Antibody-drug conjugates in lung and breast cancer: current evidence and future directions-a position statement from the ETOP IBCSG Partners Foundation.

Following the approval of the first antibody-drug conjugates (ADCs) in the early 2000s, development has increased dramatically, with 14 ADCs now approved and >100 in clinical development. In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small-cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 [datopotamab deruxtecan and sacituzumab govitecan (SG)] and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing. Thus, in the coming years, we are likely to see significant changes to treatment algorithms. As the number of available ADCs increases, biomarkers (of response and resistance) to better select patients are urgently needed. Biopsy sample collection at the time of treatment selection and incorporation of translational research into clinical trial designs are therefore critical. Biopsy samples taken peri- and post-ADC treatment combined with functional genomics screens could provide insights into response/resistance mechanisms as well as the impact of ADCs on tumour biology and the tumour microenvironment, which could improve understanding of the mechanisms underlying these complex molecules. Many ADCs are undergoing evaluation as combination therapy, but a high bar should be set to progress clinical evaluation of any ADC-based combination, particularly considering the high cost and potential toxicity implications. Efforts to optimise ADC dosing/duration, sequencing and the potential for ADC rechallenge are also important, especially considering sustainability aspects. The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access to data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes.

Oral Health Advice for Looked-After-Children: A pilot care pathway in Buckinghamshire, UK.

INTRODUCTION: Looked-After-Children (LAC) frequently are more likely to have untreated dental caries, periodontal diseases or dental trauma (McMahon et al., 2018). The COVID-19 pandemic reduced the availability of dental appointments, including for LAC. This initiative piloted the inclusion of a dental pathway into the existing LAC care pathway in Buckinghamshire. The key principle was providing oral health messaging around maintaining good oral health and preventing disease in these children by training those involved with their care. METHODS: A working group was convened, which included dental public health, clinical and training expertise. A care pathway was developed with resources drawn from existing programmes including mini Mouth Care Matters (mMCM). The care pathways were designed to identify children who needed care urgently due to pain or discomfort, signpost them to the relevant/most appropriate providers and provide oral health improvement advice for everyone. Local partners were engaged to ensure that the processes and training were appropriate. A pilot training session was then carried out for a range of staff engaged in the care of LAC within Buckinghamshire. RESULTS: The pilot dental pathway, launched in March 2022, initiative was welcomed by all stakeholders, including dental commissioners. The pilot training session received positive feedback from participants, with requests for more sessions. Training sessions were subsequently translated into video sessions, accessible when needed, for new staff or as refresher sessions. CONCLUSION: There are opportunities to reduce future inequalities for these children by inculcating positive behaviours early in their care journey. This will reduce their need for care. Identifying and implementing the most appropriate initiatives requires collaboration and commitment from all stakeholders.

Pathologist-initiated reflex testing for biomarkers in non-small-cell lung cancer: expert consensus on the rationale and considerations for implementation.

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

Who moves in vulnerable Caribbean neighborhoods? Positive deviance for physical activity: Findings from the Jamaica health and Lifestyle Survey 2017 (JHLS III).

Decreased physical activity (PA) has been associated with residents living in neighborhoods perceived as being disordered or having high crime levels. What is unknown are the characteristics of individuals who engage in moderate to vigorous levels of PA (MVPA) despite living in these vulnerable neighborhoods, or who may be referred to as positive deviants (PD). We examined the factors associated with PD for PA among Jamaicans. Between 2016 and 2017 the Jamaica Health and Lifestyle Survey, a cross-sectional nationally representative survey (n = 2807), was conducted on individuals aged 15 years and older. Regression analyses were performed to identify associations with PD, defined using engagement in MVPA among persons living in vulnerable neighborhoods (N = 1710). Being female (odds ratio [OR]a = 0.64 (0.48, 0.86); p = 0.003), obese while living in an urban area (ORa = 0.39; 95 % CI = 0.26, 0.59; p < 0.0001), unemployed (ORa = 0.53; 95 % CI = 0.39, 0.73; p < 0.0001), or a student (ORa = 0.62; 95 % CI = 0.39, 0.98); p = 0.041) was associated with a significantly lower likelihood of PD, while having a personal medical history of at least one chronic disease significantly increased likelihood (ORa = 1.43; 95 % CI = 1.08, 1.90; p = 0.014). Taking a PD approach may be one angle to consider in trying to determine what is working and for whom, so that this may be harnessed in policy, prevention and intervention programming to increase PA.

