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Tuberculosis (TB) caused by bacteria of the Mycobacterium tuberculosis complex remains one of the most important infectious diseases of mankind. Rifampicin is a first line drug used in multi-drug treatment of TB, however, the necessary duration of treatment with these drugs is long and development of resistance is an increasing impediment to treatment programmes. As a result, there is a requirement for research and development of new TB drugs, which can form the basis of new drug combinations, either due to their own anti-mycobacterial activity or by augmenting the activity of existing drugs such as rifampicin. This study describes a TnSeq analysis to identify mutants with enhanced sensitivity to sub-minimum inhibitory concentrations (MIC) of rifampicin. The rifampicin-sensitive mutants were disrupted in genes of a variety of functions and the majority fitted into three thematic groups: firstly, genes that were involved in DNA/RNA metabolism, secondly, genes involved in sensing and regulating mycobacterial cellular systems, and thirdly, genes involved in the synthesis and maintenance of the cell wall. Selection at two concentrations of rifampicin (1/250 and 1/62 MIC) demonstrated a dose response for mutants with statistically significant sensitivity to rifampicin. The dataset reveals mechanisms of how mycobacteria are innately tolerant to and initiate an adaptive response to rifampicin; providing putative targets for the development of adjunctive therapies that potentiate the action of rifampicin.
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Pruebas de Sensibilidad Microbiana , Mycobacterium bovis , Rifampin , Rifampin/farmacología , Mycobacterium bovis/efectos de los fármacos , Mycobacterium bovis/genética , Antituberculosos/farmacología , Mutación , Farmacorresistencia Bacteriana/genéticaRESUMEN
BACKGROUND: No evidence-based treatments exist for atypical anorexia nervosa (AAN) and little is known about differences in response to treatment between anorexia nervosa (AN) and AAN. The purpose of this paper is to explore treatment outcomes in two pilot trials for those with AN and AAN. METHODS: Study 1 (Nâ¯=â¯127) examined treatment outcomes in a digital imaginal exposure trial and Study 2 (Nâ¯=â¯34) examined outcomes in a personalized treatment trial. Participants with an active eating disorder (ED) were eligible and those with AN or AAN were included in these analyses. ED symptoms and ED-related fears were assessed at pre-treatment, post-treatment, and one and six-month follow-up. Linear mixed effects models explored treatment outcomes by diagnosis. RESULTS: There were no significant differences in treatment response between diagnoses for most outcome measures. In Study 2, participants with AAN had a significant decrease in global ED symptoms across time, while AN did not. LIMITATIONS: The samples were primarily white and female, limiting the generalizability of the studies. Additionally, due to limited consensus on "significant weight loss," a less conservative definition was used to diagnose AAN which may impact the results. CONCLUSIONS: In general, those with AN and AAN may respond to treatment similarly, with some small differences. Digital exposure therapy may be effective treatments for both AN and AAN, especially for ED-related fears. Personalized treatment may be more effective for those with AAN than those with AN.
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OBJECTIVE: Imaginal exposure is a novel intervention for eating disorders (EDs) that has been investigated as a method for targeting ED symptoms and fears. Research is needed to understand mechanisms of change during imaginal exposure for EDs, including whether within- and between-session distress reduction is related to treatment outcomes. METHOD: Study 1 tested four sessions of online imaginal exposure (N = 143). Study 2 examined combined imaginal and in vivo exposure, comprising six imaginal exposure sessions (N = 26). ED symptoms and fears were assessed pre- and posttreatment, and subjective distress and state anxiety were collected during sessions. RESULTS: Subjective distress tended to increase within-session in both studies, and within-session reduction was not associated with change in ED symptoms or fears. In Study 1, between-session reduction of distress and state anxiety was associated with greater decreases in ED symptoms and fears pre-to posttreatment. In Study 2, between-session distress reduction occurred but was not related to outcomes. CONCLUSIONS: Within-session distress reduction may not promote change during exposure for EDs, whereas between-session distress reduction may be associated with better treatment outcomes. These findings corroborate research on distress reduction during exposure for anxiety disorders. Clinicians might consider approaches to exposure-based treatment that focus on distress tolerance and promote between-session distress reduction.
