Looking Toward the Future of Integrated Care: History, Developments, and Opportunities.

For almost five decades, the development and implementation of integrated care-the simultaneous combination of primary care with mental health and substance use care-has been a major challenge for the behavioral health care field. Integrated care is exceptionally important because many people with behavioral health conditions also have chronic physical health conditions. Early research findings in the mid-1980s showed that persons with mental illness are likely to develop chronic physical conditions earlier and more severely than other people. These findings precipitated efforts to understand this problem and to develop further appropriate integrated care solutions. Subsequently, the US Surgeon General made care integration a major focus of his landmark 1999 Report on Mental Health, as did the 2008 Mental Health Parity and Addiction Equity Act and the 2010 Patient Protection and Affordable Care Act. However, it was not until 2014, and later, that integrated care actually began to be implemented more broadly. This article reviews these major developmental milestones, examines current activities, and explores likely developments over the next several years. Major current issues include the response to the COVID-19 pandemic, adjusting to its effects on the behavioral health care workforce, and the growing realization that behavioral health care must address the social determinants of life. Likely developments over the next several years will include devising ways to address our workforce crisis, developing effective community interventions, and implementing population health management strategies; implementing the CMS Innovation in Behavioral Health Model; improving reimbursement practices; and exploring the potential of AI for integrated care. Implications for future service organization and training of behavioral health care providers also are discussed. Granted the severity of the current workforce crisis in behavioral health care, urgent efforts are needed to advance the deployment of integrated care in the short-term future.

Slow and steady: auditory features for discriminating animal vocalizations.

We propose that listeners can use temporal regularities - spectro-temporal correlations that change smoothly over time - to discriminate animal vocalizations within and between species. To test this idea, we used Slow Feature Analysis (SFA) to find the most temporally regular components of vocalizations from birds (blue jay, house finch, American yellow warbler, and great blue heron), humans (English speakers), and rhesus macaques. We projected vocalizations into the learned feature space and tested intra-class (same speaker/species) and inter-class (different speakers/species) auditory discrimination by a trained classifier. We found that: 1) Vocalization discrimination was excellent (> 95%) in all cases; 2) Performance depended primarily on the ~10 most temporally regular features; 3) Most vocalizations are dominated by ~10 features with high temporal regularity; and 4) These regular features are highly correlated with the most predictable components of animal sounds.

High-throughput micro-CT analysis identifies sex-dependent biomarkers of erosive arthritis in TNF-Tg mice and differential response to anti-TNF therapy.

BACKGROUND: Development of reliable disease activity biomarkers is critical for diagnostics, prognostics, and novel drug development. Although computed tomography (CT) is the gold-standard for quantification of bone erosions, there are no consensus approaches or rationales for utilization of specific outcome measures of erosive arthritis in complex joints. In the case of preclinical models, such as sexually dimorphic tumor necrosis factor transgenic (TNF-Tg) mice, disease severity is routinely quantified in the ankle through manual segmentation of the talus or small regions of adjacent bones primarily due to the ease in measurement. Herein, we sought to determine the particular hindpaw bones that represent reliable biomarkers of sex-dependent disease progression to guide future investigation and analysis. METHODS: Hindpaw micro-CT was performed on wild-type (n = 4 male, n = 4 female) and TNF-Tg (n = 4 male, n = 7 female) mice at monthly intervals from 2-5 (females) and 2-8-months (males) of age, since female TNF-Tg mice exhibit early mortality from cardiopulmonary disease at approximately 5-6-months. Further, 8-month-old WT (n = 4) and TNF-Tg males treated with anti-TNF monoclonal antibodies (n = 5) or IgG placebo isotype controls (n = 6) for 6-weeks were imaged with micro-CT every 3-weeks. For image analysis, we utilized our recently developed high-throughput and semi-automated segmentation strategy in Amira software. Synovial and osteoclast histology of ankle joints was quantified using Visiopharm. RESULTS: First, we demonstrated that the accuracy of automated segmentation, determined through analysis of ~9000 individual bones by a single user, was comparable in wild-type and TNF-Tg hindpaws before correction (79.2±8.9% vs 80.1±5.1%, p = 0.52). Compared to other bone compartments, the tarsal region demonstrated a sudden, specific, and significant bone volume reduction in female TNF-Tg mice, but not in males, by 5-months (4-months 4.3± 0.22 vs 5-months 3.4± 0.62 mm3, p<0.05). Specifically, the cuboid showed significantly reduced bone volumes at early timepoints compared to other tarsals (i.e., 4-months: Cuboid -24.1±7.2% vs Talus -9.0±5.9% of 2-month baseline). Additional bones localized to the anterolateral region of the ankle also exhibited dramatic erosions in the tarsal region of females, coinciding with increased synovitis and osteoclasts. In TNF-Tg male mice with severe arthritis, the talus and calcaneus exhibited the most sensitive response to anti-TNF therapy measured by effect size of bone volume change over treatment period. CONCLUSIONS: We demonstrated that sexually dimorphic changes in arthritic hindpaws of TNF-Tg mice are bone-specific, where the cuboid serves as a reliable early biomarker of erosive arthritis in female mice. Adoption of automated segmentation approaches in pre-clinical or clinical models has potential to translate quantitative biomarkers to monitor bone erosions in disease and evaluate therapeutic efficacy.

