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IMPORTANCE:. Initial Society of Critical Care Medicine Discovery Viral Infection and Respiratory illness Universal Study (VIRUS) Registry analysis suggested that improvements in critical care processes offered the greatest modifiable opportunity to improve critically ill COVID-19 patient outcomes. OBJECTIVES:. The Structured Team-based Optimal Patient-Centered Care for Virus COVID-19 ICU Collaborative was created to identify and speed implementation of best evidence based COVID-19 practices. DESIGN, SETTING, AND PARTICIPANTS:. This 6-month project included volunteer interprofessional teams from VIRUS Registry sites, who received online training on the Checklist for Early Recognition and Treatment of Acute Illness and iNjury approach, a structured and systematic method for delivering evidence based critical care. Collaborators participated in weekly 1-hour videoconference sessions on high impact topics, monthly quality improvement (QI) coaching sessions, and received extensive additional resources for asynchronous learning. MAIN OUTCOMES AND MEASURES:. Outcomes included learner engagement, satisfaction, and number of QI projects initiated by participating teams. RESULTS:. Eleven of 13 initial sites participated in the Collaborative from March 2, 2021, to September 29, 2021. A total of 67 learners participated in the Collaborative, including 23 nurses, 22 physicians, 10 pharmacists, nine respiratory therapists, and three nonclinicians. Site attendance among the 11 sites in the 25 videoconference sessions ranged between 82% and 100%, with three sites providing at least one team member for 100% of sessions. The majority reported that topics matched their scope of practice (69%) and would highly recommend the program to colleagues (77%). A total of nine QI projects were initiated across three clinical domains and focused on improving adherence to established critical care practice bundles, reducing nosocomial complications, and strengthening patient- and family-centered care in the ICU. Major factors impacting successful Collaborative engagement included an engaged interprofessional team; an established culture of engagement; opportunities to benchmark performance and accelerate institutional innovation, networking, and acclaim; and ready access to data that could be leveraged for QI purposes. CONCLUSIONS AND RELEVANCE:. Use of a virtual platform to establish a learning collaborative to accelerate the identification, dissemination, and implementation of critical care best practices for COVID-19 is feasible. Our experience offers important lessons for future collaborative efforts focused on improving ICU processes of care.

Objective: To improve quality of life (QOL) in patients at risk for post–intensive care syndrome (PICS). Patients and Methods: We conducted a mixed-method, prospective, observational, pre-post interventional study in an adult medical and mixed medical/surgical/transplant intensive care unit (ICU) at a tertiary academic hospital. Preintervention included patients admitted from October 1 through October 31, 2016, and postintervention included patients admitted from January 15 through February 14, 2017. First, a multidisciplinary team of stakeholders identified barriers associated with decreased QOL in patients at risk for PICS. Next, interventions were designed and implemented. The effect of interventions was assessed using a mixed-method analysis. The qualitative analysis used a modified grounded theory approach. The quantitative analysis included assessment of preexisting symptoms and risk factors associated with PICS. The 36-Item Short-Form Health Status Survey (SF-36), which surveys physical and mental composite scores, was used to assess QOL. Results: Barriers identified were lack of awareness and understanding of PICS. Interventions included educational videos, paper and online education and treatment materials, and online and in-person support groups for education and treatment. After interventions, the qualitative analysis found that patients who participated in the interventions after hospital discharge showed improved QOL, whereas education during hospitalization alone was not effective. The quantitative analysis did not find improvement in QOL, as defined by SF-36 physical or mental composite scores. Conclusion: Interventions targeted to patients after hospitalization may offer subjective improvement in QOL for those at risk for PICS.

Background . Research remains inconclusive about the most effective frame for encouraging health preventative behaviors. Aims . To examine the impact of gain- and loss-framed health messages on nutrition and physical activity (PA) knowledge in fourth-grade youth participating in the Shaping Healthy Choices Program (SHCP), a multicomponent nutrition program. Methods . Youth were recruited to participate in this 9-month quasi-experimental study and divided into 3 groups: (1) comparison (n = 50), (2) loss-framed (n = 76), and (3) gain-framed (n = 67). All youth participated in the SHCP, and the gain- and loss-framed groups also viewed weekly health messages. Paired t tests or Wilcoxon signed-rank test, ANOVA (analysis of variance), and Bonferroni for multiple comparisons were used for analysis. Results . Youth who participated in the SHCP improved nutrition knowledge (+2.0 points; P < .01) and PA knowledge (+1.8 points; P < .01). Nutrition knowledge improved in the comparison group (+1.3 points; P = .04), loss-framed group (+1.9 points; P = .01), and gain-framed group (+2.6 points; P = .01). Improvements in PA knowledge were also demonstrated in the comparison group (+1.6 points; P < .01), the loss-framed group (+1.3 points; P < .01), and the gain-framed group (+2.5 points; P = .01). There were no significant differences between groups. Youth in the loss-framed group reported a decrease in self-efficacy (−1.2; P = .05), while this was not observed in the other groups. Discussion . The SHCP improves nutrition and PA knowledge, and the positive reinforcement further strengthens some of these improvements, while loss-framed messaging can contribute to undesirable outcomes. Conclusions . Incorporating positive reinforcement through gain-framed messages can be a relatively low-cost avenue for supporting beneficial outcomes.