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Ansiedad , Trastornos de Alimentación y de la Ingestión de Alimentos , Terapia Implosiva , Distrés Psicológico , Humanos , Femenino , Terapia Implosiva/métodos , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Resultado del Tratamiento , Adulto , Adulto Joven , Ansiedad/terapia , Ansiedad/psicología , Adolescente , Miedo/psicología , Masculino , Estrés Psicológico/terapia , Estrés Psicológico/psicologíaRESUMEN
Eating disorders (EDs) are maintained by core fears, which lead to avoidance behaviors, such as food avoidance or compensatory behaviors. Previously tested exposure-based treatments for EDs have generally focused on proximal outcomes (e.g., food), rather than addressing core fears (e.g., fear of weight gain and its consequences). The current study tested the feasibility and initial clinical efficacy of 10 sessions of imaginal and in vivo exposure for core ED fears (termed "Facing Eating Disorder Fears"), mainly fear of weight gain and its associated consequences. Participants were 36 adults with anorexia nervosa (AN), bulimia nervosa, or other specified feeding and eating disorders determined by semistructured diagnostic interviews. ED symptoms, fears, and body mass index (BMI) were assessed at pretreatment, posttreatment, and 1-month follow-up. Treatment involved 10 sessions of imaginal and in vivo exposure to ED fears in combination with in vivo exposures to feared and avoided situations as homework. ED symptoms and fears decreased from pre- to posttreatment and at 1-month follow-up. BMI increased significantly from pre- to posttreatment, particularly for those with AN. Effect sizes ranged from small to very large. ED symptoms and fears decreased and BMI increased following exposure. Increases in BMI occurred without any direct intervention on eating, suggesting that weight gain can be achieved without a specific focus on food during ED treatment. Facing Eating Disorder Fears may be a feasible stand-alone intervention for EDs. Future research must test comparative efficacy through randomized controlled trials.
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Anorexia Nerviosa , Trastorno por Atracón , Bulimia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Adulto , Humanos , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Bulimia Nerviosa/diagnóstico , Bulimia Nerviosa/terapia , Anorexia Nerviosa/terapia , Miedo , Aumento de Peso , Trastorno por Atracón/terapiaRESUMEN
Tuberculosis remains the most pervasive infectious disease and the recent emergence of drug-resistant strains emphasizes the need for more efficient drug treatments. A key feature of pathogenesis, conserved between the human pathogen Mycobacterium tuberculosis and the model pathogen Mycobacterium marinum, is the metabolic switch to lipid catabolism and altered expression of virulence genes at different stages of infection. This study aims to identify genes involved in sustaining viable intracellular infection. We applied transposon sequencing (Tn-Seq) to M. marinum, an unbiased genome-wide strategy combining saturation insertional mutagenesis and high-throughput sequencing. This approach allowed us to identify the localization and relative abundance of insertions in pools of transposon mutants. Gene essentiality and fitness cost of mutations were quantitatively compared between in vitro growth and different stages of infection in two evolutionary distinct phagocytes, the amoeba Dictyostelium discoideum and the murine BV2 microglial cells. In the M. marinum genome, 57% of TA sites were disrupted and 568 genes (10.2%) were essential, which is comparable to previous Tn-Seq studies on M. tuberculosis and M. bovis. Major pathways involved in the survival of M. marinum during infection of D. discoideum are related to DNA damage repair, lipid and vitamin metabolism, the type VII secretion system (T7SS) ESX-1, and the Mce1 lipid transport system. These pathways, except Mce1 and some glycolytic enzymes, were similarly affected in BV2 cells. These differences suggest subtly distinct nutrient availability or requirement in different host cells despite the known predominant use of lipids in both amoeba and microglial cells.IMPORTANCEThe emergence of biochemically and genetically tractable host model organisms for infection studies holds the promise to accelerate the pace of discoveries related to the evolution of innate immunity and the dissection of conserved mechanisms of cell-autonomous defenses. Here, we have used the genetically and biochemically tractable infection model system Dictyostelium discoideum/Mycobacterium marinum to apply a genome-wide transposon-sequencing experimental strategy to reveal comprehensively which mutations confer a fitness advantage or disadvantage during infection and compare these to a similar experiment performed using the murine microglial BV2 cells as host for M. marinum to identify conservation of virulence pathways between hosts.