Analytical Determination of Aflatoxin in Ground Corn Check Samples Completed by Multiple Laboratories over Several Years.

Mycotoxins are toxic molecules produced by multiple fungal species, including Aspergillus and Fusarium. Fungal infection of crops can result in mycotoxins entering the animal and human food supply. Enzyme-linked immunosorbent assays and other immunological assays have been developed to detect mycotoxins in foods. To calibrate the response of those methods, reference materials with known amounts of homogeneously dispersed mycotoxins are often utilized, where the mycotoxin concentrations have been determined using high-performance liquid chromatography coupled with absorbance or fluorescence detection methods, or high-performance liquid chromatography coupled with mass spectrometry detection methods. Therefore, it is important that the analytical methods provide accurate and precise quantitation of mycotoxins. The reference materials must also contain homogeneously dispersed known quantities of mycotoxin. To evaluate the accuracy and precision of mycotoxin reference materials and the analytical methods, quantitative results from multiple laboratories were completed each year for several years on ground corn check samples containing known levels of mycotoxins. Results for the quantitation of aflatoxin-containing corn reference samples are presented in this article.

A proposed pathway from D-glucose to D-arabinose in eukaryotes.

In eukaryotes, the D-enantiomer of arabinose (D-Ara) is an intermediate in the biosynthesis of D-erythroascorbate in yeast and fungi and in the biosynthesis of the nucleotide sugar GDP-α-D-arabinopyranose (GDP-D-Arap) and complex α-D-Arap-containing surface glycoconjugates in certain trypanosomatid parasites. Whereas the biosynthesis of D-Ara in prokaryotes is well understood, the route from D-glucose (D-Glc) to D-Ara in eukaryotes is unknown. In this paper, we study the conversion of D-Glc to D-Ara in the trypanosomatid Crithidia fasciculata using positionally labeled [13C]-D-Glc and [13C]-D-ribose ([13C]-D-Rib) precursors and a novel derivatization and gas chromatography-mass spectrometry procedure applied to a terminal metabolite, lipoarabinogalactan. These data implicate the both arms of pentose phosphate pathway and a likely role for D-ribulose-5-phosphate (D-Ru-5P) isomerization to D-Ara-5P. We tested all C. fasciculata putative sugar and polyol phosphate isomerase genes for their ability to complement a D-Ara-5P isomerase-deficient mutant of Escherichia coli and found that one, the glutamine fructose-6-phosphate aminotransferase (GFAT) of glucosamine biosynthesis, was able to rescue the E. coli mutant. We also found that GFAT genes of other trypanosomatid parasites, and those of yeast and human origin, could complement the E. coli mutant. Finally, we demonstrated biochemically that recombinant human GFAT can isomerize D-Ru-5P to D-Ara5P. From these data, we postulate a general eukaryotic pathway from D-Glc to D-Ara and discuss its possible significance. With respect to C. fasciculata, we propose that D-Ara is used not only for the synthesis of GDP-D-Arap and complex surface glycoconjugates but also in the synthesis of D-erythroascorbate.

Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying KMT2A gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have garnered attention for their potential therapeutic efficacy in treating KMT2A-rearranged acute leukemias. However, resistance to menin inhibition poses challenges, and identifying which patients would benefit from revumenib treatment is crucial. Here, we investigated the in vitro response to revumenib in KMT2A-rearranged ALL and AML. While ALL samples show rapid, dose-dependent induction of leukemic cell death, AML responses are much slower and promote myeloid differentiation. Furthermore, we reveal that acquired resistance to revumenib in KMT2A-rearranged ALL cells can occur either through the acquisition of MEN1 mutations or independently of mutations in MEN1. Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia.

Factors associated with phenotypes of dyspnea in post-COVID-19 condition: a cross-sectional study.

Post-COVID-19 condition (PCC) is defined as the persistence of symptoms, like fatigue and dyspnea, at least 3 months post-COVID infection. As dyspnea is a common symptom, we attempted to further clinically phenotype those with PCC-associated dyspnea. 1642 adults (average age of 49.6y with 63% female-predominance and BMI of 31.2 kg/m2) with physician confirmed diagnosis of PCC from June 2020-April 2023 in Alberta, Canada were included. Those with dyspnea were more likely to be female (56.5%, p = 0.005) and have higher BMI (31.3 kg/m2 vs. 29.5 kg/m2; p = 0.0008), history of asthma (21.1% vs. 12.3%; p < 0.001), more persistent PCC symptoms (p = 0.0001), more functional limitations, as well as lower quality of life (p < 0.0001). Multivariable-adjusted logistic regression analysis demonstrated dyspnea was independently associated with fatigue (OR = 4.20; CI = 2.71,6.59) and inversely associated with hospitalization for COVID-19 (OR = 0.53; CI = 0.32,0.91), age (OR = 0.98 per one year of age; CI = 0.96,0.99) and 6-min-walk-distance per 10 m difference (OR = 0.98, CI = 0.96,1.0). Fatigue was a predictor of dyspnea, and was associated with milder infection, higher BMI, and reduced 6-min-walk-distance despite normal pulmonary function. Reduced TLC or DLCO was associated with more severe infection and reduced 6-min-walk-distance. Thus, we speculate there are at least two dyspnea-associated phenotypes: phenotype with pronounced fatigue (normal PFT) and phenotype with pronounced pulmonary abnormalities (abnormal PFT). Improved understanding of the dyspnea-associated phenotypes may allow for better targeted rehabilitation.

Comparative Genomic Analysis of Bacterial Data in BV-BRC: An Example Exploring Antimicrobial Resistance.

As genomic and related data continue to expand, research biologists are often hampered by the computational hurdles required to analyze their data. The National Institute of Allergy and Infectious Diseases (NIAID) established the Bioinformatics Resource Centers (BRC) to assist researchers with their analysis of genome sequence and other omics-related data. Recently, the PAThosystems Resource Integration Center (PATRIC), the Influenza Research Database (IRD), and the Virus Pathogen Database and Analysis Resource (ViPR) BRCs merged to form the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) at https://www.bv-brc.org/ . The combined BV-BRC leverages the functionality of the original resources for bacterial and viral research communities with a unified data model, enhanced web-based visualization and analysis tools, and bioinformatics services. Here we demonstrate how antimicrobial resistance data can be analyzed in the new resource.

Oxidative Stress is a shared characteristic of ME/CFS and Long COVID.

More than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). With no current treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in over 16 healthy controls, 15 ME/CFS, and 15 LC, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, relative to healthy controls, especially in the memory subset. Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we also observed aberrations in ROS clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase levels, and glutathione peroxidase 4 mediated lipid oxidative damage. Critically, these changes in redox pathways show striking sex-specific trends. While females diagnosed with ME/CFS exhibit higher total ROS and mitochondrial calcium levels, males with an ME/CFS diagnosis have normal ROS levels, but larger changes in lipid oxidative damage. Further analyses show that higher ROS levels correlates with hyperproliferation of T cells in females, consistent with the known role of elevated ROS levels in the initiation of proliferation. This hyperproliferation of T cells can be attenuated by metformin, suggesting this FDA-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Thus, we report that both ME/CFS and LC are mechanistically related and could be diagnosed with quantitative blood cell measurements. We also suggest that effective, patient tailored drugs might be discovered using standard lymphocyte stimulation assays.