Editorial - Management of the oral health of care home residents in general and those with dementia.

Health Education England (HEE) is responsible for educating and training the health workforce in England, ensuring the workforce has the right numbers, skills, values, and behaviours to support patients. This includes developing a multi-professional dental care workforce able to meet the needs of current and future service requirements. The recognised challenge will be to train and develop clinicians to address the changing needs concomitant with the population demographics.

ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer.

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study.

BACKGROUND: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10-8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. RESULTS: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-ß signalling and Th17 cell differentiation. CONCLUSIONS: Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

How dirty is your QWERTY? The risk of healthcare pathogen transmission from computer keyboards.

INTRODUCTION: Healthcare environmental surfaces may be contaminated with micro-organisms that cause healthcare-associated infections (HCAIs). Special attention is paid to near-patient surfaces but sites outside the patient zone receive less attention. This paper presents data on keyboard contamination and the risk of pathogen transmission from keyboards. METHODS: Keyboards from nursing stations in three hospitals and a dental practice were analysed for bacterial contamination. Surfaces were pre-treated to remove planktonic bacteria so that any remaining bacteria were presumed to be associated with biofilm. Bacterial transfer from keyboard keys was studied following wiping with sterile water or sodium hypochlorite. The presence of multi-drug-resistant organisms (MDROs) was sought using selective culture. RESULTS: Moist swabbing did not detect bacteria from any keyboard samples. Use of enrichment broth, however, demonstrated MDROs from most samples. Gram-negative bacteria were recovered from almost half (45%) of the samples, with meticillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus and MDR Acinetobacter spp. recovered from 72%, 31% and 17% of samples, respectively. Isolates were transferred from 69% of samples after wiping with sterile water, and from 54% of samples after wiping with 1000 ppm sodium hypochlorite. DISCUSSION: While moist swabbing failed to detect bacteria from keyboards, pathogens were recovered using enrichment culture. Use of water- or NaOCl-soaked wipes transferred bacteria from most samples tested. This study implies that hospital keyboards situated outside the patient zone commonly harbour dry surface biofilms (DSBs) that offer a potential reservoir for transferable pathogens. While the role of keyboards in transmission is uncertain, there is a need to pursue effective solutions for eliminating DSBs from keyboards.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

Rates, determinants and success of implementing deprescribing in people with type 2 diabetes: A scoping review.

BACKGROUND: Individualizing goals for people with type 2 diabetes may result in deintensification of medication, but a comprehensive picture of deprescribing practices is lacking. AIMS: To conduct a scoping review in order to assess the rates, determinants and success of implementing deprescribing of glucose-, blood pressure- or lipid-lowering medications in people with diabetes. METHODS: A systematic search on MEDLINE and Embase between January 2007 and January 2019 was carried out for deprescribing studies among people with diabetes. Outcomes were rates of deprescribing related to participant characteristics, the determinants and success of deprescribing, and its implementation. Critical appraisal was conducted using predefined tools. RESULTS: Fourteen studies were included; eight reported on rates, nine on determinants and six on success and implementation. Bias was high for studies on success of deprescribing. Deprescribing rates ranged from 14% to 27% in older people with low HbA1c levels, and from 16% to 19% in older people with low systolic blood pressure. Rates were not much affected by age, gender, frailty or life expectancy. Rates were higher when a reminder system was used to identify people with hypoglycaemia, which led to less overtreatment and fewer hypoglycaemic events. Most healthcare professionals accepted the concept of deprescribing but differed on when to conduct it. Deprescribing glucose-lowering medications could be successfully conducted in 62% to 75% of participants with small rises in HbA1c . CONCLUSIONS: Deprescribing of glucose-lowering medications seems feasible and acceptable, but was not widely implemented in the covered period. Support systems may enhance deprescribing. More studies on deprescribing blood pressure- and lipid-lowering medications in people with diabetes are needed.

