Codon-specific KRAS mutations predict survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.

Use of cidofovir in a patient with severe mpox and uncontrolled HIV infection.

A 48-year-old man with poorly controlled HIV presented with severe human monkeypox virus (hMPXV) infection, having completed 2 weeks of tecovirimat at another hospital. He had painful, ulcerating skin lesions on most of his body and oropharyngeal cavity, with subsequent Ludwig's angina requiring repeated surgical interventions. Despite commencing a second, prolonged course of tecovirimat, he did not objectively improve, and new lesions were still noted at day 24. Discussion at the UK National Health Service England High Consequence Infectious Diseases Network recommended the use of 3% topical and then intravenous cidofovir, which was given at 5 mg/kg; the patient made a noticeable improvement after the first intravenous dose. He received further intravenous doses at 7 days and 21 days after the dose and was discharged at day 52. Cidofovir is not licensed for use in treatment of hMPXV infection. Data for cidofovir use in hMPXV are restricted to studies in animals. Four other documented cases of cidofovir use against hMPXV have been reported in the USA in 2022, but we present its first use in the UK. The scarcity of studies into the use of cidofovir in this condition clearly shows the need for robust studies to assess efficacy, optimum dosage, timing, and route of administration.

Increasing trends in hemodialysis and living donor kidney transplantation for children and young people in the United Kingdom.

BACKGROUND: The UK Renal Registry is responsible for the national collection and reporting of data on all children receiving long-term kidney replacement therapy [KRT], including kidney transplantation. METHODS: All 13 UK pediatric nephrology centers contributed to providing individual patient data from the pediatric population incident to and prevalent to KRT as per the date 31 December 2018. Data for children aged 16-<18 years were presented separately as some were managed under adult care settings with different methods of data collection. Demographics and biochemical data, including kidney function and prevalence of cardiovascular risk factors [hypertension, hypercholesterolemia, BMI] were reported. RESULTS: Eight hundred and twenty-six children (65.4 per million age-related population [pmarp]) and 199 young people (139.4pmarp) in the United Kingdom were prevalent to KRT on 31 December 2018. Overall, the incidence of KRT during 2018 was 9.1 pmarp and 12.6 pmarp in children and young people, respectively. Congenital anomalies of the kidney and urinary tract (CAKUT) were the most prevalent primary diagnoses (52%). Living and deceased donor transplantation was the most common treatment modality (78%). Patients on dialysis had lower age standardized mean height and weight ranges recorded in comparison to transplant patients [median height z score -1.8 vs. -1.1]. 73.1% patients had one or more cardiovascular disease risk factors. CONCLUSIONS: This study highlights increasing prevalence of hemodialysis and living donor transplantation as modalities for KRT. Of those incident to KRT, the highest patient survival was seen among 8-12 years and lowest <2 years. Moreover, there was a demographic shift from Caucasian toward Asian/other ethnicity and from CAKUT to other primary kidney diseases.

The multidisciplinary, theory-based co-design of a new digital health intervention supporting the care of oesophageal cancer patients.

OBJECTIVE: Oesophageal cancer patients have complex care needs. Cancer clinical nurse specialists play a key role in coordinating their care but often have heavy workloads. Digital health interventions can improve patient care but there are few examples for oesophageal cancer. This paper aims to describe the multidisciplinary co-design process of a digital health intervention to improve the experience of care and reduce unmet needs among patients with oesophageal cancer. METHODS: A theory-based, multi-disciplinary, co-design approach was used to inform the developmental process of the digital health intervention. Key user needs were elicited using mixed methodology from systematic reviews, focus groups and interviews and holistic need assessments. Overarching decisions were discussed among a core team of patients, carers, health care professionals including oncologists and cancer clinical nurse specialists, researchers and digital health providers. A series of workshops incorporating a summary of findings of key user needs resulted in the development of a minimum viable product. This was further refined after a pilot study based on feedback from end users. RESULTS: The final digital health intervention consists of a mobile app feature for patients and carers connected to a dashboard with supporting additional features for clinical nurse specialist. It contains a one-way messaging function for clinical nurse specialists to communicate with patients, functions for patients to record weight and holistic need assessment results which could be viewed by their clinical nurse specialists as well as a library of informative articles. CONCLUSIONS: The multidisciplinary co-design of a digital health intervention providing support for oesophageal cancer patients and health care professionals has been described. Future studies to establish its impact on patient outcomes are planned.