Urinary Proteomic Biomarkers of Trabecular Bone Volume Change during Army Basic Combat Training.

PURPOSE: Optimize a dMS-based urinary proteomic technique and evaluate the relationship between urinary proteome content and adaptive changes in bone microarchitecture during BCT. METHODS: Urinary proteomes were analyzed with an optimized dMS technique in two groups of 13 recruits (n = 26) at the beginning (Pre) and end (Post) of BCT. Matched by age (21 ± 4 yr), sex (16 W), and baseline tibial trabecular bone volume fractions (Tb.BV/TV), these groups were distinguished by the most substantial (High) and minimal (Low) improvements in Tb.BV/TV. Differential protein expression was analyzed with mixed permutation ANOVA and false discovery proportion-based adjustment for multiple comparisons. RESULTS: Tibial Tb.BV/TV increased from pre- to post-BCT in High (3.30 ± 1.64%, p < 0.0001) but not Low (-0.35 ± 1.25%, p = 0.4707). The optimized dMS technique identified 10,431 peptides from 1,368 protein groups that represented 165 integrative biological processes. 74 urinary proteins changed from pre- to post-BCT (p = 0.0019) and neutrophil mediated immunity was the most prominent ontology. Two proteins (Immunoglobulin heavy constant gamma 4 and C-type lectin domain family 4 member G) differed from pre- to post-BCT in High and Low (p = 0.0006). CONCLUSIONS: The dMS technique can identify more than 1000 urinary proteins. At least 74 proteins are responsive to BCT, and other principally immune system-related proteins show differential expression patterns that coincide with adaptive bone formation.

Combining CRISPR-Cas9 and TCR exchange to generate a safe and efficient cord blood-derived T cell product for pediatric relapsed AML.

BACKGROUND: Hematopoietic cell transplantation (HCT) is an effective treatment for pediatric patients with high-risk, refractory, or relapsed acute myeloid leukemia (AML). However, a large proportion of transplanted patients eventually die due to relapse. To improve overall survival, we propose a combined strategy based on cord blood (CB)-HCT with the application of AML-specific T cell receptor (TCR)-engineered T cell therapy derived from the same CB graft. METHODS: We produced CB-CD8+ T cells expressing a recombinant TCR (rTCR) against Wilms tumor 1 (WT1) while lacking endogenous TCR (eTCR) expression to avoid mispairing and competition. CRISPR-Cas9 multiplexing was used to target the constant region of the endogenous TCRα (TRAC) and TCRß (TRBC) chains. Next, an optimized method for lentiviral transduction was used to introduce recombinant WT1-TCR. The cytotoxic and migration capacity of the product was evaluated in coculture assays for both cell lines and primary pediatric AML blasts. RESULTS: The gene editing and transduction procedures achieved high efficiency, with up to 95% of cells lacking eTCR and over 70% of T cells expressing rWT1-TCR. WT1-TCR-engineered T cells lacking the expression of their eTCR (eTCR-/- WT1-TCR) showed increased cell surface expression of the rTCR and production of cytotoxic cytokines, such as granzyme A and B, perforin, interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα), on antigen recognition when compared with WT1-TCR-engineered T cells still expressing their eTCR (eTCR+/+ WT1-TCR). CRISPR-Cas9 editing did not affect immunophenotypic characteristics or T cell activation and did not induce increased expression of inhibitory molecules. eTCR-/- WT1-TCR CD8+ CB-T cells showed effective migratory and killing capacity in cocultures with neoplastic cell lines and primary AML blasts, but did not show toxicity toward healthy cells. CONCLUSIONS: In summary, we show the feasibility of developing a potent CB-derived CD8+ T cell product targeting WT1, providing an option for post-transplant allogeneic immune cell therapy or as an off-the-shelf product, to prevent relapse and improve the clinical outcome of children with AML.

Real-World Evidence of the Impact of a Novel Surgical Irrigant on Surgical Site Infections in Primary Total Knee Arthroplasty Performed at an Ambulatory Surgery Center.