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Amoeba , Dictyostelium , Mycobacterium marinum , Mycobacterium tuberculosis , Tuberculosis , Animales , Ratones , Humanos , Virulencia/genética , Microglía , Mycobacterium marinum/genética , Dictyostelium/genética , LípidosRESUMEN
Anorexia nervosa (AN) is a serious and persistent psychiatric illness. Many individuals with AN cycle between stages of remission (i.e., relapse), with research documenting that cognitive remission generally lags behind nutritional/weight restoration. Yet, little is known about which mechanisms promote movement from partial remission in AN (defined as nutritional, but not cognitive, recovery) to full remission. Fear-based processes, including avoidance and approach behaviors, likely contribute to the persistence of cognitive-behavioral AN symptoms after nutritional restoration. The current study used intensive longitudinal data to characterize these processes during partial remission (N = 41 participants with partially remitted AN; 4306 total observations). We aimed to a) characterize frequency of fear-based processes in real-time, b) investigate associations across fear-based processes and behavioral urges, and c) test if real-time associations among symptoms differed across commonly feared stimuli (e.g., food, social situations). On average, participants endorsed moderate fear and avoidance, with weight-gain fears rated higher than other feared stimuli. Momentary fear, avoidance, approach, and distress were all positively associated with AN behavior urges at one time-point and prospectively. Central symptoms and symptom connections differed across models with different feared stimuli. These findings provide empirical support for the theorized fear-avoidance-urge cycle in AN, which may contribute to the persistence of eating pathology during partial remission. Fear approach may be associated with temporary increases in urges, which should be considered during treatment. Future research should explore these associations in large, heterogeneous samples, and test the effectiveness of exposure-based interventions during partial remission.
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Anorexia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Anorexia Nerviosa/terapia , Factores de Tiempo , Miedo , Respuesta Patológica CompletaRESUMEN
Importance: Equitable allocation of scarce medications is an important health policy goal. There are few data about attempts to achieve equitable allocation in the community setting. Objective: To describe the development and use of a weighted lottery to allocate a scarce supply of tixagevimab with cilgavimab as preexposure prophylaxis to COVID-19 for immunocompromised individuals and examine whether this promoted equitable allocation to disadvantaged populations. Design, Setting, and Participants: This quality improvement study analyzed a weighted lottery process from December 8, 2021, to February 23, 2022, that assigned twice the odds of drug allocation of 450 tixagevimab with cilgavimab doses to individuals residing in highly disadvantaged neighborhoods according to the US Area Deprivation Index (ADI) in a 35-hospital system in Pennsylvania, New York, and Maryland. In all, 10â¯834 individuals were eligible for the lottery. Weighted lottery results were compared with 10â¯000 simulated unweighted lotteries in the same cohort performed after drug allocation occurred. Main Outcomes: Proportion of individuals from disadvantaged neighborhoods and Black individuals who were allocated and received tixagevimab with cilgavimab. Results: Of the 10â¯834 eligible individuals, 1800 (16.6%) were from disadvantaged neighborhoods and 767 (7.1%) were Black. Mean (SD) age was 62.9 (18.8) years, and 5471 (50.5%) were women. A higher proportion of individuals from disadvantaged neighborhoods was allocated the drug in the ADI-weighted lottery compared with the unweighted lottery (29.1% vs 16.6%; P < .001). The proportion of Black individuals allocated the drug was greater in the weighted lottery (9.1% vs 7.1%; P < .001). Among the 450 individuals allocated tixagevimab with cilgavimab in the ADI-weighted lottery, similar proportions of individuals from disadvantaged neighborhoods accepted the allocation and received the drug compared with those from other neighborhoods (27.5% vs 27.9%; P = .93). However, Black individuals allocated the drug were less likely to receive it compared with White individuals (3 of 41 [7.3%] vs 118 of 402 [29.4%]; P = .003). Conclusions and Relevance: The findings of this quality improvement study suggest an ADI-weighted lottery process to allocate scarce resources is feasible in a large health system and resulted in more drug allocation to and receipt of drug by individuals who reside in disadvantaged neighborhoods. Although the ADI-weighted lottery also resulted in more drug allocation to Black individuals compared with an unweighted process, they were less likely to accept allocation and receive it compared with White individuals. Further strategies are needed to ensure that Black individuals receive scarce medications allocated.
