A vaccine targeting resistant tumours by dual T cell plus NK cell attack.

Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.

Real-world experience of maralixibat in Alagille syndrome: Novel findings outside of clinical trials.

OBJECTIVE: Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients aged ≥3 months with Alagille syndrome (ALGS). Approval was based on reductions in pruritus from the pivotal ICONIC trial, information from two additional trials (ITCH and IMAGO), and long-term extension studies. Although participants in these trials met strict inclusion and exclusion criteria, patients have received maralixibat under broader circumstances as part of an expanded access program or commercially. The expanded access and postapproval settings inform a real-world understanding of effectiveness and safety. The objective was to report on the use of maralixibat in the real-world setting in eight patients who otherwise would not have met entrance criteria for the clinical trials, providing unique insights into its effectiveness in the management of ALGS. METHODS: We reviewed records of patients with ALGS who received maralixibat but would have been excluded from trials due to surgical biliary diversion, reduction of antipruritic/cholestatic concomitant medications, administration of medication through a gastrostomy or nasogastric tube, or use in patients under consideration for transplantation. RESULTS: Maralixibat appeared to be effective with reductions in pruritus compared to baseline. Consistent with clinical trials, maralixibat was well tolerated without appreciable gastrointestinal complications. Liver enzyme elevations were observed but were interpreted as consistent with normal fluctuations observed in ALGS, with no increases in bilirubin. CONCLUSION: Maralixibat may be effective and well tolerated in patients with ALGS in broader clinical contexts than previously reported.

Frailty identification and management among Brazilian healthcare professionals: a survey.

BACKGROUND: National and international guidelines on frailty assessment and management recommend frailty screening in older people. This study aimed to determine how Brazilian healthcare professionals (HCPs) identify and manage frailty in practice. METHODS: An anonymous online survey on the assessment and management of frailty was circulated virtually through HCPs across Brazil. RESULTS: Most of the respondants used non-specific criteria such as gait speed (45%), handgrip strength (37.6%), and comprehensive geriatric assessment (33.2%). The use of frailty-specific criteria was lower than 50%. The most frequently used criteria were the Frailty Index (19.1%), Frailty Phenotype (13.2%), and FRAIL (12.5%). Only 43.5% felt confident, and 40% had a plan to manage frailty. In the multivariate-adjusted models, training was the most crucial factor associated with assessing frailty, confidence, and having a management plan (p < 0.001 for all). Those with fewer years of experience were more likely to evaluate frailty (p = 0.009). Being a doctor increased the chance of using a specific tool; the opposite was true for dietitians (p = 0.03). Those who assisted more older people had a higher likelihood of having a plan (p = 0.011). CONCLUSION: Frailty assessment was heterogeneous among healthcare professions groups, predominantly using non-specific criteria. Training contributed to frailty assessment, use of specific criteria, confidence, and having a management plan. This data informs the need for standardized screening criteria and management plans for frailty, in association with increasing training at the national level for all the HCPs who assist older people.

Independent associations of food addiction and binge eating measures with real-time eating behaviors and contextual factors: An exploratory ecological momentary assessment study.

Food addiction (FA) is a concept centered around the addictive potential of highly palatable processed foods, though there is debate over the discriminative validity of FA as a distinct construct from binge-eating symptomatology. This study explored how trait measures of FA and binge-eating symptoms independently and interactively predicted eating behaviors and posited correlates of FA and binge eating measured via ecological momentary assessment (EMA). Adult participants (N = 49) who met the criteria for FA and/or binge-eating disorder completed baseline measures of FA (Yale Food Addiction Scale [YFAS 2.0]) and binge-eating symptoms (Eating Pathology Symptom Inventory [EPSI] binge eating scale) followed by a 10-day EMA protocol. Generalized linear mixed models examined the independent effects of YFAS 2.0, EPSI, and their interaction predicting EMA outcomes. Higher YFAS 2.0 symptom count scores were uniquely related to greater EMA-measured overeating, loss of control eating, negative and positive affect, and impulsivity when controlling for EPSI scores. Conversely, higher EPSI scores were uniquely related to greater EMA-measured eagerness and urge to eat, and expectancies that eating would improve mood. No interaction effects were significant. These results highlight potential distinctions between phenomena captured by FA and other measures of binge eating, in that FA symptoms may be a marker of heightened binge-eating severity, emotional arousal, and impulsivity.