Background: Total knee arthroplasty (TKA) is one of the most common inpatient and outpatient surgical procedures performed in the United States and is predicted to increase 401% by 2040. Surgical site infections (SSIs) at an incidence rate of approximately 2% are costly post-operative complications in TKA. Intra-operative surgical irrigants are used to decrease contaminating microbial bioburden within the surgical site to prevent SSI. The primary objective of this retrospective study was to evaluate the impact of a novel surgical irrigant called XPERIENCE® Advanced Surgical Irrigation (XP; Next Science, Jacksonville, FL) on SSI incidence in primary TKA performed at an ambulatory surgery center (ASC). Patients and Methods: Primary TKAs were performed at a free-standing ASC. The novel surgical irrigant was used intra-operatively to rinse away debris and micro-organisms from the surgical site. Retrospective data collation included SSI rates, complication rates, and re-admissions due to SSI within 90 days of index surgery. Results: Among the 524 primary TKA surgeries, one peri-prosthetic joint infection (PJI) was diagnosed within 90 days of index surgery and one superficial incisional SSI was diagnosed within 30 days of index surgery. The PJI was attributed to an exogenously acquired upper respiratory tract infection rather than due to the failure of intra-operative regimes. The 0.19% PJI incidence rate indicated significant efficacy of XP in decreasing PJI. An overall complication rate of 7.82% was noted with none of the complications associated with usage of the novel surgical irrigant. Conclusions: XPERIENCE is a promising intra-operative antimicrobial irrigant that can be easily incorporated into a broader infection prevention strategy.

Posterior atlantoaxial fixation of osteoporotic odontoid fracture: biomechanical analysis of the Magerl versus harms techniques in a cadaver model.

BACKGROUND CONTEXT: Odontoid fractures are among the most common cervical spine fractures in the elderly and are associated with increased morbidity and mortality. Clinical evidence suggests improved survival and quality of life after operative intervention compared to nonoperative treatment. PURPOSE: This study seeks to examine the stability of an osteoporotic Type II odontoid fracture following posterior atlantoaxial fixation with either the Magerl transarticular fixation technique or the Harms C1 lateral mass screws C2 pedicle screw rod fixation. STUDY DESIGN: Biomechanical cadaveric study. METHODS: Eighteen cadaveric specimens extending from the cephalus to C7 were used in this study. Reflective marker arrays were attached to C1 and C2 and a single marker on the dens to measure movement of each during loading with C2-C3 and occiput-C1 being allowed to move freely. A biomechanical testing protocol imparted moments in flexion-extension, axial rotation, and lateral bending while a motion capture system recorded the motions of C1, C2, and the dens. The spines were instrumented with either the Harms fixation (n=9) or Magerl fixation (n=9) techniques, and a simulated Type II odontoid fracture was created. Motions of each instrumented spine were recorded for all moments, and then again after the instrumentation was removed to model the injured, noninstrumented state. RESULTS: Both Harms and Magerl posterior C1-C2 fixation allowed for C1, C2, and the dens to move as a relative unit. Without fixation the dens motion was coupled with C1. No significant differences were found in X, Y, Z translation motion of the dens, C1 or C2 during neutral zone motions between the Magerl and Harms fixation techniques. There were no significant differences found in Euler angle motion between the two techniques in either flexion-extension, axial rotation, or lateral bending motion. CONCLUSIONS: Our findings suggest that both Harms and Magerl fixation can significantly reduce dens motion in Type II odontoid fractures in an osteoporotic cadaveric bone model. CLINICAL SIGNIFICANCE: Both Harms and Magerl posterior atlantoaxial fixation techniques allowed for C1, C2, and the dens to move as a relative unit following odontoid fracture, establishing more anatomic stability to the upper cervical spine.

A Rare Case of Complete Inguinoscrotal Bladder Herniation With Ureteric Involvement: Assessing Diagnostic Challenges and Complex Surgical Management.

Inguinoscrotal hernias involving the urinary bladder are exceedingly rare, constituting a small subset of inguinal hernias. We present a case of a 47-year-old male with long-standing scrotal enlargement and obstructive uropathy due to complete herniation of the bladder with ureteric involvement. Diagnostic imaging confirmed the condition. Following an open laparotomy, the bladder was reduced, and a modified Bassini technique with orchiopexy was used for repair. Recurrence of the inguinoscrotal hernia with evidence of the bladder in the scrotal sac required additional surgery. This case underscores the rarity, diagnostic complexity, and potential complications of inguinoscrotal bladder hernias. Specialized surgical techniques and a multidisciplinary approach are crucial for successful management, especially in cases of complete bladder herniation. Future considerations should include innovative approaches to enhance primary repair outcomes for extensive hernias involving the bladder.