Introduction: Natural killer (NK) cell-based therapies are a promising new method for treating indolent cancer, however engineering new therapies is complex and progress towards therapy for solid tumors is slow. New methods for determining the underlying intracellular signaling driving the killing phenotype would significantly improve this progress., Methods: We combined single-cell RNA sequencing with live cell imaging of a model system of NK cell killing to correlate transcriptomic data with functional output. A model of NK cell activity, the NK-92 cell line killing of HeLa cervical cancer cells, was used for these studies. NK cell killing activity was observed by microscopy during co-culture with target HeLa cells and killing activity subsequently manually mapped based on NK cell location and Annexin V expression. NK cells from this culture system were profiled by single-cell RNA sequencing using the 10× Genomics platform, and transcription factor activity inferred using the Viper and DoRothEA R packages. Luminescent microscopy of reporter constructs in the NK cells was then used to correlate activity of inferred transcriptional activity with killing activity., Results: NK cells had heterogeneous killing activity during 10 h of culture with target HeLa cells. Analysis of the single cell sequencing data identified Nuclear Factor Kappa B (NF-κB), Signal Transducer and Activator of Transcription 1 (STAT1) and MYC activity as potential drivers of NK cell functional phenotype in our model system. Live cell imaging of the transcription factor activity found NF-κB activity was significantly correlated with past killing activity. No correlation was observed between STAT1 or MYC activity and NK cell killing., Conclusions: Combining luminescent microscopy of transcription factor activity with single-cell RNA sequencing is an effective means of assigning functional phenotypes to inferred transcriptomics data., Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00812-3., Competing Interests: Competing InterestsThe authors declare no competing interests related to this work., (© The Author(s), under exclusive licence to Biomedical Engineering Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: IRX-2 is a multi-cytokine immune-activating agent with anti-tumor activity in non-metastatic head and neck squamous cell carcinoma (HNSCC). Here, we evaluated combined IRX-2 and durvalumab in patients with recurrent and/or metastatic HNSCC., Materials and Methods: This was a phase Ib trial consisting of dose escalation and expansion. Primary endpoints were safety and biomarkers to assess the immune response in the tumor microenvironment including significant increases in PD-L1 expression and CD8 + tumor infiltrating lymphocytes (TIL) comparing pre- and on-treatment tumor biopsies. Secondary endpoints were objective response rates (ORR) and survival outcomes., Results: Sixteen patients were evaluable for response, and nine patients were evaluable for biomarkers. Thirteen patients (68 %) had exposure to prior anti-PD-1 therapy. No dose-limiting or grade ≥ 3 treatment-related adverse events were observed. On-treatment biopsies showed significantly increased PD-L1 (p = 0.005), CD3+ (p = 0.020), CD4+ (p = 0.022), and CD8 + T cells (p = 0.017) compared to pre-treatment. Median overall survival and progression-free survival (PFS) were 6.18 months (95 % CI, 2.66-8.61) and 2.53 months (95 % CI, 1.81-4.04), respectively. One patient had an objective response (ORR, 5.3 %) with an ongoing PFS of > 25 months. Disease control rate was 42 %. The responder harbored an ARID1A variant of unknown significance (VUS) that was predicted to bind her HLA-I alleles with a higher affinity than the reference peptide., Conclusions: IRX-2 and durvalumab were safe and elicited the evidence of immune activation in the tumor microenvironment determined by increased PD-L1 expression and CD8+ TILs., Clinical Trial Registration Number: NCT03381183., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CHC and RJCS—honoraria from Fulgent, Genmab, AVEO, Seagen, Regeneron, and Exelixis for ad hoc Scientific Advisory Board participation. KK – Advisory Board for MyCareGorithm, LLC. I own stock in Seattle Genetics, Oncternal Therapeutics, and Veru; Consulting for A2BioTherapeutics. ALA – Global Advisory Board member and paid consultant for LG Chem Life Sciences Innovation Center. MSH − Moffitt Cancer Center has licensed Intellectual Property (IP) related to the proliferation and expansion of tumor infiltrating lymphocytes (TILs) to Iovance Biotherapeutics. MSH is a co-inventor on such Intellectual Property. MSH reports common stock holdings in AbbVie, Inc., Amgen, Inc., BioHaven Pharmaceuticals, and Bristol Myers Squibb. The rest of the authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Strong molecular photooxidants are important in many disciplines including organic synthesis and renewable energy. In these fields, strongly oxidizing chromophores are employed to drive various transformations from challenging bond formations to energy storage systems. A range of photooxidant strengths are needed to drive these processes. A series of 8 symmetrically bisarylated 5,6-dicyano[2,1,3]benzothiadiazole (DCBT) dyes were studied for their tunability toward breadth of light absorption and photooxidant strength. The dye oxidation strength and light absorption tunability is the result of appending various aryl substituents on the periphery of the DCBT core which shows remarkable tunability of the final chromophore. The dyes are studied via steady-state absorption and emission, time-correlated single photon counting, computational analysis, and cyclic voltammetry. In changing the peripheral aryl substituents via electronics, sterics, and π-conjugation length, a series of dyes are arrived at with a dramatic 1.5 eV range in oxidizing strength and >200 nm (0.95 eV) absorption maxima tunability. Furthermore, two dyes in the series exhibit strong oxidizing strength while still approaching red light absorbance (>650 nm onset) which provides unique opportunities for the use of lower energy light to affect chemical transformations. Ultimately, this series provides options for photooxidations that allow for energetic tuning and selectivity for a given chemical transformation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) is a promising immunotherapeutic approach for patients with advanced solid tumors. While numerous advances have been made, the contribution of neoantigen-specific CD4 + T cells within TIL infusion products remains underexplored and therefore offers a significant opportunity for progress., Methods: We analyzed infused TIL products from metastatic melanoma patients previously treated with ACT for the presence of neoantigen-specific T cells. TILs were enriched on reactivity to neoantigen peptides derived and prioritized from patient sample-directed mutanome analysis. Enriched TILs were further investigated to establish the clonal neoantigen response with respect to function, transcriptomics, and persistence following ACT., Results: We discovered that neoantigen-specific TIL clones were predominantly CD4 + T cells and were present in both therapeutic responders and non-responders. CD4 + TIL demonstrated an effector T