Cardiovascular magnetic resonance predictors of heart failure in hypertrophic cardiomyopathy: the role of myocardial replacement fibrosis and the microcirculation.

INTRODUCTION: Heart failure (HF) in hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality. Predictors of HF, in particular the role of myocardial fibrosis and microvascular ischemia remain unclear. We assessed the predictive value of cardiovascular magnetic resonance (CMR) for development of HF in HCM in an observational cohort study. METHODS: Serial patients with HCM underwent CMR, including adenosine first-pass perfusion, left atrial (LA) and left ventricular (LV) volumes indexed to body surface area (i) and late gadolinium enhancement (%LGE- as a % of total myocardial mass). We used a composite endpoint of HF death, cardiac transplantation, and progression to NYHA class III/IV. RESULTS: A total of 543 patients with HCM underwent CMR, of whom 94 met the composite endpoint at baseline. The remaining 449 patients were followed for a median of 5.6 years. Thirty nine patients (8.7%) reached the composite endpoint of HF death (n = 7), cardiac transplantation (n = 2) and progression to NYHA class III/IV (n = 20). The annual incidence of HF was 2.0 per 100 person-years, 95% CI (1.6-2.6). Age, previous non-sustained ventricular tachycardia, LV end-systolic volume indexed to body surface area (LVESVI), LA volume index ; LV ejection fraction, %LGE and presence of mitral regurgitation were significant univariable predictors of HF, with LVESVI (Hazard ratio (HR) 1.44, 95% confidence interval (95% CI) 1.16-1.78, p = 0.001), %LGE per 10% (HR 1.44, 95%CI 1.14-1.82, p = 0.002) age (HR 1.37, 95% CI 1.06-1.77, p = 0.02) and mitral regurgitation (HR 2.6, p = 0.02) remaining independently predictive on multivariable analysis. The presence or extent of inducible perfusion defect assessed using a visual score did not predict outcome (p = 0.16, p = 0.27 respectively). DISCUSSION: The annual incidence of HF in a contemporary ambulatory HCM population undergoing CMR is low. Myocardial fibrosis and LVESVI are strongly predictive of future HF, however CMR visual assessment of myocardial perfusion was not.

Admissions to a Low-Resource Neonatal Unit in Malawi Using a Mobile App: Digital Perinatal Outcome Audit.

BACKGROUND: Mobile health (mHealth) is showing increasing potential to address health outcomes in underresourced settings as smartphone coverage increases. The NeoTree is an mHealth app codeveloped in Malawi to improve the quality of newborn care at the point of admission to neonatal units. When collecting vital demographic and clinical data, this interactive platform provides clinical decision support and training for the end users (health care professionals [HCPs]), according to evidence-based national and international guidelines. OBJECTIVE: This study aims to examine 1 month's data collected using NeoTree in an outcome audit of babies admitted to a district-level neonatal nursery in Malawi and to demonstrate proof of concept of digital outcome audit data in this setting. METHODS: Using a phased approach over 1 month (November 21-December 19, 2016), frontline HCPs were trained and supported to use NeoTree to admit newborns. Discharge data were collected by the research team using a discharge form within NeoTree, called NeoDischarge. We conducted a descriptive analysis of the exported pseudoanonymized data and presented it to the newborn care department as a digital outcome audit. RESULTS: Of 191 total admissions, 134 (70.2%) admissions were completed using NeoTree, and 129 (67.5%) were exported and analyzed. Of 121 patients for whom outcome data were available, 102 (84.3%) were discharged alive. The overall case fatality rate was 93 per 1000 admitted babies. Prematurity with respiratory distress syndrome, birth asphyxia, and neonatal sepsis contributed to 25% (3/12), 58% (7/12), and 8% (1/12) of deaths, respectively. Data were more than 90% complete for all fields. Deaths may have been underreported because of phased implementation and some families of babies with imminent deaths self-discharging home. Detailed characterization of the data enabled departmental discussion of modifiable factors for quality improvement, for example, improved thermoregulation of infants. CONCLUSIONS: This digital outcome audit demonstrates that data can be captured digitally at the bedside by HCPs in underresourced newborn facilities, and these data can contribute to a meaningful review of the quality of care, outcomes, and potential modifiable factors. Coverage may be improved during future implementation by streamlining the admission process to be solely via digital format. Our results present a new methodology for newborn audits in low-resource settings and are a proof of concept for a novel newborn data system in these settings.