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Anticuerpos Monoclonales , COVID-19 , Disparidades en Atención de Salud , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , COVID-19/terapia , Política de Salud , Hospitales , Negro o Afroamericano , Recursos en SaludRESUMEN
OBJECTIVE: Eating disorders (EDs) are serious mental illnesses with high mortality and relapse rates and carry significant societal and personal costs. Nevertheless, there are few evidence-based treatments available. One aspect that makes treatment difficult is the high heterogeneity in symptom presentation. This heterogeneity makes it challenging for clinicians to identify pertinent treatment targets. Personalized treatment based on idiographic models may be well-suited to address this heterogeneity, and, in turn, presumably improve treatment outcomes. METHODS: In the current randomized controlled trial, participants will be randomly assigned to either 20 sessions of enhanced cognitive behavioral therapy (CBT-E) or transdiagnostic network-informed personalized treatment for EDs (T-NIPT-ED). Assessment of ED symptoms, clinical impairment, and quality of life will occur at pre-, mid-, posttreatment, and 1-month follow-up. RESULTS: We will examine the acceptability and feasibility of T-NIPT-ED compared to CBT-E. We also will test the initial clinical efficacy of T-NIPT-ED versus CBT-E on clinical outcomes (i.e., ED symptoms and quality of life). Finally, we will test if the network-identified precision targets are the mechanisms of change. DISCUSSION: Ultimately, this research may inform the development and dissemination of evidence-based personalized treatments for EDs and serve as an exemplar for personalized treatment development across the broader field of psychiatry. PUBLIC SIGNIFICANCE: Current evidence-based treatments for eating disorders result in low rates of recovery, especially for adults with AN. Our study aims to test the feasibility, acceptability, and clinical efficacy of a data-driven, individualized approach to ED treatment, network-informed personalized treatment, compared to the current evidence-based treatment for EDs, Enhanced CBT. Findings have the potential to improve treatment outcomes for EDs by identifying and targeting core symptoms maintaining EDs.
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Terapia Cognitivo-Conductual , Trastornos de Alimentación y de la Ingestión de Alimentos , Adulto , Humanos , Calidad de Vida , Proyectos Piloto , Medicina de Precisión , Terapia Cognitivo-Conductual/métodos , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Resultado del TratamientoRESUMEN
PURPOSE: Fear of weight gain may play a central role in maintaining eating disorders (EDs), but research on the role of fear of weight gain during cognitive behavioral therapy (CBT-E) for binge-spectrum EDs is sparse. We examined changes in fear of weight gain during CBT-E for binge-spectrum EDs. We investigated whether fear of weight gain predicted loss of control (LOC) eating or weight change. METHODS: Participants (N = 63) were adults of any gender recruited as part of a larger trial. Participants received 12 sessions of CBT-E, completed diagnostic assessments at pre-, mid-, and post-treatment, and completed brief surveys before sessions. RESULTS: Fear of weight gain decreased across treatment, moderated by diagnosis. Those with bulimia nervosa spectrum EDs (BN-spectrum), compared to binge eating disorder, reported higher fear of weight gain at baseline and experienced a larger decrease in fear across treatment. Those reporting higher fear of weight gain at a given session experienced more frequent LOC episodes the following week. Fear of weight gain was not associated with session-by-session changes in BMI. CONCLUSION: CBT-E results in decreases in fear of weight gain, but levels remain high at post-treatment, especially for those with BN-spectrum EDs. Future interventions should consider targeting fear of weight gain as a maintaining factor for LOC episodes TRIAL REGISTRATION: NCT04076553. LEVEL OF EVIDENCE: Level II controlled trial without randomization.