cell response with cytotoxicity toward autologous tumor in a major histocompatibility complex class II-dependent manner. These results were validated by paired TCR and single cell RNA sequencing, which elucidated transcriptomic profiles distinct to neoantigen-specific CD4 + TIL., Conclusions: Despite methods which often focus on CD8+T cells, our study supports the importance of prospective identification of neoantigen-specific CD4 + T cells within TIL products as they are a potent source of tumor-specific effectors. We further advocate for the inclusion of neoantigen-specific CD4 + TIL in future ACT protocols as a strategy to improve antitumor immunity., Competing Interests: Competing interests: Moffitt Cancer Center has licensed Intellectual Property (IP) related to the proliferation and expansion of tumor infiltrating lymphocytes (TILs) to Iovance Biotherapeutics. MSH, JEM, SP-T and AS are coinventors on such Intellectual Property. AS and SP-T are coinventors on a patent application with Provectus Biopharmaceuticals. MSH, DA-D, AS and SP-T are coinventors in provisional patent applications filed by Moffitt Cancer Center, including one resulting from the work described in this manuscript. MSH and AMH report common stock holdings in AbbVi, Amgen, BioHaven Pharmaceuticals, and Bristol Myers Squibb. JKT, XY, AS and SP-T participate in a sponsored research agreement with Turnstone Biologics. JJM is Associate Center Director at Moffitt Cancer Center and founder of Piranha Oncology, has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, AffyImmune, Aleta BioTherapeutics, Ankyra Therapeutics, and is a paid consultant/paid advisory board member for ONCoPEP, CG Oncology, Mersana Therapeutics, Turnstone Biologics, Aleta BioTherapeutics, Iovance Biotherapeutics, Vault Pharma, ORI Capital, UbiVac, Vycellix, AffyImmune, and Ankyra. JEM participates in sponsored research agreements with Intellia Therapeutics and SQZ Biotech that are not related to this research. JEM has received research support that is not related to this research from the following entities: Ocala Royal Dames and V Foundation. JEM has received ad hoc consulting fees from Iovance Biotherapeutics, Lyell Therapeutics, and Merit Medical. AS has received Ad hoc consulting fees from Iovance Biotherapeutics, Guidepoint, Defined Health, Huron Consulting Group, KeyQuest Health Inc, Istari, and Gerson Lehrman Group. AS has received speaker fees from Physicians’ Educational Resource (PER), Medscape and Medstar Health. Moffitt has also licensed IP to Tuhura Biopharma. SP-T is an inventor on such Intellectual Property. SP-T participates in sponsored research agreements with Provectus Biopharmaceuticals, Intellia Therapeutics, Dyve Biosciences, and Iovance Biotherapeutics that are not related to this research. SP-T has received consulting fees from Seagen and KSQ Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Question: Is exposure to toxic metal cadmium associated with increased endometriosis prevalence among a nationally representative sample of the US population?, Summary Answer: Concentrations of urinary cadmium, a long-term biomarker (10-30 years) of cadmium exposure, were associated with an increased prevalence of endometriosis., What Is Known Already: Cadmium exhibits estrogenic properties and may increase the risk of endometriosis, a gynecologic condition associated with substantial morbidity, for which estrogen has a central pathogenic role. Previous epidemiological studies of cadmium and endometriosis have yielded mixed results, with null, positive, and inverse associations being reported., Study Design, Size, Duration: We conducted a cross-sectional study using data from four cycles of the National Health and Nutrition Examination Survey (NHANES) 1999-2006., Participants/materials, Setting, Methods: The study population comprised participants aged 20-54 years who had an endometriosis diagnosis, available data on urinary cadmium, and a glomerular filtration rate ≥60 ml/min/1.73 m2 (unweighted n = 1647). Urinary cadmium was measured by inductively coupled plasma-mass spectrometry, and we used urinary creatinine concentrations and covariate-adjusted standardization to account for urinary dilution. Self-reported diagnosis of endometriosis was ascertained by interview. We examined the association between quartiles of urinary cadmium and endometriosis using log-binomial regression to estimate adjusted prevalence ratios (aPRs) and 95% CIs., Main Results and the Role of Chance: We observed twice the prevalence of endometriosis for participants with cadmium concentrations in the second quartile (versus the first quartile) (aPR 2.0, 95% CI: 1.1, 3.9) and the third quartile (versus the first quartile) (aPR 2.0, 95% CI: 1.1, 3.7). Our data also suggested a 60% increased prevalence of endometriosis with urinary cadmium concentrations in the fourth quartile (versus the first quartile) (aPR 1.6, 95% CI: 0.8, 3.2). In a sensitivity analysis, restricting the study population to premenopausal participants with an intact uterus and at least one ovary (unweighted n = 1298), stronger associations accompanied by wider CIs were observed., Limitations, Reasons for Caution: We were limited by the ascertainment of urinary cadmium and endometriosis diagnosis at a single time point, given the cross-sectional study design, and we relied on self-report of endometriosis diagnosis. However, urinary cadmium characterizes long-term exposure and findings from validation studies suggest that misclassification of self-reported endometriosis diagnosis may be minimal., Wider Implications of the Findings: This study suggests that cadmium is associated with an increased endometriosis prevalence. Given the substantial morbidity conferred by endometriosis and that the general population is ubiquitously exposed to cadmium, further research is warranted to confirm our findings., Study Funding/competing Interest(s): This work was supported by the National Institute of Nursing Research (grant R00NR017191 to K.U.) of the National Institutes of Health. The authors report no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Biomaterial scaffolds mimicking the environment in metastatic organs can deconstruct complex signals and facilitate the study of cancer progression and metastasis. Here we report that a subcutaneous scaffold implant in mouse models of metastatic breast cancer in female mice recruits lung-tropic circulating tumor cells yet suppresses their growth through potent in situ antitumor immunity. In contrast, the lung, the endogenous metastatic organ for these models, develops lethal metastases in aggressive breast cancer, with less aggressive tumor models developing dormant lungs suppressing tumor growth. Our study reveals multifaceted roles of neutrophils in regulating metastasis. Breast cancer-educated neutrophils infiltrate the scaffold implants and lungs, secreting the same signal to attract lung-tropic circulating tumor cells. Second, antitumor and pro-tumor neutrophils are selectively recruited to the dormant scaffolds and lungs, respectively, responding to distinct groups of chemoattractants to establish activated or suppressive immune environments that direct different fates of cancer cells., (© 2023. Springer Nature Limited.)