Prehabilitation in elective abdominal cancer surgery in older patients: systematic review and meta-analysis.

BACKGROUND: Prehabilitation has emerged as a strategy to prepare patients for elective abdominal cancer surgery with documented improvements in postoperative outcomes. The aim of this study was to assess the evidence for prehabilitation interventions of relevance to the older adult. METHODS: Systematic searches were conducted using MEDLINE, Web of Science, Scopus, CINAHL and PsychINFO. Studies of preoperative intervention (prehabilitation) in patients undergoing abdominal cancer surgery reporting postoperative outcomes were included. Age limits were not set as preliminary searches revealed this would be too restrictive. Articles were screened and selected based on PRISMA guidelines, and assessment of bias was performed. Qualitative, quantitative and meta-analyses of data were conducted as appropriate. RESULTS: Thirty-three studies (3962 patients) were included. Interventions included exercise, nutrition, psychological input, comprehensive geriatric assessment and optimization, smoking cessation and multimodal (two or more interventions). Nine studies purposely selected high-risk, frail or older patients. Thirty studies were at moderate or high risk of bias. Ten studies individually reported benefits in complication rates, with meta-analyses for overall complications demonstrating significant benefit: multimodal (risk difference -0·1 (95 per cent c.i. -0·18 to -0·02); P = 0·01, I2  = 18 per cent) and nutrition (risk difference -0·18 (-0·26 to -0·10); P < 0·001, I2  = 0 per cent). Seven studies reported reductions in length of hospital stay, with no differences on meta-analysis. CONCLUSION: The conclusions of this review are limited by the quality of the included studies, and the heterogeneity of interventions and outcome measures reported. Exercise, nutritional and multimodal prehabilitation may reduce morbidity after abdominal surgery, but data specific to older patients are sparse.

ANTECEDENTES: La pre-habilitación ha surgido como una estrategia para preparar a los pacientes para la cirugía electiva del cáncer abdominal con mejoras documentadas en los resultados postoperatorios. El objetivo de este estudio fue evaluar la evidencia sobre las intervenciones de pre-habilitación relevantes en adultos de edad avanzada. MÉTODOS: Se realizaron búsquedas sistemáticas utilizando MEDLINE, Web of Science, Scopus, CINAHL y PsychINFO. Registro PROSPERO: CRD42019120381. Se incluyeron estudios de intervención preoperatoria (pre-habilitación) en pacientes sometidos a cirugía oncológica abdominal que describiesen resultados postoperatorios. No se fijaron límites en la edad dado que las búsquedas preliminares revelaron que ello sería demasiado restrictivo. Los artículos fueron examinados y seleccionados en base a las guías PRISMA y se realizó una evaluación del sesgo. Se llevó a cabo un análisis cualitativo, cuantitativo y metaanálisis de los datos según fuese apropiado. RESULTADOS: Se incluyeron 33 estudios (3.962 patients). Las intervenciones incluyeron ejercicio, nutrición, intervención psicológica, evaluación geriátrica global y optimización, abandono del tabaquismo y multimodal (dos o más intervenciones). Nueve estudios seleccionaron expresamente una población de pacientes de elevado riesgo, frágiles o de edad avanzada. Treinta estudios presentaban un riesgo moderado/alto de sesgo. Diez estudios describieron de forma individual beneficios en las tasas de complicaciones con metaanálisis para las complicaciones globales demostrando un beneficio significativo: multimodal (diferencia de riesgo -0,1 (i.c. del 95% −0,18 a −0,02); P = 0,01, I2 = 18%) e intervención nutricional (diferencia de riesgo −0,18 (i.c. del 95% −0,26 a −0,10); P < 0,001, I2 = 0%). Siete estudios describieron reducciones en la duración de la estancia hospitalaria, sin diferencias en el metaanálisis. CONCLUSIÓN: Las conclusiones de esta revisión están limitadas por la calidad de los estudios incluidos, heterogeneidad de las intervenciones y descripción de las medidas de resultados. Las intervenciones de pre-habilitación de ejercicio, nutricionales y multimodales puede reducir la morbilidad tras cirugía abdominal, pero los datos concretos en pacientes de edad avanzada son escasos.

