Positron emission tomography in the evaluation of endometriosis: A systematic review.

Despite the profound impact of endometriosis worldwide, delays in diagnosis and suboptimal surveillance techniques are well-recognised issues. Case studies have reported incidental uptake of 18F-FDG PET tracer in endometriotic lesions. However, the utility of PET imaging as a non-invasive diagnostic tool for endometriosis is currently unclear. The purpose of this systematic review was to summarise the existing evidence and determine the value of available PET scanning techniques in the detection and monitoring of endometriosis. MEDLINE, EMBASE, CENTRAL, SCOPUS and Web of Science were searched from conception to 05/03/23. Eligible studies included participants with a history of known or suspected endometriosis who underwent a PET scan for any indication. All PET tracers and protocols were eligible. Outcomes included correlation of PET tracer uptake with the presence of endometriosis seen at laparoscopy or confirmed on histology, sensitivity of tracer uptake, specificity of tracer uptake, site of lesions with tracer uptake, stage of lesions with tracer uptake, SUVmax of endometriosis lesions and adverse reactions to PET imaging. The protocol for this review was registered with PROSPERO (ID: CRD42023405260). Eight studies describing 110 participants were eligible for inclusion. Six studies assessed 18F-FDG with combined PET-CT, one study assessed 18F-FDG PET alone, and the remaining study assessed PET-CT with an alternative tracer, 68Ga-DOTATATE. For 18F-FDG imaging, the correlation of PET avidity with lesions or sites of endometriosis ranged from 0-55 %. Pre-operative 68Ga-DOTATATE PET-CT detected endometriosis in 33 % of cases. All included studies were cohort studies, six were assessed to have low risk of bias, one with moderate risk and one with high risk of bias. Overall, 18F-FDG PET scanning does not appear to consistently identify endometriotic lesions, and therefore its reliability and usefulness in endometriosis diagnosis is limited. The utility of 68Ga-DOTATATE PET-CT remains uncertain. Findings are constrained by limited available evidence reporting outcomes of PET imaging for endometriosis. Other existing PET tracers with biological plausibility in the detection or monitoring of endometriosis warrant further investigation.

Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety.

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.

Pursuing Clinical Predictors and Biomarkers for Progression in ILD: Analysis of the Pulmonary Fibrosis Foundation (PFF) Registry.

INTRODUCTION: Pulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry. METHODS: Biomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3). RESULTS: PFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low. CONCLUSIONS: Our findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs.

The Digital Navigator: Standardizing Human Technology Support in App-Integrated Clinical Care.

Background: Mental health apps offer scalable care, yet clinical adoption is hindered by low user engagement and integration challenges into clinic workflows. Human support staff called digital navigators, trained in mental health technology, could enhance care access and patient adherence and remove workflow burdens from clinicians. While the potential of this role is clear, training staff to become digital navigators and assessing their impact are primary challenges. Methods: We present a detailed manual/framework for implementation of the Digital Navigator within a short-term, cognitive-behavioral therapy-focused hybrid clinic. We analyze patient engagement, satisfaction, and digital phenotyping data quality outcomes. Data from 83 patients, for the period spanning September 2022 to September 2023, included Digital Navigator satisfaction, correlated with demographics, mindLAMP app satisfaction, engagement, and passive data quality. Additionally, average passive data across 33 clinic patients from November 2023 to January 2024 were assessed for missingness. Results: Digital Navigator satisfaction averaged 18.8/20. Satisfaction was not influenced by sex, race, gender, or education. Average passive data quality across 33 clinic patients was 0.82 at the time this article was written. Digital Navigator satisfaction scores had significant positive correlation with both clinic app engagement and perception of that app. Conclusions: Results demonstrate preliminary support and patient endorsement for the Digital Navigator role and positive outcomes around digital engagement and digital phenotyping data quality. Through sharing training resources and standardizing the role, we aim to enable clinicians and researchers to adapt and utilize the Digital Navigator for their own needs.

Improved Disabilities of the Arm, Shoulder and Hand scores after myoelectric arm orthosis use at home in chronic stroke: A retrospective study.

BACKGROUND: Most stroke survivors have persistent upper limb impairments after completing standard clinical care. The resulting impairments can adversely affect their quality of life and ability to complete self-care tasks and remain employed, leading to increased healthcare and societal costs. A myoelectric arm orthosis can be used effectively to support the affected weak arm and increase an individual's use of that arm. OBJECTIVE: The study objective was to retrospectively evaluate the outcomes and clinical benefits provided by the MyoPro® orthosis in individuals 65 years and older with upper limb impairment secondary to a stroke. METHODS: The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire was administered to individuals who have chronic stroke both before and after receiving their myoelectric orthosis. A Generalized Estimating Equation model was analyzed. RESULTS: After using the MyoPro, 19 individuals with chronic stroke had a mean improvement (decrease) in DASH score of 18.07, 95% CI = (-25.41, -10.72), adjusted for 8 covariates. This large change in DASH score was statistically significant and clinically meaningful as participants self-reported an improvement with engagement in functional tasks. CONCLUSIONS: Use of the MyoPro increases independence in functional tasks as reported by the validated DASH outcome measure for older participants with chronic stroke.

