Implementation of a perioperative registry in Ethiopia to enhance surgical quality improvement.

BACKGROUND: Despite a glaring need and proven efficacy, prospective surgical registries are lacking in low- and middle-income countries. The objective of this study was to design and implement a comprehensive prospective perioperative registry in a low-income country. METHODS: This study was conducted at Hawassa University Comprehensive Specialized Hospital in Hawassa, Ethiopia. Design of the registry occurred from June 2021 to May 2022 and pilot implementation from May 2022 to May 2023. All patients undergoing elective or emergent general surgery were included. Following one year, operability and fidelity of the registry were analyzed by assessing capture rate, incidence of missing data, and accuracy. RESULTS: A total of 67 variables were included in the registry including demographics, preoperative, operative, post-operative, and 30-day data. Of 440 eligible patients, 226 (51.4%) were successfully captured. Overall incidence of missing data and accuracy was 5.4% and 90.2% respectively. Post pilot modifications enhanced capture rate to 70.5% and further optimized data collection processes. CONCLUSION: The establishment of a low-cost electronic prospective perioperative registry in a low-income country represents a significant step forward in enhancing surgical care in under-resourced settings. The initial success of this registry highlights the feasibility of such endeavors when strong partnerships and local context are at the center of implementation. Continuous efforts to refine this registry are ongoing, which will ultimately lead to enhanced surgical quality, research output, and expansion to other sites.

Patient Satisfaction Using BREAST-Q and Breast Implant Illness after Breast Reconstruction in Transwomen.

Background: Gender-affirming breast augmentation comprises an increasing portion of breast augmentations performed by plastic surgeons. Satisfaction and breast implant illness (BII) symptoms in this population have not been well studied. This study aimed to evaluate satisfaction and BII symptoms in transwomen who received nontextured implants as part of their breast reconstruction. Methods: We conducted a retrospective review of transwomen who underwent breast augmentation for gender-affirming surgery. We performed telephone survey evaluation using the BREAST-Q questionnaire preoperatively, 6 months and 1 year after breast implant placement. Survey evaluation asking about BII symptoms was also administered at the same time points. Results: Twenty-six patients completed the BREAST-Q survey, which demonstrated significantly improved satisfaction postoperatively at 6 and 12 months when compared with median preoperative scores for psychosocial (P < 0.001; P < 0.001), sexual (P < 0.001; P < 0.001), and overall satisfaction with breasts (P < 0.001; P < 0.001). Physical well-being of the chest decreased at 6 months (P < 0.001) but improved in comparison with 12 months (P < 0.001). Thirty-four patients completed the BII survey, with 18% reporting symptoms at 3 months and 29% at 1 year. Zero patients requested explantation. Conclusions: Transwomen exhibit a significant increase in breast, psychosocial, and sexual well-being after breast augmentation. However, patients experienced a decreased physical well-being, and many report symptoms associated with BII. These results can be used to better counsel these individuals preoperatively and set reasonable postoperative expectations. Further studies investigating long-term satisfaction in larger cohorts are needed.

Competitive fitness of asymptomatic bacteriuria E. coli strain 83972 against uropathogens in human urine.

Urinary tract infection (UTI) is one of the most common bacterial infections worldwide. The main causative agent of UTI is uropathogenic Escherichia coli (UPEC). There is an immediate need for novel prophylactic and treatment strategies against UTI because of the increasing incidence of antimicrobial resistance among uropathogens. ABU 83972, an asymptomatic bacteriuria-causing E. coli strain, prevents UTI by suppressing the colonization of UPEC. However, the nature of competition and growth repression of UPEC by ABU 83972 is unclear and is the subject of our investigation. Here, we characterized the growth kinetics of ABU 83972 and uropathogens in human urine and laboratory media. Next, we performed a series of competitive co-culture experiments where ABU 83972 and uropathogens were inoculated at a 1:1 ratio in human urine and in various media, and their relative abundance was determined. In human urine, ABU 83972 outcompeted UPEC and additional uropathogens, reaching up to 90% of the total population after 24 hours of incubation. In contrast, UPEC outcompeted ABU 83972 in LB and M9 minimal media and exhibited superior colonization than ABU 83972 in the mouse urinary bladder. Since engineered living materials (ELMs) can be used to retain an organism of interest in a particular location, we developed ABU 83972-containing ELMs that effectively outcompeted UPEC in human urine. In summary, our work establishes that ABU 83972 outcompetes UPEC in a milieu- and cell-density-dependent manner, highlighting the importance of the metabolites and nutrients found in the human urine as determinants of the competitive fitness of ABU 83972.