Associations between affect dynamics and eating regulation in daily life: a preliminary ecological momentary assessment study.

Disordered eating behaviors consistently associated with emotion regulation difficulties. However, most studies have focused on affect intensity without considering dynamic affective patterns. We examined these patterns in relation to daily overeating, loss of control eating (LOCE), dietary restraint, and food craving in young adults using ecological momentary assessment (EMA).Adults (N = 24) completed a 10-day EMA protocol during which they reported momentary affect and eating patterns. Generalized linear mixed-models examined each index in relation to eating variable.Higher PA instability (within-person) was associated with higher ratings of binge-eating symptoms (B = 0.15, SE = 0.06, p = 0.007). Lower NA differentiation (within-person) was associated with higher levels of food craving (B = -10.11, SE = 4.74, p = 0.033).Our results support previous findings suggesting that acute fluctuations in PA may increase risk of binge-eating symptoms. Further, inability to differentiate between momentary states of NA was associated with cravings. This study highlights the importance of examining multiple facets of NA and PA in relation to eating regulation.Trial registration: ClinicalTrials.gov identifier: NCT02945475.

Momentary mechanisms of binge-eating symptoms using ecological momentary assessment: The moderating role of food addiction.

OBJECTIVE: Food addiction (FA) shows phenotypic and diagnostic overlap with eating disorders characterised by binge eating, though it is unknown how momentary processes driving binge-eating symptoms differ by FA. The present study examined the possible moderating influence of FA severity on momentary mechanisms underlying binge-eating symptomatology using ecological momentary assessment (EMA). METHOD: Adults (N = 49, mean age = 34.9 ± 12.1, cis-gender female = 77.1%) who met criteria for FA and/or binge-eating disorder completed baseline measures including the Yale Food Addiction Scale (YFAS) followed by a 10-day EMA protocol. Generalised linear mixed models assessed main effects of YFAS, momentary antecedents (affect, impulsivity, food cue exposure, appetite, and eating expectancies) and two-way interactions between YFAS and within-person antecedents. RESULTS: FA severity moderated momentary associations between food cue exposure and subsequent binge-eating symptoms: the association was stronger among participants with lower but not higher YFAS scores. No other interactions were significant. CONCLUSIONS: Some functional associations underlying binge-eating symptoms vary based on individuals' level of FA symptoms. Future research to further understand how observed associations may differ amongst diverse populations and over course of illness may also inform future prevention and interventions.

See One, Do One, Improve One's Wellness: Resident Autonomy in US General Surgery Programs, A Mixed-methods Study.

OBJECTIVE: We sought to examine the factors associated with resident perceptions of autonomy and to characterize the relationship between resident autonomy and wellness. BACKGROUND: Concerns exist that resident autonomy is decreasing, impacting competence. METHODS: Quantitative data were collected through a cross-sectional survey administered after the 2020 ABSITE. Qualitative data were collected through interviews and focus groups with residents and faculty at 15 programs. RESULTS: Seven thousand two hundred thirty-three residents (85.5% response rate) from 324 programs completed the survey. Of 5139 residents with complete data, 4424 (82.2%) reported appropriate autonomy, and these residents were less likely to experience burnout [odds ratio (OR) 0.69; 95% CI 0.58-0.83], suicidality (OR 0.69; 95% CI 0.54-0.89), and thoughts of leaving their programs (OR 0.45; 95% CI 0.37-0.54). Women were less likely to report appropriate autonomy (OR 0.81; 95% CI 0.68-0.97). Residents were more likely to report appropriate autonomy if they also reported satisfaction with their workload (OR 1.65; 95% CI 1.28-2.11), work-life balance (OR 2.01; 95% CI 1.57-2.58), faculty engagement (OR 3.55; 95% CI 2.86-4.35), resident camaraderie (OR 2.23; 95% CI, 1.78-2.79), and efficiency and resources (OR 2.37; 95% CI 1.95-2.88). Qualitative data revealed that (1) autonomy gives meaning to the clinical experience of residency, (2) multiple factors create barriers to autonomy, and (3) autonomy is not inherent to the training paradigm, requiring residents to learn behaviors to "earn" it. CONCLUSION: Autonomy is not considered an inherent part of the training paradigm such that residents can assume that they will achieve it. Resources to function autonomously should be allocated equitably to support all residents' educational growth and wellness.