Since 2012, control of invasive wild pigs (Sus scrofa) in the United States (US) has become a state and national priority due to their propensity to damage agricultural commodities and infrastructure, transmit disease, detrimentally affect ecological processes, and compete with native wildlife for resources. While several life-history characteristics certainly aided their proliferation, the recreational value of wild pigs was likely the stimulus for translocation and subsequent establishment of populations in ≥35 states, causing an annual economic burden of $1.5 billion in the US. Consequently, state-level legislative procedures regarding wild pigs are expanding in scope and priority, but policy among states lacks uniformity. States vary in their treatment of wild pig control based on differing resource appropriations and stakeholder interests. We conducted an evaluation to determine if policy was associated with state-level 1) presence of wild pigs, 2) spatial extent of wild pig population occupancy, and 3) trajectory of wild pig population occupancy. Our results suggest the presence of wild pigs in various states was influenced by hunting preserves and the sale of hunting opportunities. In occupied states, the spatial extent of wild pigs was again associated with the sale of hunting opportunities and a wild pig hunting culture. Finally, the trajectory of state-level wild pig spatial occupancy was positively influenced by the sale of hunting opportunities, and negatively influenced by transportation policies. Based on these findings, we propose state governments standardize transportation policy and fenced hunting regulations across regions of the US in a more prohibitive fashion to diminish range expansion through illegal and negligent introductions via transportation, release, and escapes from game farms. Moreover, in states where wild pigs have yet to establish, we strongly recommend states proactively prohibit transportation through intra- and interstate movement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: The mainstay of assessment of the fetal lungs in clinical practice is via evaluation of pulmonary size, primarily using 2D ultrasound and more recently with anatomical magnetic resonance imaging. The emergence of advanced magnetic resonance techniques such as T2* relaxometry in combination with the latest motion correction post-processing tools now facilitates assessment of the metabolic activity or perfusion of fetal pulmonary tissue in vivo., Objective: This study aimed to characterize normal pulmonary development using T2* relaxometry, accounting for fetal motion across gestation., Methods: Datasets from women with uncomplicated pregnancies that delivered at term, were analyzed. All subjects had undergone T2-weighted imaging and T2* relaxometry on a Phillips 3T magnetic resonance imaging system antenatally. T2* relaxometry of the fetal thorax was performed using a gradient echo single-shot echo planar imaging sequence. Following correction for fetal motion using slice-to-volume reconstruction, T2* maps were generated using in-house pipelines. Lungs were manually segmented and mean T2* values calculated for the right and left lungs individually, and for both lungs combined. Lung volumes were generated from the segmented images, and the right and left lungs, as well as both lungs combined were assessed., Results: Eighty-seven datasets were suitable for analysis. The mean gestation at scan was 29.9±4.3 weeks (range: 20.6-38.3) and mean gestation at delivery was 40±1.2 weeks (range: 37.1-42.4). Mean T2* values of the lungs increased over gestation for right and left lungs individually and for both lungs assessed together (P=.003; P=.04; P=.003, respectively). Right, left, and total lung volumes were also strongly correlated with increasing gestational age (P<.001 in all cases)., Conclusion: This large study assessed developing lungs using T2* imaging across a wide gestational age range. Mean T2* values increased with gestational age, which may reflect increasing perfusion and metabolic requirements and alterations in tissue composition as gestation advances. In the future, evaluation of findings in fetuses with conditions known to be associated with pulmonary morbidity may lead to enhanced prognostication antenatally, consequently improving counseling and perinatal care planning., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the association between breastfeeding history, including lifetime exclusive breastfeeding, and risk of adenomyosis., Design: We used data from a case-control study designed with 2 control groups to address the challenge of selecting noncases for a valid epidemiologic study when cases are identified by hysterectomy. The case-control study was conducted among premenopausal and postmenopausal enrollees aged 18-59 years in a large, integrated health care system in western Washington state., Patient(s): Cases were enrollees with incident, pathology-confirmed adenomyosis diagnosed during 2001-2006 (n = 386). The 2 control groups were as follows: (1) randomly selected age-matched enrollees with intact uteri ("population controls," n = 323) and (2) hysterectomy controls (n = 233)., Intervention(s): Data on breastfeeding history were collected by in-person interviews. For each reported live birth, participants were asked whether they breastfed, along with infant age at supplemental feeding introduction and breastfeeding discontinuation., Main Outcome Measure(s): Among participants with at least 1 live birth (330 cases, 246 population controls, and 198 hysterectomy controls), we used unconditional logistic regression to estimate adjusted odds ratios and 95% confidence intervals (CIs) for the associations between the following: (1) ever breastfeeding, (2) ever breastfeeding for ≥8 weeks, (3) lifetime breastfeeding, and (4) lifetime exclusive breastfeeding and risk of adenomyosis. Analyses were adjusted for age, reference year, smoking, education, and parity., Result(s): In analyses comparing cases with population controls, we observed a 40% decreased odds of adenomyosis with a history of ever breastfeeding (adjusted odds ratio, 0.6; 95% CI, 0.3-1.0) and breastfeeding for ≥8 weeks (adjusted odds ratio, 0.6; 95% CI, 0.4-0.8). The strongest associations, 60%-70% decreased odds of adenomyosis, were observed with ≥12 months of lifetime breastfeeding (vs. <3 months) (adjusted odds ratio, 0.4; 95% CI, 0.2-0.6) and 9 to <12 months of lifetime exclusive breastfeeding (vs. <3 months) (adjusted odds ratio, 0.3; 95% CI, 0.2-0.6), comparing cases to population controls. In analyses using hysterectomy controls, we observed similar patterns of associations slightly attenuated in magnitude., Conclusion(s): Breastfeeding history was associated with a 40% decreased odds of adenomyosis, a condition that can confer substantial morbidity and requires hysterectomy for definitive treatment. The consistency of our findings with that of a previous study lends support that breastfeeding may modify risk of adenomyosis., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Metastatic melanoma is a tumor amenable to immunotherapy in part due to the presence of antigen-specific tumor-infiltrating lymphocytes (TIL). These T cells can be activated and expanded for adoptive cell transfer (ACT), which has resulted in relatively high rates of clinical responses. Similarly, immune checkpoint inhibitors, specifically programmed cell death protein 1 (PD-1) blocking antibodies, augment antitumor immunity and increase the influx of T cells into tumors. Thus, we hypothesized that addition of PD-1 inhibition may improve the outcomes for patients undergoing ACT with TILs., Patients and Methods: Patients with stage III/IV metastatic melanoma with unresectable disease who were anti-PD-1 treatment-naïve were enrolled. TILs were generated in the presence of anti-4-1BB antibody in vitro and expanded for ACT. Patients in cohort 1 received TIL infusion followed by nivolumab. Patients in cohort 2 also received nivolumab prior to surgical harvest and during TIL production., Results: A total of 11 patients were enrolled, all of whom were evaluated for response, and nine completed ACT. Predominantly CD8+ TILs were successfully expanded from all ACT-treated patients and were tumor reactive in vitro. The trial met its safety endpoint, as there were no protocol-defined dose-limiting toxicity events. The objective response rate was 36%, and median progression-free survival was 5 months. Two nonresponders who developed new metastatic lesions were analyzed to determine potential mechanisms of therapeutic resistance, which included clonal divergence and intrinsic TIL dysfunction., Conclusions: Combination therapy with TILs and nivolumab was safe and feasible for patients with metastatic melanoma and provides important insights for future therapeutic developments in ACT with TILs., (©2022 American Association for Cancer Research.)