Ulcerative stomatitis associated with yellow bristle grass in New Zealand dairy cows.

CASE HISTORY: A line of 25 cull cows were all found to have ulcerative lesions of the tongue at post-mortem inspection in a New Zealand slaughter plant. A further 9 of 10 cows inspected at the farm of origin had similar oral lesions. There were no other clinical signs or indicators of ill-health observed at ante-mortem inspection in the abattoir or on the farm. The cows had been fed baleage for 3 weeks prior to slaughter, made from pasture in paddocks heavily contaminated with yellow bristle grass (Setaria pumila). CLINICAL FINDINGS: There was extensive and deep transverse linear ulceration in the lingual fossa immediately rostral to the torus linguae. At histological examination, full-thickness ulceration of the stratified squamous epithelium was observed with a bed of disorganised collagenous tissue and extensive mixed inflammatory infiltrate extending into the sub-epithelial connective tissue and skeletal muscle. Barbed plant fragments were embedded in both the superficial and deeper areas of inflammation. Detailed examination of the baleage also found that yellow bristle grass seedheads were present. DIAGNOSIS: Based on the presence of barbed plant material in the tongue and yellow bristle grass seeds in the baleage, a diagnosis of ulcerative stomatitis associated with yellow bristle grass was made. CLINICAL RELEVANCE: Clinicians should be aware of the potential for hay or baleage contaminated with yellow bristle grass to cause oral lesions in cattle.

School Readiness in Preschool-Age Children with Critical Congenital Heart Disease.

This study examined the nature, variability, and predictors of school readiness difficulties in young children with critical congenital heart disease (CCHD). We hypothesized that, compared to a community control (CC) group, children with CCHD would score less well on measures of readiness and that readiness would be associated with CCHD-related risk factors. Children (60 CCHD and 60 CC) were 4 to 5 years of age and not yet attending kindergarten. Readiness measures included tests of cognition, executive function, motor ability, and pre-academic skills. Caregivers provided child behavior ratings. Analyses examined group differences in readiness, readiness profiles, and associations of readiness with CCHD-related medical risk factors. The CCHD group had lower scores than the CC group on testing and higher caregiver ratings of problems in social communication, as well as higher rates of deficits on several of the measures. Latent class analysis provided evidence for different readiness profiles, with more children with CCHD displaying profiles characterized by weaknesses in readiness. CCHD-related medical risk factors associated with readiness problems in the CCHD group included a co-morbid genetic disorder, postnatal diagnosis of CCHD, major perioperative complication, and longer periods of hospitalizations, cardiopulmonary bypass, and aortic cross-clamp placements. Findings document multiple problems in school readiness in young children with CCHD. Deficits vary across individuals and are associated with higher medical risk. Results confirm the importance of screening for school readiness in these children and suggest areas to target in designing screening measures and providing early childhood interventions.

Predicting stress in first-year college students using sleep data from wearable devices.

Consumer wearables have been successful at measuring sleep and may be useful in predicting changes in mental health measures such as stress. A key challenge remains in quantifying the relationship between sleep measures associated with physiologic stress and a user's experience of stress. Students from a public university enrolled in the Lived Experiences Measured Using Rings Study (LEMURS) provided continuous biometric data and answered weekly surveys during their first semester of college between October-December 2022. We analyzed weekly associations between estimated sleep measures and perceived stress for participants (N = 525). Through mixed-effects regression models, we identified consistent associations between perceived stress scores and average nightly total sleep time (TST), resting heart rate (RHR), heart rate variability (HRV), and respiratory rate (ARR). These effects persisted after controlling for gender and week of the semester. Specifically, for every additional hour of TST, the odds of experiencing moderate-to-high stress decreased by 0.617 or by 38.3% (p<0.01). For each 1 beat per minute increase in RHR, the odds of experiencing moderate-to-high stress increased by 1.036 or by 3.6% (p<0.01). For each 1 millisecond increase in HRV, the odds of experiencing moderate-to-high stress decreased by 0.988 or by 1.2% (p<0.05). For each additional breath per minute increase in ARR, the odds of experiencing moderate-to-high stress increased by 1.230 or by 23.0% (p<0.01). Consistent with previous research, participants who did not identify as male (i.e., female, nonbinary, and transgender participants) had significantly higher self-reported stress throughout the study. The week of the semester was also a significant predictor of stress. Sleep data from wearable devices may help us understand and to better predict stress, a strong signal of the ongoing mental health epidemic among college students.