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Trastorno por Atracón , Bulimia Nerviosa , Terapia Cognitivo-Conductual , Trastornos de Alimentación y de la Ingestión de Alimentos , Adulto , Humanos , Trastorno por Atracón/terapia , Bulimia Nerviosa/terapia , Miedo , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Aumento de PesoRESUMEN
BACKGROUND: Whether surrogate decision makers regret decisions about the use of life support for incapacitated, critically ill patients remain uncertain. We sought to determine the prevalence of decision regret among surrogates of adult ICU patients and identify factors that influence regret. METHODS: We conducted a secondary analysis of data from the PARTNER 2 trial, which tested a family support intervention for surrogates of critically ill adults. At 6-month follow-up, surrogates rated their regret about life support decisions using the Decision Regret Scale (DRS), scored from 0 to 100, with higher scores indicating more regret. We used multiple linear regression to identify covariates associated with decision regret based on a psychological construct of regret. We constructed two models using the full cohort; model 1 included patient outcomes; model 2 focused on covariates known at the time of ICU decision-making. Subgroup analyses were also conducted based on patient survival status at hospital discharge and 6-month follow-up. RESULTS: 748 of 848 surrogates had complete DRS data. The median (IQR) DRS score was 15 (0, 25). Overall, 54% reported mild regret (DRS 5-25), 19% moderate-strong regret (DRS 30-100), and 27% no regret (DRS 0). Poor patient outcome at 6 months (death or severe functional dependence) was associated with more regret in model 1 (ß 10.1; 95% C.I. 3.2, 17.0). In model 2, palliative care consultation (3.0; 0.1, 5.9), limitations in life support (LS) prior to death (6.3; 3.1, 9.4) and surrogate black race (6.3; 0.3, 12.3) were associated with more regret. Other modulators of regret in subgroup analyses included surrogate age and education level, surrogate-patient relationship, death in hospital (compared to the post-discharge period), and code status at time of ICU admission. CONCLUSIONS: One in five ICU surrogate decision makers experience moderate to strong regret about life support decisions in ICU. Poor patient outcomes are linked to more regret. Decisions to limit life support prior to patient death may also increase regret. Future studies are needed to understand how regret relates to decision quality and how to lessen lasting regret.
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Enfermedad Crítica , Toma de Decisiones , Adulto , Humanos , Enfermedad Crítica/epidemiología , Enfermedad Crítica/terapia , Prevalencia , Cuidados Posteriores , Unidades de Cuidados Intensivos , Alta del PacienteRESUMEN
OBJECTIVE: Eating disorders (EDs) are maintained by fear and anxiety, which lead to disordered eating behaviors thought to prevent the occurrence of feared outcomes. Fear of weight gain and food are among the most common fears present in the EDs. However, theory and clinical observation suggest that the feared consequences of eating or weight gain are diverse and individualized. Further research is needed to delineate specific fears underlying ED pathology. METHOD: 167 participants with any ED participated in an online four-session imaginal exposure intervention. Imaginal exposure scripts were rated by trained coders using items derived from the Eating Disorder Fear Interview to identify fears present. Frequencies of fears present in scripts were quantified. RESULTS: Two-thirds of scripts mentioned fears of food and weight or body-related fears. In over half of scripts, fear of judgment and fear of loss of control were identified. Diagnostic differences were found, including that those with anorexia nervosa (AN) and bulimia nervosa (BN) had highest fears of food, whereas those with AN and other specified feeding and eating disorder (OSFED) had higher weight gain/body-focused fears. LIMITATIONS: We were underpowered to make comparisons between ED diagnoses other than AN, BN, and OSFED. CONCLUSIONS: Imaginal exposure scripts contained a large number of fears related to food, weight/shape, judgment, and loss of control, among others. These findings extend the current understanding of ED fears and provide evidence for the individualized and varied nature of fears. Identification of ED fears can further inform research on designing personalized, exposure-based treatment approaches.