Background: Understanding teachers' appraisals of student wellness services and supports during COVID-19 is essential to strengthening services and improving student health outcomes. This mixed-method study aimed to examine US PK-12 teachers' appraisals of student wellness services and supports during COVID-19., Methods: This study focuses on qualitative data from 291 teachers' open-ended responses to the question: "What do you wish your school leaders knew about this (wellness support) aspect of your work?" and whose responses described wellness services and supports. A qualitative content analysis was conducted by an interdisciplinary research team using open- and axial coding., Results: Three main themes emerged. (1) insufficient access to mental health professionals and programming at schools, (2) concern about the quality of available services, and (3) a need for teacher professional development and support on student wellness. Statistically significant differences in teacher appraisals of insufficient access to mental health professionals and programming were found based on grade level taught and percentage of immigrant students in the school., Conclusion: With amplified student wellness needs, school personnel, including school leaders, must consider ways to allocate additional resources/staffing, assess the quality of services and supports, and design professional development opportunities to support teachers' involvement in supporting student wellness needs., (© 2022 The Authors. Journal of School Health published by Wiley Periodicals LLC on behalf of American School Health Association.)

ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism, is highly expressed in the liver. It regulates the overall flux of folate-bound one-carbon groups by converting 10-formyltetrahydrofolate to tetrahydrofolate and CO 2 in a NADP + -dependent reaction. Our previous study revealed that Aldh1l1 knockout (KO) mice have an altered liver metabotype with metabolic symptoms of folate deficiency when fed a standard chow diet containing 2 ppm folic acid. Here we performed untargeted metabolomic analysis of liver and plasma of KO and wild-type (WT) male and female mice fed for 16 weeks either standard or folate-deficient diet. OPLS-DA, a supervised multivariate technique that was applied to 6595 and 10,678 features for the liver and plasma datasets, respectively, indicated that genotype and diet, alone or in combination, gave distinct metabolic profiles in both types of biospecimens. A more detailed analysis of affected metabolic pathways based on most confidently identified metabolites in the liver and plasma (OL1 and OL2a ontology level) indicated that the dietary folate restriction itself does not fully recapitulate the metabolic effect of the KO. Of note, dietary folate withdrawal enhanced the metabolic perturbations linked to the ALDH1L1 loss only for a subset of metabolites. Importantly, both the ALDH1L1 loss and dietary folate deficiency produced sex-specific metabolic effects.