Convergent Validity Between the Motor Domain of PediaTracTM and Ages and Stages in Term and Preterm Infants at 2, 4, 6, and 9 Months of Age.

The primary aim of this study was to evaluate the convergent validity of the Motor domain (MOT) of PediaTracTM v3.0, an online developmental tracking instrument based on caregiver reports, with fine and gross motor domains (ASQ-FM and ASQ-GM) of the Ages and Stages Questionnaire (ASQ-3) in infants between 2- and 9 months of age. Participants were caregivers of 571 infants born term or preterm (gestational age <37 weeks) enrolled in a multi-site psychometric study of PediaTracTM. Findings revealed significant correlations between MOT and ASQ-3 scores at 2, 4, 6, and 9 months across time periods, term-preterm status, and biological sex. A significantly higher percentage of infants born preterm, compared with those born at term, was identified as a moderate or high risk on both the ASQ-3 and PediaTrac. Future investigations are warranted to further examine the psychometric properties of the MOT domain, including sensitivity, specificity, and positive and negative predictive value.

Resource competition predicts assembly of gut bacterial communities in vitro.

Microbial community dynamics arise through interspecies interactions, including resource competition, cross-feeding and pH modulation. The individual contributions of these mechanisms to community structure are challenging to untangle. Here we develop a framework to estimate multispecies niche overlaps by combining metabolomics data of individual species, growth measurements in spent media and mathematical models. We applied our framework to an in vitro model system comprising 15 human gut commensals in complex media and showed that a simple model of resource competition accounted for most pairwise interactions. Next, we built a coarse-grained consumer-resource model by grouping metabolomic features depleted by the same set of species and showed that this model predicted the composition of 2-member to 15-member communities with reasonable accuracy. Furthermore, we found that incorporation of cross-feeding and pH-mediated interactions improved model predictions of species coexistence. Our theoretical model and experimental framework can be applied to characterize interspecies interactions in bacterial communities in vitro.

Long-Term Outcomes of Pediatric Traumatic Brain Injury Following Inpatient Rehabilitation.

OBJECTIVE: Assess residual disability in youth with traumatic brain injury (TBI) treated in a pediatric inpatient rehabilitation unit and examine associations of disability with inpatient status and measures of concurrent functioning. SETTING: Large, urban, quaternary care children's hospital in the Midwestern United States. PARTICIPANTS: Forty-five youth aged 6 to 18 years treated in an inpatient rehabilitation unit for mild-complicated to severe TBI at a minimum of 12 months postdischarge (mean = 3.5 years). DESIGN: Retrospective chart review of clinical data collected from standard clinical care at admission and discharge combined with follow-up data examining current functioning at the time of study enrollment. MAIN OUTCOME MEASURES: Glasgow Outcome Scale-Extended, Pediatric Revision (GOS-E Peds), Neurology Quality of Life Measurement System Short Form (NeuroQOL) Social Interaction with Peers and Cognitive Short Forms, Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale, Strengths and Difficulties Questionnaire, and the Behavior Rating Inventory of Executive Function, 2nd Edition (BRIEF-2). RESULTS: Based on parent report at follow-up, 62% of the children had residual TBI-related disabilities on the GOS-E Peds, while 38% reported "good recovery." Children with residual disability also reported more long-term problems in overall health, social relationships, emotional regulation, behaviors, and executive functioning than those with no residual disability. Measures of functional independence and cognitive recovery at discharge were associated with these impairments. CONCLUSIONS: More than half of the children with TBI in this study had residual disability more than 1 year after inpatient rehabilitation. Findings highlight the associations between measures of functional independence and cognitive recovery during inpatient rehabilitation with later outcomes and underscore the need for continued services to support the needs of children with TBI following their inpatient rehabilitation stay.