Pioglitazone reverses alcohol-induced alterations in alveolar macrophage mitochondrial phenotype.

BACKGROUND: People with alcohol use disorder (AUD) have an increased risk of developing pneumonia and pulmonary diseases. Alveolar macrophages (AMs) are immune cells of the lower respiratory tract that are necessary for clearance of pathogens. However, alcohol causes AM oxidative stress, mitochondrial damage and dysfunction, and diminished phagocytic capacity, leading to lung injury and immune suppression. METHODS: AMs were isolated by bronchoalveolar lavage from people with AUD and male and female C57BL/6J mice given chronic ethanol (20% w/v, 12 weeks) in drinking water. The peroxisome proliferator-activated receptor γ ligand, pioglitazone, was used to treat human AMs ex vivo (10 µM, 24 h) and mice in vivo by oral gavage (10 mg/kg/day). Levels of AM mitochondrial superoxide and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA, a marker of oxidative stress, were measured by fluorescence microscopy and RT-qPCR, respectively. Mouse AM phagocytic ability was determined by internalized Staphylococcus aureus, and mitochondrial capacity, dependency, and flexibility for glucose, long-chain fatty acid, and glutamine oxidation were measured using an extracellular flux analyzer. In vitro studies used a murine AM cell line, MH-S (±0.08% ethanol, 72 h) to investigate mitochondrial fuel oxidation and ATP-linked respiration. RESULTS: Pioglitazone treatment decreased mitochondrial superoxide in AMs from people with AUD and ethanol-fed mice and HIF-1α mRNA in ethanol-fed mouse lungs. Pioglitazone also reversed mouse AM glutamine oxidation and glucose or long-chain fatty acid flexibility to meet basal oxidation needs. In vitro, ethanol decreased the rate of AM mitochondrial and total ATP production, and pioglitazone improved changes in glucose and glutamine oxidation. CONCLUSIONS: Pioglitazone reversed chronic alcohol-induced oxidative stress in human AM and mitochondrial substrate oxidation flexibility and superoxide levels in mouse AM. Decreased ethanol-induced AM HIF-1α mRNA with pioglitazone suggests that this pathway may be a focus for metabolic-targeted therapeutics to improve morbidity and mortality in people with AUD.

Cucurbit[8]uril Binds Nonterminal Dipeptide Sites with High Affinity and Induces a Type II ß-Turn.

In an effort to target polypeptides at nonterminal sites, we screened the binding of the synthetic receptor cucurbit[8]uril (Q8) to a small library of tetrapeptides, each containing a nonterminal dipeptide binding site. The resulting leads were characterized in detail using a combination of isothermal titration calorimetry, 1H NMR spectroscopy, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS), and X-ray crystallography. The equilibrium dissociation constant values determined for the binding of Q8 to nonterminal dipeptide sites Lys-Phe (KF) and Phe-Lys (FK) were 60 and 86 nm, respectively. These are to the best of our knowledge the highest affinities reported to date for any synthetic receptor targeting a nonterminal site on an unmodified peptide. A 0.79 Å resolution crystal structure was obtained for the complex of Q8 with the peptide Gly-Gly-Leu-Tyr-Gly-Gly-Gly (GGLYGGG) and reveals structural details of the pair-inclusion motif. The molecular basis for recognition is established to be the inclusion of the side chains of Leu and Tyr residues, as well as an extensive network of hydrogen bonds between the peptide backbone, the carbonyl oxygens of Q8, and proximal water molecules. In addition, the crystal structure reveals that Q8 induces a type II ß-turn. The sequence-selectivity, high affinity, reversibility, and detailed structural characterization of this system should facilitate the development of applications involving ligand-induced polypeptide folding.

Xist ribonucleoproteins promote female sex-biased autoimmunity.

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.

The impact of guided versus supportive coaching on mental health app engagement and clinical outcomes.