Purpose: To examine strategies utilized by physical therapists that contributed to patient perceptions of basic psychological needs support articulated within Self-Determination Theory (SDT)., Methods: Semi-structured interviews were conducted with physical therapists (n = 9) and physical therapy patients (n = 9) undergoing rehabilitation for a variety of musculoskeletal injuries., Results: Both patients and practitioners articulated the value of specific competence (e.g. matching rehabilitation challenges with patient abilities) and autonomy support strategies (e.g. active decision-making). Interestingly, both patients and therapists emphasized the salience of relatedness need support, a finding indicative of the potential importance of this need in a rehabilitation environment. The possibility that relatedness need support may be of equal - or potentially greater - importance than the other two needs in a rehabilitation setting, is however, antithetical to SDT contentions. Whether the primacy of relatedness need support is an artifact of the sample used in the current study or a reflection of a broader rehabilitation trend, is uncertain and remains a topic for further investigation., Conclusions: Understanding the strategies physical therapists use to support patients' psychological needs may have substantial implications for patient motivation and rehabilitation adherence, such as, improved psychological well-being, enhanced function, and increased adherence to physical therapists' recommendations.

Background: The jejunal mesentery supplied by the superior mesenteric vascular tree has emerged as a viable site for vascularized lymph node transplantation. Among other benefits, it has the advantage of avoidance of the risk of donor-site lymphedema. This article reports the technique and outcomes of a novel approach to jejunal mesenteric vascularized lymph node transplantation with flap harvest from the mesenteric root to reduce the risk of small bowel ischemic complications., Methods: A consecutive series of patients that underwent jejunal mesenteric vascularized lymph node transplantation to treat upper extremity lymphedema were included. Preoperative and postoperative measurements were taken at fixed intervals using standardized techniques including Perometer volumetry, LDex bioimpedance spectroscopy, the Lymphedema Life Impact Scale, and the Quick Disabilities of the Arm, Shoulder and Hand tool. Demographic, treatment, and outcomes data were collected, and descriptive statistics were used., Results: There were 25 patients included, all of whom had maximized their conservative therapy before undergoing surgery. At 12 months postoperatively reduction in limb volume difference was 36.7 percent (p < 0.001), reduction in LDex score was 41.4 percent (p = 0.0015), and reductions in the Lymphedema Life Impact Scale and Quick Disabilities of the Arm, Shoulder and Hand scores were 55.7 percent (p = 0.0019) and 47.5 percent (p = 0.027), respectively. In 11 patients, there was a history of cellulitis (multiple episodes in eight), and at up to 24 months' follow-up postoperatively there were no episodes reported (p < 0.001)., Conclusion: Upper extremity lymphedema can be effectively treated surgically using the jejunal mesenteric vascularized lymph node transplantation, resulting in reduced limb volume and extracellular fluid, and improved patient-reported limb function and outcomes measures compared with optimized conservative therapy alone., Clinical Question/level of Evidence: Therapeutic, IV., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background and Objectives: This study evaluates clinical outcomes of vascularized lymph node transplantation (VLNT) from the lateral thoracic region and technical modifications., Methods: Consecutive patients that underwent lateral thoracic VLNT to treat extremity lymphedema were included. Demographic and treatment data were recorded, and outcomes data including limb volume, LDex score, and Lymphedema Life Impact Scale (LLIS), QuickDASH, and LEFS questionnaires, were collected prospectively. Consecutive patients that underwent single-photon emission computed tomography (SPECT/CT) lymphoscintigraphy axillary reverse lymphatic mapping (RLM) were analyzed to characterize the physiological drainage of the normal upper extremity., Results: A consecutive series of 32 flaps were included. At 24 months postoperatively mean reduction in limb volume excess was 47.2% (±11.6; p = 0.0085), LDex score was 63.1% (±8.5; p < 0.001), and LLIS score was 65.1% (±7.4; p < 0.001). Preoperatively 14/31 patients (45.2%) reported cellulitis, and postoperatively there were no episodes at up to 24 months (p < 0.001). No patient developed donor extremity lymphedema at mean 18.6 (±8.3) months follow-up. SPECT/CT-RLM of 182 normal axillae demonstrated that the sentinel lymph node(s) of the upper extremity was consistently anatomically located in the upper outer quadrant of the axilla (97%)., Conclusions: VLNT from the lateral thoracic region is effective and versatile for the treatment of lymphedema with a low donor site complication rate., (© 2022 Wiley Periodicals LLC.)

Given the limitations of current inventories of basic psychological need measurement, and the importance of psychological need support within an injury rehabilitation context, there is an evident need to develop the present inventory. Utilizing Self-Determination Theory (SDT) as a theoretical framework, two studies were conducted to develop and psychometrically test a measure of patients' perceptions of basic psychological needs support in physical therapy: The Basic Psychological Needs Support in Physical Therapy Questionnaire (BPNS-PT). In study 1, a panel of Self-Determination Theory academics assessed a pool of items for content relevance, representativeness, and item clarity. In study 2, responses from 199 physical therapy patients were used to identify the best fitting model through confirmatory factor analysis. A 3-factor 10-item measure displayed good fit to the data and illustrated evidence of internal consistency. Findings from these studies provide initial psychometric support (i.e. internal consistency and evidence of construct validity) for the BPNSPT as a measure of patient perceptions of basic psychological needs support in a physical therapy context.

Broadly defined, restorative justice (RJ) is a set of procedures based in Indigenous peacemaking practices that reduces recidivism and guides the effective reparation of harm. RJ practices provide harm-affected parties an opportunity for engagement in the resolution process, which theoretically enhances community well-being. RJ practices overlap significantly with behavior-analytic principles. Implementing RJ practices from a context-focused, appetitive-based approach that focuses on classes of behaviors may address harmful behaviors within police organizations. RJ practices may also facilitate changes in contexts that support behaviors valued by the community. The current review discusses criminal and restorative justice, RJ processes and practices, the effectiveness of RJ in various contexts, how RJ overlaps with behavior-analytic principles and existing behavior science models in general, research suggestions, and recommendations for behavior analysts implementing RJ within police organizations and communities to address officer misconduct., Competing Interests: Conflict of InterestsThe authors have no conflicts of interest to disclose., (© Association for Behavior Analysis International 2021.)