Impacts of Deforestation on Childhood Malaria Depend on Wealth and Vector Biology.

Ecosystem change can profoundly affect human well-being and health, including through changes in exposure to vector-borne diseases. Deforestation has increased human exposure to mosquito vectors and malaria risk in Africa, but there is little understanding of how socioeconomic and ecological factors influence the relationship between deforestation and malaria risk. We examined these interrelationships in six sub-Saharan African countries using demographic and health survey data linked to remotely sensed environmental variables for 11,746 children under 5 years old. We found that the relationship between deforestation and malaria prevalence varies by wealth levels. Deforestation is associated with increased malaria prevalence in the poorest households, but there was not significantly increased malaria prevalence in the richest households, suggesting that deforestation has disproportionate negative health impacts on the poor. In poorer households, malaria prevalence was 27%-33% larger for one standard deviation increase in deforestation across urban and rural populations. Deforestation is also associated with increased malaria prevalence in regions where Anopheles gambiae and Anopheles funestus are dominant vectors, but not in areas of Anopheles arabiensis. These findings indicate that deforestation is an important driver of malaria risk among the world's most vulnerable children, and its impact depends critically on often-overlooked social and biological factors. An in-depth understanding of the links between ecosystems and human health is crucial in designing conservation policies that benefit people and the environment.

Efficacy of a virtual reality-based cognitive interactive training program for children with traumatic brain injuries: study protocol for a parallel-group randomized controlled trial.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of disability in children. Cognitive rehabilitation for this population is critical for their long-term health outcomes. This trial aims to evaluate the efficacy of a virtual reality-based program (VICT) for training executive functions in children with TBI. METHODS: A parallel group randomized controlled trial will be conducted among up to 32 children with TBI. Children in the intervention group will receive the VICT training while children in the control group will play a comparable VR game without executive function training. Each participant will be assessed at baseline, post-intervention, and 1-month follow-up. Outcomes will include core executive functions, attention, and health-related quality of life measured by computerized tasks or standardized questionnaires. DISCUSSION: Cognitive rehabilitation is among the top healthcare needs for pediatric TBI patients. Virtual reality-based training is promising due to its versatile content, flexibility, and potential cost savings for both patients and providers. Findings of this trial will provide data on the efficacy of the VICT program on core executive functions, attention problems, and health-related quality of life and serve as the empirical foundation for future larger multi-site effectiveness trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04526639 . Registered on August 18, 2020.

Measuring Early Relational Health Using PediaTrac TM in a Diverse Sample of Infant-Caregiver Dyads.

OBJECTIVE: Early relational health (ERH) is a key developmental predictor and outcome in infancy and early childhood that reflects social-emotional well-being and promotes resilience throughout childhood. Currently, there is no gold-standard developmental screening tool for ERH in pediatric care settings. This study examined the psychometric properties of items assessing ERH that are part of a web-based, caregiver-report screening tool called PediaTrac TM . It was hypothesized that ERH could be reliably estimated and that second-order factors would be revealed within the latent construct ERH. METHOD: Participants included 571 caregivers of term (n = 331; ≥37 weeks) and preterm (n = 240; <37 weeks) infants recruited shortly after birth from several academic medical centers and a community health clinic. Caregivers completed PediaTrac modules at birth and 2, 4, 6, 9, 12, 15, and 18 months; data for this study are from the newborn through 12-month periods. RESULTS: Results from Item Response Theory Graded Response Modeling revealed excellent reliability for the PediaTrac ERH domain at all time points, ranging from 0.96 to 0.98. Exploratory factor analyses revealed 4 to 5 second-order factors, representing Parent-Child Relationship, Parent Distress, Parenting Stress, Parenting Efficacy, Sensitivity, and Perceptions of Child, depending on period. CONCLUSION: The caregiver-report developmental screening tool, PediaTrac, reliably measures ERH during the first year of life. The measure has promising clinical utility in pediatric clinic settings for tracking ERH over time to ensure early social-emotional well-being and to identify concerns as early as possible.

Predicting Survival with Brain Metastases in the Stereotactic Radiosurgery Era: are Existing Prognostic Scores Still Relevant? Or Can we do Better?