International Analgesia and Sedation Weaning and Withdrawal Practices in Critically Ill Adults: The Adult Iatrogenic Withdrawal Study in the ICU.

OBJECTIVES: Iatrogenic withdrawal syndrome (IWS) associated with opioid and sedative use for medical purposes has a reported high prevalence and associated morbidity. This study aimed to determine the prevalence, utilization, and characteristics of opioid and sedative weaning and IWS policies/protocols in the adult ICU population. DESIGN: International, multicenter, observational, point prevalence study. SETTING: Adult ICUs. PATIENTS: All patients aged 18 years and older in the ICU on the date of data collection who received parenteral opioids or sedatives in the previous 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ICUs selected 1 day for data collection between June 1 and September 30, 2021. Patient demographic data, opioid and sedative medication use, and weaning and IWS assessment data were collected for the previous 24 hours. The primary outcome was the proportion of patients weaned from opioids and sedatives using an institutional policy/protocol on the data collection day. There were 2,402 patients in 229 ICUs from 11 countries screened for opioid and sedative use; 1,506 (63%) patients received parenteral opioids, and/or sedatives in the previous 24 hours. There were 90 (39%) ICUs with a weaning policy/protocol which was used in 176 (12%) patients, and 23 (10%) ICUs with an IWS policy/protocol which was used in 9 (0.6%) patients. The weaning policy/protocol for 47 (52%) ICUs did not define when to initiate weaning, and the policy/protocol for 24 (27%) ICUs did not specify the degree of weaning. A weaning policy/protocol was used in 34% (176/521) and IWS policy/protocol in 9% (9/97) of patients admitted to an ICU with such a policy/protocol. Among 485 patients eligible for weaning policy/protocol utilization based on duration of opioid/sedative use initiation criterion within individual ICU policies/protocols 176 (36%) had it used, and among 54 patients on opioids and/or sedatives ≥ 72 hours, 9 (17%) had an IWS policy/protocol used by the data collection day. CONCLUSIONS: This international observational study found that a small proportion of ICUs use policies/protocols for opioid and sedative weaning or IWS, and even when these policies/protocols are in place, they are implemented in a small percentage of patients.

Closing the gap between science and management of cold-water refuges in rivers and streams.

Human activities and climate change threaten coldwater organisms in freshwater ecosystems by causing rivers and streams to warm, increasing the intensity and frequency of warm temperature events, and reducing thermal heterogeneity. Cold-water refuges are discrete patches of relatively cool water that are used by coldwater organisms for thermal relief and short-term survival. Globally, cohesive management approaches are needed that consider interlinked physical, biological, and social factors of cold-water refuges. We review current understanding of cold-water refuges, identify gaps between science and management, and evaluate policies aimed at protecting thermally sensitive species. Existing policies include designating cold-water habitats, restricting fishing during warm periods, and implementing threshold temperature standards or guidelines. However, these policies are rare and uncoordinated across spatial scales and often do not consider input from Indigenous peoples. We propose that cold-water refuges be managed as distinct operational landscape units, which provide a social and ecological context that is relevant at the watershed scale. These operational landscape units provide the foundation for an integrated framework that links science and management by (1) mapping and characterizing cold-water refuges to prioritize management and conservation actions, (2) leveraging existing and new policies, (3) improving coordination across jurisdictions, and (4) implementing adaptive management practices across scales. Our findings show that while there are many opportunities for scientific advancement, the current state of the sciences is sufficient to inform policy and management. Our proposed framework provides a path forward for managing and protecting cold-water refuges using existing and new policies to protect coldwater organisms in the face of global change.