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Anorexia Nerviosa , Bulimia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Miedo , Bulimia Nerviosa/terapia , Anorexia Nerviosa/terapia , Anorexia Nerviosa/diagnóstico , Aumento de PesoRESUMEN
AIMS: FOCUS4 was a phase II/III umbrella trial, recruiting patients with advanced or metastatic colorectal cancer, between 2014 and 2020. Molecular profiling of patients' formalin-fixed, paraffin-embedded tumour blocks was undertaken at two centralised biomarker laboratories (Leeds and Cardiff), and the results fed directly to the Medical Research Council Clinical Trials Unit, and used for subsequent randomisation. Here the laboratories discuss their experiences. METHODS: Following successful tumour content assessment, blocks were sectioned for DNA extraction and immunohistochemistry (IHC). Pyrosequencing was initially used to determine tumour mutation status (KRAS, NRAS, BRAF and PIK3CA), then from 2018 onwards, next-generation sequencing was employed to allow the inclusion of TP53. Protein expression of MLH1, MSH2, MSH6, PMS2 and pTEN was determined by IHC. An interlaboratory comparison programme was initiated, allowing sample exchanges, to ensure continued assay robustness. RESULTS: 1291 tumour samples were successfully analysed. Assay failure rates were very low; 1.9%-3.3% for DNA sequencing and 0.9%-1.3% for IHC. Concordance rates of >98% were seen for the interlaboratory comparisons, where a result was obtained by both laboratories. CONCLUSIONS: Practical and logistical problems were identified, including poor sample quality and difficulties with sample anonymisation. The often last-minute receipt of a sample for testing and a lack of integration with National Health Service mutation analysis services were challenging. The laboratories benefitted from both pretrial validations and interlaboratory comparisons, resulting in robust assay development and provided confidence during the implementation of new sequencing technologies. We conclude that our centralised approach to biomarker testing in FOCUS4 was effective and successful.
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Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Laboratorios , Medicina Estatal , Proteínas Proto-Oncogénicas B-raf/genética , Mutación , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
Exposure therapy has been investigated as a treatment for eating disorders, but prior research has largely neglected core fears underlying the disorder such as rejection, abandonment, disgust, and loss of control. We tested the feasibility and acceptability of using imaginal exposure to target disordered eating related fears by randomizing participants (N = 47) with disordered eating to: imaginal exposure (IE), imaginal exposure preceded by a brief food exposure (IE + Food), or an assessment control. Participants attended two in-person visits and completed pretreatment, posttreatment, and one-month follow-up questionnaires. IE was rated more acceptable than IE + Food. Retention was high across conditions. Habituation occurred for subjective distress and believability of feared outcomes, suggesting that imaginal exposure effectively activates core fears. Distress tolerance and confidence in ability to change improved. Disordered eating symptoms, fears, preoccupations, and rituals decreased in all conditions, indicating that IE was not specifically responsible for improvement.