The management and referral of iliofemoral deep venous thrombosis in North West London.

BACKGROUND: Post-thrombotic syndrome is a common complication of iliofemoral deep venous thrombosis (IFDVT). Existing evidence and National Institute for Health and Care Excellence guidelines suggest that this can be reduced by prompt thrombolytic therapy or thrombectomy. We aimed to evaluate the characteristics of IFDVT patients and to identify whether patients are being offered the recommended treatment pathway. METHODS: A multicenter cross-sectional study was conducted across eight hospital sites in the North West London region, of which two were hub hospitals in their local vascular service networks. Patients with proximal DVT were identified using International Classification of Diseases, Tenth Revision coding during a 1-year period. Data on demographics, diagnostic methods used, interventions, and referrals were extracted from electronic and paper medical records. RESULTS: During the study period, 132 patients with IFDVT were identified (mean age, 59.4 years; 55% female); 75% of these patients had an IFDVT. In this cohort, the biggest predisposing factors were previous DVT (n = 35), malignant disease (n = 35), and immobility (n = 20). In total, 104 patients were administered anticoagulation, and 88 of these patients received anticoagulation within 24 hours. The cases of 45 patients were either discussed with or promptly referred to a vascular service, after which 20 patients were treated solely with anticoagulation, whereas 20 patients received thrombolysis of varying methods. CONCLUSIONS: A significant proportion (56%) of symptomatic IFDVT patients are not being appropriately referred to or discussed with vascular services. Of these, 43% would have been eligible for consideration of early thrombus removal. Adherence to the National Institute for Health and Care Excellence guidelines could be improved by increasing awareness among emergency department colleagues.

The association between sodium fluctuations and mortality in surgical patients requiring intensive care.

PURPOSE: Serum sodium derangement is the most common electrolyte disturbance among patients admitted to intensive care. This study aims to validate the association between dysnatremia and serum sodium fluctuation with mortality in surgical intensive care patients. METHOD: We performed a retrospective analysis of the Medical Information Mart for Intensive Care II database. Dysnatremia was defined as a sodium concentration outside physiologic range (135-145mmol/L) and subjects were categorized by severity of dysnatremia and sodium fluctuation. Univariate and multivariable logistic regressions were used to test for associations between sodium fluctuations and mortality. RESULTS: We identified 8600 subjects, 39% of whom were female, with a median age of 66years for analysis. Subjects with dysnatremia were more likely to be dead at 28 days (17% vs 7%; P<.001). There was a significant association between sodium fluctuation and mortality at 28 days (adjusted odds ratio per 1mmol/L change, 1.10 [95% confidence interval, 1.08-1.12; P<.001]), even in patients who remained normotremic during their intensive care unit stay (1.12 [95% confidence interval, 1.09-1.16; P<.001]) CONCLUSIONS: This observational study validates previous findings of an association between serum sodium fluctuations and mortality in surgical intensive care patients. This association was also present in subjects who remained normonatremic throughout their intensive care unit admission.

#PlasticSurgery.

BACKGROUND: Social media use is growing inexorably, and there is public appetite for evidence-based information. Little is known about engagement by plastic surgeons with social media. The aim of this study was to examine posting about plastic surgery on Twitter, to best inform how board-certified plastic surgeons could use the hashtag #PlasticSurgery as a tool to educate patients and the public. METHODS: A prospective analysis of 2880 "tweets" containing the words "plastic surgery" was performed. The following were assessed: identity of author, use of the hashtag #PlasticSurgery, subject matter, whether link to study was provided, and whether posts by surgeons were self-promotional or educational. RESULTS: Social media posting about plastic surgery is dominated by the public, accounting for 70.6 percent of posts versus only 6.0 percent by plastic surgeons. Only 5.4 percent of all tweets contained the hashtag #PlasticSurgery, although almost half of those that did were by plastic surgeons. Of these, 61.3 percent of posts by plastic surgeons were about aesthetic surgery; additional posts were about basic science, patient safety, and reconstruction (13.9, 4.0, and 2.3 percent, respectively). Eighteen scientific articles were referenced, with a link to the Journal site posted in two tweets. Of posts by plastic surgeons, 37.0 percent were self-promotional. CONCLUSIONS: The American Society of Plastic Surgeons and its Journal have recognized that social media may be used to educate and engage. Board-certified plastic surgeons have a great opportunity to promote evidence-based plastic practice by means of #PlasticSurgery in the interests of supporting patients and the profession.