Although mobile mental health apps have the unique potential to increase access to care, evidence reveals engagement is low unless coupled with coaching. However, most coaching protocols are limited in their scalability. This study assesses how human support and guidance from a Digital Navigator (DN), a scalable coach, can impact mental health app engagement and effectiveness on anxiety and depressive symptoms. This study aims to detach components of coaching, specifically personalized recommendations versus general support, to inform scalability of coaching models for mental health apps. 156 participants were split into the DN Guide versus DN Support groups for the 6-week study. Both groups utilized the mindLAMP app for the duration of the study and had equal time with the DN, but the Guide group received personalized app recommendations. The Guide group completed significantly more activities than the Support group. 34% (49/139) of all participants saw a 25% decrease in PHQ-9 scores and 38% (53/141) saw a 25% decrease in GAD-7 scores. These findings show mental health apps, especially when supported by DNs, can reduce depression and anxiety symptoms when coupled with coaching, suggesting a feasible path for large-scale deployment.

Variability in Cognitive Task Performance in Early Adolescence Is Associated With Stronger Between-Network Anticorrelation and Future Attention Problems.

Background: Intraindividual variability (IIV) during cognitive task performance is a key behavioral index of attention and a consistent marker of attention-deficit/hyperactivity disorder. In adults, lower IIV has been associated with anticorrelation between the default mode network (DMN) and dorsal attention network (DAN)-thought to underlie effective allocation of attention. However, whether these behavioral and neural markers of attention are 1) associated with each other and 2) can predict future attention-related deficits has not been examined in a developmental, population-based cohort. Methods: We examined relationships at the baseline visit between IIV on 3 cognitive tasks, DMN-DAN anticorrelation, and parent-reported attention problems using data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 11,878 participants, ages 9 to 10 years, female = 47.8%). We also investigated whether behavioral and neural markers of attention at baseline predicted attention problems 1, 2, and 3 years later. Results: At baseline, greater DMN-DAN anticorrelation was associated with lower IIV across all 3 cognitive tasks (B = 0.22 to 0.25). Older age at baseline was associated with stronger DMN-DAN anticorrelation and lower IIV (B = -0.005 to -0.0004). Weaker DMN-DAN anticorrelation and IIV were cross-sectionally associated with attention problems (B = 1.41 to 7.63). Longitudinally, lower IIV at baseline was associated with less severe attention problems 1 to 3 years later, after accounting for baseline attention problems (B = 0.288 to 0.77). Conclusions: The results suggest that IIV in early adolescence is associated with worsening attention problems in a representative cohort of U.S. youth. Attention deficits in early adolescence may be important for understanding and predicting future cognitive and clinical outcomes.

Myoelectric Arm Orthosis Assists Functional Activities: A 3-Month Home Use Outcome Report.

Objective: The objective was to compare task performance in individuals with upper limb impairments with and without a myoelectric arm orthosis. Design: Three-month observational study. Participants met at 4 time points after receiving their myoelectric orthosis (2-Weeks, Month-1, Month-2, Month-3) to complete 4 standardized common daily tasks. Setting: Nationwide sessions completed remotely over videoconference calls at home. There were no specific clinic affiliations. Participants: Adults with upper limb impairment due to stroke who were in the process of being fit with a myoelectric arm orthosis as a first-time user. Interventions: The orthosis was a custom-fabricated myoelectric arm orthosis called the MyoPro®. Main Outcome Measures: Functional tasks were completed at each session with and without the MyoPro. Participants were evaluated on their success and the time required to complete each functional task. Longitudinal mixed and longitudinal mixed logistic regression models were analyzed. Results: Eighteen individuals with chronic arm weakness due to stroke were included in the analysis. Statistically significant and clinically meaningful improvements were observed on the functional tasks in the participants' homes. By 3 months, participants successfully used the MyoPro to accomplish the tasks, reduced the amount of time spent to complete the tasks, and had a higher probability of success as compared with at 2 weeks. With the MyoPro, participants showed significant improvement in overall task completion and completed the tasks in a significantly decreased time as compared with without the MyoPro. Conclusions: The MyoPro provides a stabilizing support to the weak arm of individuals after stroke and enables individuals to use their impaired arm to complete functional tasks independently in the home environment.

Ancestry-based differences in the immune phenotype are associated with lupus activity.

Systemic lupus erythematosus (SLE) affects 1 in 537 Black women, which is >2-fold more than White women. Black patients develop the disease at a younger age, have more severe symptoms, and have a greater chance of early mortality. We used a multiomics approach to uncover ancestry-associated immune alterations in patients with SLE and healthy controls that may contribute biologically to disease disparities. Cell composition, signaling, epigenetics, and proteomics were evaluated by mass cytometry; droplet-based single-cell transcriptomics and proteomics; and bead-based multiplex soluble mediator levels in plasma. We observed altered whole blood frequencies and enhanced activity in CD8+ T cells, B cells, monocytes, and DCs in Black patients with more active disease. Epigenetic modifications in CD8+ T cells (H3K27ac) could distinguish disease activity level in Black patients and differentiate Black from White patient samples. TLR3/4/7/8/9-related gene expression was elevated in immune cells from Black patients with SLE, and TLR7/8/9 and IFN-α phospho-signaling and cytokine responses were heightened even in immune cells from healthy Black control patients compared with White individuals. TLR stimulation of healthy immune cells recapitulated the ancestry-associated SLE immunophenotypes. This multiomic resource defines ancestry-associated immune phenotypes that differ between Black and White patients with SLE, which may influence the course and severity of SLE and other diseases.