Background: A growing body of evidence supports the efficacy of surgical treatments for lymphedema. This study reports the outcomes of vascularized lymph node transplantation (VLNT) for the treatment of patients with lymphedema compared with maximal conservative treatment alone., Study Design: Consecutive patients undergoing VLNT to treat primary and secondary lymphedema affecting the upper or lower extremities were included. All patients were optimized preoperatively with conservative therapy. Demographic and treatment information was collected, and outcomes data were electronically captured prospectively; descriptive statistics were performed., Results: There were 134 patients included that had achieved maximal reductions by conservative therapy preoperatively. This series included jejunal mesenteric (n = 25), groin (n = 43), lateral thoracic (n = 31), omental or right gastroepiploic (n = 21), and submental (n = 14) VLN flaps. At 24 months postoperatively, there were significant reductions in limb volume change (mean [SD] 45.7% [8.7%]; p = 0.002) LDex score (mean [SD] 59.8% [8.7%]; p < 0.001), Lymphedema Life Impact Scale score (mean [SD] 61.6% [5.9]; p < 0.001), and cellulitis episodes (97.9%; p < 0.001). At 3 and 6 months postoperatively, limb volume change was significantly greater for the upper than the lower extremity, otherwise outcomes were similar. There were no flap losses and overall outcomes were similar between the different VLN flap types., Conclusions: Treatment of lymphedema using VLNT resulted in progressive, significant reductions in limb volume, bioimpedance spectroscopy measurements of extracellular fluid, and episodes of cellulitis, with improved patient-reported outcomes and limb function measures compared with maximal conservative therapy alone. The complication rate was low and there were no significant outcomes differences between the VLNT types., (Copyright © 2021 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to examine: (1) motivations of patients with chronic low back pain to attend physical therapy; (2) relationships between competence perceptions, motivational regulations, and pain/disability; and (3) whether patient motivations to attend physical therapy mediate the relationship between competence perceptions and pain/disability., Methods: A sample of 64 participants completed baseline assessment (1-week prior to initiation of physical therapy) and 6-week follow-up assessment. Differences between motivation variables at baseline were examined using one-way within-person ANOVA. Relationships between competence perceptions, motivation subscales, and pain/disability were calculated using bivariate correlations and multiple mediation analyses., Results: Participants reported significantly higher levels of autonomous versus controlled motivation (mean difference = 3.5, p < 0.001, d = 2.3) and amotivation (mean difference = 3.6, p < 0.001, d = 2.4). Competence was positively associated with autonomous motivation ( r = 0.45, p ≤ 0.05) and negatively associated with controlled motivation ( r = -0.26, p ≤ 0.05), amotivation ( r = -0.57, p ≤ 0.05), pain ( r = -0.35, p ≤ 0.05), and disability ( r = -0.34, p ≤ 0.05). Amotivation significantly mediated the competence-pain relationship (Amotivation IE = -0.19, 95% CI (-0.44, -0.06), p < 0.05) and the competence-disability relationship (Amotivation IE = -0.07, 95% CI (-0.17, -0.01), p < 0.05)., Conclusion: Findings highlight the role of competence perceptions in mitigating amotivation for physical therapy and the deleterious implications of amotivation for patient-centered outcomes.Implications for rehabilitationWhile it is normal for patients to experience periods where they lack motivation for rehabilitation exercises, practitioners can encourage patients to assume responsibility for their recovery by informing them that amotivated states may increase the likelihood of increased pain perceptions and disability.Health-care practitioners should seek to foster competence perceptions in patients about to undergo physical therapy.Competence building strategies such as patient education, goal setting, and role modeling may be valuable in facilitating autonomous motivation and reducing amotivation for physical therapy.

Background: Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO 2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation., Methods: We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways., Results: Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2 -/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired β-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria., Conclusions: The ALDH1L2 function is important for CoA-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell.

Biomaterial systems have enabled the in vitro production of complex, emergent tissue behaviors that were not possible with conventional two-dimensional culture systems, allowing for analysis of both normal development and disease processes. We propose that the path towards developing the design parameters for biomaterial systems lies with identifying the molecular drivers of emergent behavior through leveraging technological advances in systems biology, including single cell omics, genetic engineering, and high content imaging. This growing research opportunity at the intersection of the fields of tissue engineering and systems biology - systems tissue engineering - can uniquely interrogate the mechanisms by which complex tissue behaviors emerge with the potential to capture the contribution of i) dynamic regulation of tissue development and dysregulation, ii) single cell heterogeneity and the function of rare cell types, and iii) the spatial distribution and structure of individual cells and cell types within a tissue. By leveraging advances in both biological and materials data science, systems tissue engineering can facilitate the identification of biomaterial design parameters that will accelerate basic science discovery and translation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pharmacogenomics test coverage and reimbursement are major obstacles to clinical uptake. Several early adopter programs have been successfully initiated through dedicated investments by federal and institutional research funding. As a result of research endeavors, evidence has grown sufficiently to support development of pharmacogenomics guidelines. However, clinical uptake is still limited. Third-party payer support plays an important role in increasing adoption, which to date has been limited to reactive single-gene testing. Access to and interest in direct-to-consumer genetic testing are driving demand for increasing healthcare providers and third-party awareness of this burgeoning field. Pharmacogenomics implementation models developed by early adopters promise to expand patient access and options, as testing continues to increase due to growing consumer interest and falling test prices.