Longitudinal cytokine and multi-modal health data of an extremely severe ME/CFS patient with HSD reveals insights into immunopathology, and disease severity.

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents substantial challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. The heterogeneity among patient populations, coupled with the absence of FDA-approved diagnostics and therapeutics, further complicates research into disease etiology and patient managment. Integrating longitudinal multi-omics data with clinical, health,textual, pharmaceutical, and nutraceutical data offers a promising avenue to address these complexities, aiding in the identification of underlying causes and providing insights into effective therapeutics and diagnostic strategies. Methods: This study focused on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) during a period of marginal symptom improvements. Longitudinal cytokine profiling was conducted alongside the collection of extensive multi-modal health data to explore the dynamic nature of symptoms, severity, triggers, and modifying factors. Additionally, an updated severity assessment platform and two applications, ME-CFSTrackerApp and LexiTime, were introduced to facilitate real-time symptom tracking and enhance patient-physician/researcher communication, and evaluate response to medical intervention. Results: Longitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy. Additionally, the data identified potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasized the importance of investigating adverse reactions to medication and supplements and drug interactions in ME/CFS severity and progression. Discussion: Our study advocates for the integration of longitudinal multi-omics with multi-modal health data and artificial intelligence (AI) techniques to better understand ME/CFS and its major comorbidities. These findings highlight the significance of dysregulated Th2-type cytokines in patient stratification and precision medicine strategies. Additionally, our results suggest exploring the use of low-dose drugs with partial agonist activity as a potential avenue for ME/CFS treatment. This comprehensive approach emphasizes the importance of adopting a patient-centered care approach to improve ME/CFS healthcare management, disease severity assessment, and personalized medicine. Overall, these findings contribute to our understanding of ME/CFS and offer avenues for future research and clinical practice.

Stepping into the future of behavioral health: Opportunities, challenges, and possibilities.

To improve our practices of today and to overcome the problems that confront us at present, the behavioral health field must anticipate what the future is likely to bring. Such foresight is particularly important right now because of the changes and disruptions that have occurred due to the COVID-19 pandemic over the past 3 years. We begin by recounting major developments in the mental health field since the founding of the National Institute of Mental Health (NIMH) more than 70 years ago, including some firsthand experiences of the senior author. Subsequently, we review the present situation of the behavioral health field with particular attention to the effects of COVID-19 and our current workforce crisis. Likely future scenarios are then described in two principal domains: clinical developments and community developments. Clinical developments over the next decade are likely to include much more self-directed, integrated, virtual, and personalized care. Community developments are likely to include self-empowering community interventions, better population health management, new collaborations with public health, and continued efforts to address stigma. To increase the probability of the future described, several facilitators are also outlined to create the conditions under which expected future developments can be expected to flourish. These include addressing the behavioral health workforce crisis, modernizing behavioral health clinical training, fostering opportunities for cross-sector work, fostering opportunities to engage in policy issues, creating centers of excellence for innovation in behavioral health, and fostering an integrated framework that undergirds behavioral health. The future we have described holds considerable promise for the behavioral health field and for all who suffer from mental or substance use conditions. We must begin working today to turn this potential future into tomorrow's reality. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells.

Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy-resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML-LSCs and may represent a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we identify HIFhigh and HIFlow specific AML subgroups (inv(16)/t(8;21) and MLLr, respectively) and provide a comprehensive single-cell expression atlas of 119,000 AML cells and AML-LSCs in paired diagnostic-relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML-LSCs compared with more differentiated AML cells but is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard-of-care chemotherapy to impair AML growth and to substantially eliminate AML-LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell-driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs.

Relation between the relative abundance and collapse of Aphanizomenon flos-aquae and microbial antagonism in Upper Klamath Lake, Oregon.