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Trastornos de Alimentación y de la Ingestión de Alimentos , Terapia Implosiva , Humanos , Miedo , Trastornos de Alimentación y de la Ingestión de Alimentos/terapiaRESUMEN
Targeted therapy against actionable variants has revolutionised the treatment landscape for non-small cell lung cancer (NSCLC). Approximately half of NSCLC adenocarcinomas have an actionable variant, making molecular testing a critical component of the diagnostic process to personalise therapeutic options, optimise clinical outcomes and minimise toxicity. Recently, genomic testing in England has undergone major changes with the introduction of Genomic Laboratory Hubs, designed to consolidate and enhance existing laboratory provision and deliver genomic testing as outlined in the National Genomic Test Directory. Similar changes are ongoing in Scotland, Wales and Northern Ireland. However, multiple challenges exist with current tissue acquisition procedures and the molecular testing pathway in the UK, including quantity and quality of available tissue, adequacy rates, test availability among genomic laboratories, turnaround times, multidisciplinary team communication, and limited guidance and standardisation. The COVID-19 pandemic has added an extra layer of complexity. Herein, we summarise best practice recommendations, based on expert opinion, to overcome existing challenges in the UK. The least invasive biopsy technique should be undertaken with the aim of acquiring the greatest quality and quantity of tissue. Use of sedation should be considered to improve patient experience. Rapid on-site evaluation may also be useful to help guide adequate sampling, and liquid biopsy may be beneficial in some instances. Sample processing should be appropriate to facilitate biomarker testing, in particular, next-generation sequencing for comprehensive genomic information. Steps to optimise tissue utilisation and turnaround times, such as planning of tissue usage, limiting immunohistochemistry, tumour enrichment, and reflex testing at diagnosis, should be implemented. Guidelines for tissue acquisition and sample processing may help to improve sample adequacy to perform downstream testing. Communication among genomic laboratories will help to standardise test availability across England and local auditing could identify further areas for optimisation, including ways to improve turnaround times and adequacy rates.
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COVID-19 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Técnicas de Diagnóstico Molecular , Pandemias , Reino UnidoRESUMEN
Background: The National Academy of Medicine recently identified improving clinicians' serious illness communication skills as a necessary step in improving patient and family outcomes near the end of life, but there is not an accepted set of core communication skills for engaging with surrogate decision makers. Objective: To determine the core serious illness communication skills clinicians should acquire to care for incapacitated, hospitalized patients with acute, life-threatening illness, including patients with Alzheimer's disease and related dementias. Methods: From January 2019 to July 2020, we conducted a modified Delphi study with a panel of 79 experts in the field of serious illness communication. We developed a preliminary list of candidate communication skills through a structured literature review. We presented the candidate skills to the panelists in the context of three prototypical serious illness conversations. Over three rounds, panelists first augmented the list of candidate skills, then voted on the skills. The final set included skills deemed "very important" or "essential" by 70% of panelists. For external validation, we engaged 11 practicing clinicians and 7 community stakeholders for their perspectives on the expert-endorsed list of skills. Results: The panelists' ratings indicate the importance of a diverse set of communication skills related to providing clear information exchange as well as emotional and psychological support to surrogates. The final set included 33 skills, 12 of which were endorsed for all three prototypical serious illness conversations. Practicing clinicians and community stakeholders supported the expert-endorsed framework with only minor additions. Conclusion: We generated a stakeholder-endorsed list of skills that can inform the content of communication skills training programs for clinicians who care for incapacitated patients in the inpatient setting. The skills go beyond those required to provide traditional cognitive decision support and suggest the need for a paradigm shift in curricular content for communication training.
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BACKGROUND: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes. METHODS: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. INTERPRETATION: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial. FUNDING: AstraZeneca and Cancer Research UK.
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Inhibidores de la Aromatasa , Neoplasias de la Mama , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Método Doble Ciego , Femenino , Fulvestrant , Humanos , Recurrencia Local de Neoplasia/patología , Fosfatidilinositol 3-Quinasas/genética , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas c-akt , Pirimidinas , Pirroles , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismoRESUMEN
BACKGROUND: Each year, approximately one million older adults die in American intensive care units (ICUs) or survive with significant functional impairment. Inadequate symptom management, surrogates' psychological distress and inappropriate healthcare use are major concerns. Pioneering work by Dr. J. Randall Curtis paved the way for integrating palliative care (PC) specialists to address these needs, but convincing proof of efficacy has not yet been demonstrated. DESIGN: We will conduct a multicenter patient-randomized efficacy trial of integrated specialty PC (SPC) vs. usual care for 500 high-risk ICU patients over age 60 and their surrogate decision-makers from five hospitals in Pennsylvania. INTERVENTION: The intervention will follow recommended best practices for inpatient PC consultation. Patients will receive care from a multidisciplinary SPC team within 24 hours of enrollment that continues until hospital discharge or death. SPC clinicians will meet with patients, families, and the ICU team every weekday. SPC and ICU clinicians will jointly participate in proactive family meetings according to a predefined schedule. Patients in the control arm will receive routine ICU care. OUTCOMES: Our primary outcome is patient-centeredness of care, measured using the modified Patient Perceived Patient-Centeredness of Care scale. Secondary outcomes include surrogates' psychological symptom burden and health resource utilization. Other outcomes include patient survival, as well as interprofessional collaboration. We will also conduct prespecified subgroup analyses using variables such as PC needs, measured by the Needs of Social Nature, Existential Concerns, Symptoms, and Therapeutic Interaction scale. CONCLUSIONS: This trial will provide robust evidence about the impact of integrating SPC with critical care on patient, family, and health system outcomes.