A precious metal-free sequential series multijunction dye-sensitized solar cell (SSM-DSC)-powered water electrolysis system is demonstrated using NanoCOT and NiMoZn electrodes. A stable 3.9% solar-to-hydrogen (STH) efficiency is achieved using a recently reported black organic dye and graphene electrodes for DSCs.

Monitoring metastatic events in distal tissues is challenged by their sporadic occurrence in obscure and inaccessible locations within these vital organs. A synthetic biomaterial scaffold can function as a synthetic metastatic niche to reveal the nature of these distal sites. These implanted scaffolds promote tissue ingrowth, which upon cancer initiation is transformed into a metastatic niche that captures aggressive circulating tumor cells. We hypothesized that immune cell phenotypes at synthetic niches reflect the immunosuppressive conditioning within a host that contributes to metastatic cell recruitment and can identify disease progression and response to therapy. We analyzed the expression of 632 immune-centric genes in tissue biopsied from implants at weekly intervals following inoculation. Specific immune populations within implants were then analyzed by single-cell RNA-seq. Dynamic gene expression profiles in innate cells, such as myeloid-derived suppressor cells, macrophages, and dendritic cells, suggest the development of an immunosuppressive microenvironment. These dynamics in immune phenotypes at implants was analogous to that in the diseased lung and had distinct dynamics compared with blood leukocytes. Following a therapeutic excision of the primary tumor, longitudinal tracking of immune phenotypes at the implant in individual mice showed an initial response to therapy, which over time differentiated recurrence versus survival. Collectively, the microenvironment at the synthetic niche acts as a sentinel by reflecting both progression and regression of disease. SIGNIFICANCE: Immune dynamics at biomaterial implants, functioning as a synthetic metastatic niche, provides unique information that correlates with disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/3/602/F1.large.jpg. See related commentary by Wolf and Elisseeff, p. 377 ., (©2019 American Association for Cancer Research.)

The physical microenvironment of tumor cells plays an important role in cancer initiation and progression. Here, we present evidence that confinement - a new physical parameter that is apart from matrix stiffness - can also induce malignant transformation in mammary epithelial cells. We discovered that MCF10A cells, a benign mammary cell line that forms growth-arrested polarized acini in Matrigel, transforms into cancer-like cells within the same Matrigel material following confinement in alginate shell hydrogel microcapsules. The confined cells exhibited a range of tumor-like behaviors, including uncontrolled cellular proliferation and invasion. Additionally, 4-6 weeks after transplantation into the mammary fad pads of immunocompromised mice, the confined cells formed large palpable masses that exhibited histological features similar to that of carcinomas. Taken together, our findings suggest that physical confinement represents a previously unrecognized mechanism for malignancy induction in mammary epithelial cells and also provide a new, microcapsule-based, high throughput model system for testing new breast cancer therapeutics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Evidence of the effectiveness of programs to change gendered social norms related to intimate partner violence (IPV) is growing, but their potential to significantly impact actual occurrence of IPV at population level is lacking. We study whether modest changes in gendered social norms related to wife-beating can result in significant changes in the incidence of emotional, physical, and sexual IPV among ever married women in Uganda. We employ an imputation-based causal inference approach, based on nationally representative Demographic Health Survey data. The steps are (1) model the association between adjusted neighborhood norms and experiences of IPV using a random effects logistic regression model, (2) impute unobserved counterfactual probabilities of experiencing IPV for each woman while manipulating her neighborhood norms by setting it to different values, (3) average the probabilities across the population, and (4) bootstrap confidence intervals. Results show that statistically significant inverse associations between more prohibitive neighborhood IPV norms and women's experiences of different forms of IPV at the population level exist. The effect is however small, that even if an entire community disapproves of wife-beating, incidence of IPV falls by about 10 percentage points to 48.5% (95% CI 46.0%-50.9%) from the observed value of 57.6% (95% CI 55.2%-59.9%). Furthermore, changes in neighborhood social norms are found to have no statistical significant effect on the incidence of sexual violence. In conclusion, changing gendered social norms related to wife-beating will not result in significant reductions in different forms for IPV at the population level.

(1) The purpose of this study was to examine the acute effects of aerobic exercise, resistance exercise, and non-exercise on measures of academic achievement and cognition in pre-adolescent students. (2) In a randomized crossover design, sixty-three participants with a mean age of 13.7 ± 0.47 years completed 20 min of aerobic exercise, resistance exercise, or non-exercise with a period of seven days between each bout. Immediately after each bout, participants were tested for academic achievement and cognitive performance. Academic achievement was assessed using standardized, age-appropriate mathematics tests. Cognition was measured using the Dot, Word, and Color tasks of the Stroop Test (Victoria version). (3) Participants scored significantly higher on the mathematics tests (F 1,62 = 4.50, p = 0.038) and all elements of the Stroop Test (Dot: F 1,62 = 8.14, p = 0.006; Word: F 1,62 = 9.90, p = 0.003; Color: F 1,62 = 7.57, p = 0.008) following acute resistance exercise as compared to non-exercise. Math test performance was not statistically different between the aerobic and resistance exercise treatments (F 1,62 = 0.214, p = 0.645), but participants did perform significantly better on all elements of the Stroop Test following resistance exercise as compared to aerobic exercise (Dot: F 1,61 = 25.82, p < 0.001; Word: F 1,62 = 14.73, p < 0.001; Color: F 1,62 = 20.14, p < 0.001). (4) Resistance exercise acutely influenced academic achievement and cognition in a positive manner. Such results add to the growing body of research that may support an increase in the prescription of varied exercise modalities within school settings for the purposes of improving academic performance and student health.