-mapping to illustrate the impact of noise rather than quantities of sound. The conclusions demonstrate that there is strategic justification for managing traffic-induced noise pollution to protect pedestrian areas within international, federal, and state government policies and implicit rationale at a local level.

Early-Stage Non-Small Cell Lung Cancer: New Challenges with Immune Checkpoint Blockers and Targeted Therapies.

The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC.

Toxicity of immune checkpoint inhibitors and tyrosine kinase inhibitor combinations in solid tumours: a systematic review and meta-analysis.

The combination of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) can be associated with significant toxicity. We performed a systematic review and meta-analysis of the toxicity of combination treatment of ICIs with TKIs (ICI + TKI) in clinical trials with solid organ malignancies. Our primary endpoint explored the incidence of grade 3 - 5 (G3-5) treatment-related toxicity and our secondary endpoints included the incidence of toxicity by treatment type, disease type and studies with run-in strategies. A total of 9750 abstracts were identified, of which 72 eligible studies were included. The most common disease types were non-small cell lung cancer (n=8, 11.1%), renal cell carcinoma (n=10, 13.8%) and hepatobiliary cancers (n=10, 13.8%). The overall incidence of G3-5 toxicity was 56% (95% CI = 50% - 61%). The most common TKIs combined with ICIs in this analysis were multi-targeted TKIs (n = 52, 72%), VEGF specific (n = 9, 12.5%), or oncogene-targeting TKIs (EGFR, ALK, BRAF, MEK) (n =11, 15.3%). Oncogene-targeted TKIs were associated a higher incidence of rashes and immune related adverse events (irAEs) and lower incidence of hypertension. In studies which used a TKI 'run-in' to mitigate toxicity, the pooled estimate of G3-5 toxicity was 71% (95% CI 57-81%). Almost half of studies (48%) omitted the incidence of G3-5 irAEs. Our work suggests that the majority of patients who receive ICI-TKI combinations will experience high grade toxicity (G3-G5) and that toxicity may be specific to TKI partner (Oncogene targeted TKIs: Rash, irAEs; VEGF/Multitargeted: Hypertension). These data did not suggest that a TKI 'run-in' was associated with a lower incidence of G3-5 toxicity. Reporting of irAEs was inconsistent supporting the need for harmonisation of adverse event reporting to include onset, duration and treatment. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022367416.

Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

En-route care capability from point of injury impacts mortality after severe wartime injury.

OBJECTIVE: The objective of this study is to characterize modern point-of-injury (POI) en-route care platforms and to compare mortality among casualties evacuated with conventional military retrieval (CMR) methods to those evacuated with an advanced medical retrieval (AMR) capability. BACKGROUND: Following a decade of war in Afghanistan, the impact of en-route care capabilities from the POI on mortality is unknown. METHODS: Casualties evacuated from POI to one level III facility in Afghanistan (July 2008-March 2012) were identified from UK and US trauma registries. Groups comprised those evacuated by a medically qualified provider-led, AMR and those by a medic-led CMR capability. Outcomes were compared per incremental Injury Severity Score (ISS) bins. RESULTS: Most casualties (n = 1054; 61.2%) were in the low-ISS (1-15) bracket in which there was no difference in en-route care time or mortality between AMR and CMR. Casualties in the mid-ISS bracket (16-50) (n = 583; 33.4%) experienced the same median en-route care time (minutes) on AMR and CMR platforms [78 (58) vs 75 (93); P = 0.542] although those on AMR had shorter time to operation [110 (95) vs 117 (126); P < 0.001]. In this mid-ISS bracket, mortality was lower in the AMR than in the CMR group (12.2% vs 18.2%; P = 0.035). In the high-ISS category (51-75) (n = 75; 4.6%), time to operation was lower in the AMR than the CMR group (66 ± 77 vs 113 ± 122; P = 0.013) but there was no difference in mortality. CONCLUSIONS: This study characterizes en-route care capabilities from POI in modern combat. Conventional platforms are effective in most casualties with low injury severity. However, a definable injury severity exists for which evacuation with an AMR capability is associated with improved survival.