Predicting survival is essential to tailoring treatment for patients diagnosed with brain metastases. We have evaluated the performance of widely used, validated prognostic scoring systems (Graded Prognostic Assessment and diagnosis-specific Graded Prognostic Assessment) in over 1000 'real-world' patients treated with stereotactic radiosurgery to the brain, selected according to National Health Service commissioning criteria. Survival outcomes from our dataset were consistent with those predicted by the prognostic systems, but with certain cancer subtypes showing a significantly better survival than predicted. Although performance status remains the simplest tool for prediction, total brain tumour volume emerges as an independent prognostic factor, and a new, improved, prognostic scoring system incorporating this has been developed.

Lipid-Encapsulated mRNAs Encoding Complex Fusion Proteins Potentiate Antitumor Immune Responses.

Lipid nanoparticle (LNP)-encapsulated mRNA has been used for in vivo production of several secreted protein classes, such as IgG, and has enabled the development of personalized vaccines in oncology. Establishing the feasibility of delivering complex multispecific modalities that require higher-order structures important for their function could help expand the use of mRNA/LNP biologic formulations. Here, we evaluated whether in vivo administration of mRNA/LNP formulations of SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT could achieve oligomerization and extend exposure, on-target activity, and antitumor responses comparable with that of the corresponding recombinant fusion proteins. Intravenous infusion of the formulated LNP-encapsulated mRNAs led to rapid and sustained production of functional hexameric proteins in vivo, which increased the overall exposure relative to the recombinant protein controls by ∼28 to 140 fold over 96 hours. High concentrations of the mRNA-encoded proteins were also observed in secondary lymphoid organs and within implanted tumors, with protein concentrations in tumors up to 134-fold greater than with the recombinant protein controls 24 hours after treatment. In addition, SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT mRNAs induced a greater increase in antigen-specific CD8+ T cells in the tumors. These mRNA/LNP formulations were well tolerated and led to a rapid increase in serum and intratumoral IL2, delayed tumor growth, extended survival, and outperformed the activities of benchmark mAb controls. Furthermore, the mRNA/LNPs demonstrated improved efficacy in combination with anti-PD-L1 relative to the recombinant fusion proteins. These data support the delivery of complex oligomeric biologics as mRNA/LNP formulations, where high therapeutic expression and exposure could translate into improved patient outcomes. SIGNIFICANCE: Lipid nanoparticle-encapsulated mRNA can efficiently encode complex fusion proteins encompassing immune checkpoint blockers and costimulators that functionally oligomerize in vivo with extended pharmacokinetics and durable exposure to induce potent antitumor immunity.

Differences between parent- and teacher-reported executive functioning behaviors after traumatic injuries.

Deficits in executive functioning (EF) behaviors are very common following pediatric traumatic brain injury (TBI) and can linger well after acute injury recovery. Raters from multiple settings provide information that may not be appreciated otherwise. We examined differences between parent and teacher ratings of EF using data examining longitudinal outcomes following pediatric TBI in comparison to orthopedic injury (OI). We used linear mixed models to determine the association of rater type and injury type with scores on the Behavior Rating Inventory of Executive Functioning (BRIEF). After controlling for demographic variables, rater type and injury type accounted for a small but significant proportion of the variance in EF. Teachers' ratings on the BRIEF were significantly higher than parent ratings for global EF and metacognition, but not for behavior regulation, regardless of injury type, indicating greater EF concerns. All BRIEF ratings, whether from teachers or parents, were higher for children with TBI than for those with OI. Results suggest that parents and teachers provide unique information regarding EF following traumatic injuries and that obtaining ratings from persons who observe children at school as well as at home can result in a better understanding of situation-specific variability in outcomes.

Caregiver-reported infant motor and imitation skills predict M-CHAT-R/F.