Introduction of an enhanced recovery protocol into a laparoscopic living donor nephrectomy programme.

INTRODUCTION: Living-donor renal transplantation is the optimal treatment for patients with end-stage renal disease. The rate of living donation in the UK is sub-optimal, and potential donor concerns regarding postoperative recovery may be contributory. Enhanced recovery programmes are well described for a number of surgical procedures, but experience in living-donor surgery is sparse. This study reports the impact of introducing an enhanced recovery protocol into a living-donor renal transplant programme. MATERIALS AND METHODS: All consecutive patients undergoing laparoscopic living-donor nephrectomy over a 25-month period were included. The principles of enhanced recovery were fluid restriction, morphine sparing and expectation management. Outcome measures were postoperative pain scores and complications for donor and recipients. RESULTS: Standard care was provided for 24 (30%) patients and 57 (70%) followed an enhanced recovery pathway. The latter group received significantly less preoperative intravenous fluid (0ml vs 841ml p < 000.1) and opiate medication (14.83mg vs 23.85mg p = 0.001). Pain scores, postoperative complications and recipient transplant outcomes were comparable in both groups. CONCLUSIONS: Enhanced recovery for living-donor nephrectomy is a safe approach for donors and recipients. Application of these techniques and further refinement should be pursued to enhance the experience of living donors.

Exceptional preservation of mid-Cretaceous marine arthropods and the evolution of novel forms via heterochrony.

Evolutionary origins of novel forms are often obscure because early and transitional fossils tend to be rare, poorly preserved, or lack proper phylogenetic contexts. We describe a new, exceptionally preserved enigmatic crab from the mid-Cretaceous of Colombia and the United States, whose completeness illuminates the early disparity of the group and the origins of novel forms. Its large and unprotected compound eyes, small fusiform body, and leg-like mouthparts suggest larval trait retention into adulthood via heterochronic development (pedomorphosis), while its large oar-like legs represent the earliest known adaptations in crabs for active swimming. Our phylogenetic analyses, including representatives of all major lineages of fossil and extant crabs, challenge conventional views of their evolution by revealing multiple convergent losses of a typical "crab-like" body plan since the Early Cretaceous. These parallel morphological transformations may be associated with repeated invasions of novel environments, including the pelagic/necto-benthic zone in this pedomorphic chimera crab.

Beware biofilm! Dry biofilms containing bacterial pathogens on multiple healthcare surfaces; a multi-centre study.

BACKGROUND: Wet biofilms associated with medical devices have been widely studied and their link with healthcare-associated infections (HCAIs) is well recognized. Little attention has been paid to the presence of dry biofilms on environmental surfaces in healthcare settings. AIM: To investigate the occurrence, prevalence, and diversity of dry biofilms on hospital surfaces. METHODS: Sixty-one terminally cleaned items were received from three different UK hospitals. The presence of dry biofilm was investigated using culture-based methods and scanning electron microscopy (SEM). Bacterial diversity within biofilms was investigated using ribosomal RNA intergenic spacer analysis (RISA)-polymerase chain reaction and next-generation sequencing. FINDINGS: Multi-species dry biofilms were recovered from 95% of 61 samples. Abundance and complexity of dry biofilms were confirmed by SEM. All biofilms harboured Gram-positive bacteria including pathogens associated with HCAI; 58% of samples grew meticillin-resistant Staphylococcus aureus. Dry biofilms had similar physical composition regardless of the type of items sampled or the ward from which the samples originated. There were differences observed in the dominance of particular species: dry biofilms from two hospitals contained mostly staphylococcal DNA, whereas more Bacillus spp. DNA was found on surfaces from the third hospital. CONCLUSION: The presence of dry biofilms harbouring bacterial pathogens is virtually universal on commonly used items in healthcare settings. The role of dry biofilms in spreading HCAIs may be underestimated. The risk may be further exacerbated by inefficient cleaning and disinfection practices for hospital surfaces.