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Enfermedad Crítica , Enfermería de Cuidados Paliativos al Final de la Vida , Anciano , Cuidados Críticos , Enfermedad Crítica/terapia , Humanos , Unidades de Cuidados Intensivos , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Cuidados Paliativos/métodos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Large-scale efforts to train clinicians in serious-illness communication skills are needed, but 2 important gaps in knowledge remain. (1) No proven training method exists that can be readily scaled to train thousands of clinicians. (2) Though the value of interprofessional collaboration to support incapacitated patients' surrogates is increasingly recognized, few interventions for training intensive care unit (ICU) nurses in important communication skills can be leveraged to provide interprofessional family support. OBJECTIVE: To develop and test a web/videoconference-based platform to train nurses to communicate about serious illness. METHODS: A user-centered process was used to develop the intervention, including (1) iteratively engaging a stakeholder panel, (2) developing prototype and beta versions of the platform, and (3) 3 rounds of user testing with 13 ICU nurses. Participants' ratings of usability, acceptability, and perceived effectiveness were assessed quantitatively and qualitatively. RESULTS: Stakeholders stressed that the intervention should leverage interactive learning and a streamlined digital interface. A training platform was developed consisting of 6 interactive online training lessons and 3 group-based video-conference practice sessions. Participants rated the program as usable (mean summary score 84 [96th percentile]), acceptable (mean, 4.5/5; SD, 0.7), and effective (mean, 4.8/5; SD, 0.6). Ten of 13 nurses would recommend the intervention over 2-day in-person training. CONCLUSIONS: Nurses testing this web-based training program judged it usable, acceptable, and effective. These data support proceeding with an appropriately powered efficacy trial.
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Comunicación , Unidades de Cuidados Intensivos , Enfermeras y Enfermeros , Educación a Distancia , Educación en Enfermería , HumanosRESUMEN
BACKGROUND: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. METHODS: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. RESULTS: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014-March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016-July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017-October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. CONCLUSION: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Fosfatidilinositol 3-Quinasa Clase I/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , HumanosRESUMEN
OBJECTIVE: Growing evidence suggests that subjective binge eating (SBE; loss of control eating involving subjectively, but not objectively, large quantities of food) is clinically concerning even though it is not currently considered a diagnostic criterion for eating disorders. However, the lived experience of SBEs has not been examined in a systematic, and data-driven way. METHOD: The current study used a qualitative, inductive interview approach to further define SBEs as described by individuals who experience them. Participants (N = 14; 11 cisgender women, Mage = 35.29, 12 White/non-Latinx) reported SBEs that occurred at least twice per week over the prior 3 months. We completed semi-structured qualitative phone interviews with participants regarding their most recent SBE and objective binge-eating episode (OBE) if applicable, as well as broader experiences and attitudes regarding non-binge eating. RESULTS: Inductive, reflexive, thematic coding yielded descriptive and interpretive codes regarding SBEs. Main themes regarding SBE experience included: (a) SBEs Occur Across Contexts and Food Types, (b) SBEs Are Contrasts to General Over-Control, (c) SBEs Are Distress- and Disconnection-Inducing, Not Relieving, (d) SBEs Are Responses to Hunger and Restriction, and (e) SBEs Can Be "Echoes" of OBEs. DISCUSSION: The current study explored the lived experiences of those who report SBEs and provides an important foundation for hypothesis generation for future research on and clinical interventions for SBEs.