Altered motor and social-communicative abilities in infancy have been linked to later ASD diagnosis. Most diagnostic instruments for ASD cannot be utilized until 12 months, and the average child is diagnosed substantially later. Imitation combines motor and social-communicative skills and is commonly atypical in infants at risk for ASD. However, few measures have been developed to assess infant imitation clinically. One barrier to the diagnostic age gap of ASD is accessibility of screening and diagnostic services. Utilization of caregiver report to reliably screen for ASD mitigates such barriers and could aid in earlier detection. The present study developed and validated a caregiver-report measure of infant imitation at 4, 6, and 9 months and explored the relationship between caregiver-reported imitation and motor abilities with later ASD risk. Participants (N = 571) were caregivers of term and preterm infants recruited as part of a large multi-site study of PediaTrac™, a web-based tool for monitoring and tracking infant development. Caregivers completed online surveys and established questionnaires on a schedule corresponding to well-child visits from birth to 18 months, including the M-CHAT-R/F at 18 months. Distinct imitation factors were derived from PediaTrac at 4, 6, and 9 months via factor analysis. The results supported validity of the imitation factors via associations with measures of infant communication (CSBS; ASQ). Imitation and motor skills at 9 months predicted 18-month ASD risk over and above gestational age. Implications for assessment of infant imitation, detecting ASD risk in the first year, and contributing to access to care are discussed.

Evaluating multidimensional facets of the maternal experience after preterm birth.

OBJECTIVE: Describe self-relating (self-criticism, self-compassion) and parenting competence (satisfaction, self-efficacy) in mothers of children born preterm, and their associations with child characteristics, maternal sociodemographics at childbirth, and maternal concurrent well-being. STUDY DESIGN: The sample comprised 1926 biological mothers of 3- to18-year-old children born preterm with self-ratings on the standardized Forms of Self-Criticising/Attacking & Self-Reassuring Scale, Self-Compassion Scale, and Parenting Sense of Competence Scale. RESULTS: Mothers of children in early childhood reported significantly (p < 0.05) lower self-compassion than in middle childhood and adolescence. They also reported significantly lower parenting satisfaction than mothers of adolescents and higher self-efficacy than their middle childhood counterparts. Maternal psychosocial well-being was most strongly associated with self-compassion, parenting satisfaction, and self-efficacy after accounting for maternal psychopathology, child gestation, and child age. CONCLUSION: Longer-term associations of preterm birth with maternal self-relating and parenting competence emphasize broadening the scope of neonatal follow-up services, extending beyond child neurodevelopmental surveillance and postpartum psychopathology screening.

Reconfigurable Growth of Engineered Living Materials.

The growth of multicellular organisms is a process akin to additive manufacturing where cellular proliferation and mechanical boundary conditions, among other factors, drive morphogenesis. Engineers have limited ability to engineer morphogenesis to manufacture goods or to reconfigure materials comprised of biomass. Herein, a method that uses biological processes to grow and regrow magnetic engineered living materials (mELMs) into desired geometries is reported. These composites contain Saccharomyces cerevisiae and magnetic particles within a hydrogel matrix. The reconfigurable manufacturing process relies on the growth of living cells, magnetic forces, and elastic recovery of the hydrogel. The mELM then adopts a form in an external magnetic field. Yeast within the material proliferates, resulting in 259 ± 14% volume expansion. Yeast proliferation fixes the magnetic deformation, even when the magnetic field is removed. The shape fixity can be up to 99.3 ± 0.3%. The grown mELM can recover up to 73.9 ± 1.9% of the original form by removing yeast cell walls. The directed growth and recovery process can be repeated at least five times. This work enables ELMs to be processed and reprocessed into user-defined geometries without external material deposition.

Material assembly from collective action of shape-changing polymers.

Some animals form transient, responsive and solid-like ensembles through dynamic structural interactions. These ensembles demonstrate emergent responses such as spontaneous self-assembly, which are difficult to achieve in synthetic soft matter. Here we use shape-morphing units comprising responsive polymers to create solids that self-assemble, modulate their volume and disassemble on demand. The ensemble is composed of a responsive hydrogel, liquid crystal elastomer or semicrystalline polymer ribbons that reversibly bend or twist. The dispersions of these ribbons mechanically interlock, inducing reversible aggregation. The aggregated liquid crystal elastomer ribbons have a 12-fold increase in the yield stress compared with cooled dispersion and contract by 34% on heating. Ribbon type, concentration and shape dictate the aggregation and govern the global mechanical properties of the solid that forms. Coating liquid crystal elastomer ribbons with a liquid metal begets photoresponsive and electrically conductive aggregates, whereas seeding cells on hydrogel ribbons enables self-assembling three-dimensional scaffolds, providing a versatile platform for the design of dynamic materials.

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer.

Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.