Aphanizomenon flos-aquae (AFA) is the dominant filamentous cyanobacterium that develops into blooms in Upper Klamath Lake, Oregon, each year. During AFA bloom and collapse, ecosystem conditions for endangered Lost River and shortnose suckers deteriorate, thus motivating the need to identify processes that limit AFA abundance and decline. Here, we investigate the relations between AFA and other members of the microbial community (photosynthetic and nonphotosynthetic bacteria and archaea), how those relations impact abundance and collapse of AFA, and the types of microbial conditions that suppress AFA. We found significant spatial variation in AFA relative abundance during the 2016 bloom period using 16S rRNA sequencing. The Pelican Marina site had the lowest AFA relative abundance, and this was coincident with increased relative abundance of Candidatus Sericytochromatia, Flavobacterium, and Rheinheimera, some of which are known AFA antagonists. The AFA collapse coincided with phosphorus limitation relative to nitrogen and the increased relative abundance of Cyanobium and Candidatus Sericytochromatia, which outcompete AFA when dissolved inorganic nitrogen is available. The data collected in this study indicate the importance of dissolved inorganic nitrogen combined with microbial community structure in suppressing AFA abundance.

WDR23 mediates NRF2 proteostasis and cytoprotective capacity in the hippocampus.

Pathogenic brain aging and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are characterized by chronic neuroinflammation and the accumulation of dysfunctional or misfolded proteins that lead to progressive neuronal cell death. Here we demonstrate that a murine model with global loss of the CUL4-DDB1 substrate receptor WDR23 (Wdr23KO) results in changes in multiple age-related hippocampal-dependent behaviors. The behavioral differences observed in Wdr23KO animals accompany the stabilization of the NRF2/NFE2L2 protein, an increase in RNA transcripts regulated by this cytoprotective transcription factor, and an increase in the steady state level of antioxidant defense proteins. Taken together, these findings reveal a role for WDR23-proteostasis in mediating cytoprotective capacity in the hippocampus and reveal the potential for targeting WDR23-NRF2 signaling interactions for development of therapies for neurodegenerative disorders.

Differentiated vulvar intraepithelial neoplasia long-term follow up and prognostic factors: An analysis of a large historical cohort.

INTRODUCTION: Differentiated vulvar intraepithelial neoplasia (dVIN) is a high-risk preinvasive vulvar lesion and precursor of human papillomavirus-independent vulvar squamous cell carcinoma (VSCC). Due to its rarity, literature data on its malignant potential are scant. The aim of the study is to assess the risk of developing VSCC in patients surgically treated for dVIN not associated with VSCC (solitary dVIN) and the risk of VSCC recurrence in patients treated for dVIN associated with VSCC (dVIN-VSCC) at first diagnosis. MATERIAL AND METHODS: A historical cohort study was performed in a northern Italy referral center for vulvar neoplasms. All consecutive women surgically treated for histologically confirmed dVIN from 1994 to 2021 were collected. Primary outcome was cancer risk or recurrent cancer risk, secondary outcomes were risk factors associated with VSCC development or recurrence. Kaplan-Meier method and log-rank test were used to estimate cancer risk or recurrent cancer risk differences and uni- and multivariate Cox regression analyses to identify risk factors associated with VSCC development in solitary dVIN and recurrence of dVIN-VSCC. RESULTS: Seventy-six patients with dVIN at preoperative biopsy were included: at excisional specimens 44 were solitary dVIN and 32 were dVIN-VSCC. The absolute risk of VSCC development after solitary dVIN treatment was 43.2% with median time to to VSCC diagnosis of 25.4 months (range 3.5-128.0 months). VSCC recurrence absolute risk in treated dVIN-VSCC patients was 31.3% with median time to VSCC recurrence of 52.9 months (range 6.5-94.8 months). At uni- and multivariate regression analyses, only compliant topical ultrapotent corticosteroid treatment after solitary dVIN excision showed an ability to prevent VSCC development. No protective effect by corticosteroid treatment was shown for VSCC recurrence in dVIN-VSCC patients. Smoking was associated with higher cancer recurrence risk in dVIN-VSCC patients on both uni- and multivariate regression analyses. CONCLUSIONS: Patients with dVIN have a high risk of developing both primary and recurring VSCC. Early recognition, long-term follow up, and compliant ultrapotent topical corticosteroid treatment are recommended.