An exploratory analysis of the effect size of the mobile mental health Application, mindLAMP.

Objectives: Despite the proliferation of mobile mental health apps, evidence of their efficacy around anxiety or depression is inadequate as most studies lack appropriate control groups. Given that apps are designed to be scalable and reusable tools, insights concerning their efficacy can also be assessed uniquely through comparing different implementations of the same app. This exploratory analysis investigates the potential to report a preliminary effect size of an open-source smartphone mental health app, mindLAMP, on the reduction of anxiety and depression symptoms by comparing a control implementation of the app focused on self-assessment to an intervention implementation of the same app focused on CBT skills. Methods: A total of 328 participants were eligible and completed the study under the control implementation and 156 completed the study under the intervention implementation of the mindLAMP app. Both use cases offered access to the same in-app self-assessments and therapeutic interventions. Multiple imputations were utilized to impute the missing Generalized Anxiety Disorder-7 and Patient Health Questionnaire-9 survey scores of the control implementation. Results: Post hoc analysis revealed small effect sizes of Hedge's g = 0.34 for Generalized Anxiety Disorder-7 and Hedge's g = 0.21 for Patient Health Questionnaire-9 between the two groups. Conclusions: mindLAMP shows promising results in improving anxiety and depression outcomes in participants. Though our results mirror the current literature in assessing mental health apps' efficacy, they remain preliminary and will be used to inform a larger, well-powered study to further elucidate the efficacy of mindLAMP.

Evaluating the evolutionary mechanisms maintaining alternative mating strategies in a simulated bull trout (Salvelinus confluentus) population.

The coexistence of distinct alternative mating strategies (AMS) is often explained by mechanisms involving trade-offs between reproductive traits and lifetime fitness; yet their relative importance remains poorly understood. Here, we used an established individual-based, spatially explicit model to simulate bull trout (Salvelinus confluentus) in the Skagit River (Washington, USA) and investigated the influence of female mating preference, sneaker-specific mortality, and variation in age-at-maturity on AMS persistence using global sensitivity analyses and boosted regression trees. We assumed that two genetically fixed AMS coexisted within the population: sneaker males (characterized by younger age-at-maturity, greater AMS-specific mortality, and lower reproductive fitness) and territorial males. After 300 years, variation in relative sneaker success in the system was explained by sneaker males' reproductive fitness (72%) and, to a lesser extent, the length of their reproductive lifespan (21%) and their proportion in the initial population (8%). However, under a wide range of parameter values, our simulated scenarios predicted the extinction of territorial males or their persistence in small, declining populations. Although these results do not resolve the coexistence of AMS in salmonids, they reinforce the importance of mechanisms reducing sneaker's lifetime reproductive success in favoring AMS coexistence within salmonid populations but also limit the prediction that, without any other selective mechanisms at play, strong female preference for mating with territorial males and differences in reproductive lifespan allow the stable coexistence of distinct AMS.

Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC.

INTRODUCTION: In KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors. METHODS: Using cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo. RESULTS: Surprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo. CONCLUSIONS: Exploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.

Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness.

The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

Relapse prediction in schizophrenia with smartphone digital phenotyping during COVID-19: a prospective, three-site, two-country, longitudinal study.

Smartphone technology provides us with a more convenient and less intrusive method of detecting changes in behavior and symptoms that typically precede schizophrenia relapse. To take advantage of the aforementioned, this study examines the feasibility of predicting schizophrenia relapse by identifying statistically significant anomalies in patient data gathered through mindLAMP, an open-source smartphone app. Participants, recruited in Boston, MA in the United States, and Bangalore and Bhopal in India, were invited to use mindLAMP for up to a year. The passive data (geolocation, accelerometer, and screen state), active data (surveys), and data quality metrics collected by the app were then retroactively fed into a relapse prediction model that utilizes anomaly detection. Overall, anomalies were 2.12 times more frequent in the month preceding a relapse and 2.78 times more frequent in the month preceding and following a relapse compared to intervals without relapses. The anomaly detection model incorporating passive data proved a better predictor of relapse than a naive model utilizing only survey data. These results demonstrate that relapse prediction models utilizing patient data gathered by a smartphone app can warn the clinician and patient of a potential schizophrenia relapse.