Baseline and end-of-treatment host serum biomarkers predict relapse in adults with pulmonary tuberculosis.

BACKGROUND: There is a need for new tools for monitoring of the response to TB treatment. Such tools may allow for tailored treatment regimens, and stratify patients initiating TB treatment into different risk groups. We evaluated combinations between previously published host biomarkers and new candidates, as tools for monitoring TB treatment response, and prediction of relapse. METHODS: Serum samples were collected at multiple time points, from patients initiating TB treatment at research sites situated in South Africa (ActionTB study), Brazil and Uganda (TBRU study). Using a multiplex immunoassay platform, we evaluated the concentrations of selected host inflammatory biomarkers in sera obtained from clinically cured patients with and without subsequent relapse within 2 years of TB treatment completion. RESULTS: A total of 130 TB patients, 30 (23%) of whom had confirmed relapse were included in the study. The median time to relapse was 9.7 months in the ActionTB study (n=12 patients who relapsed), and 5 months (n=18 patients who relapsed) in the TBRU study. Serum concentrations of several host biomarkers changed during TB treatment with IL-6, IP-10, IL-22 and complement C3 showing potential individually, in predicting relapse. A six-marker signature comprising of TTP, BMI, sICAM-1, IL-22, IL-1ß and complement C3, predicted relapse, prior to the onset of TB treatment with 89% sensitivity and 94% specificity. Furthermore, a 3-marker signature (Apo-CIII, IP-10 and sIL-6R) predicted relapse in samples collected at the end of TB treatment with sensitivity of 71% and specificity of 74%. A previously identified baseline relapse prediction signature (TTP, BMI, TNF-ß, sIL-6R, IL-12p40 and IP-10) also showed potential in the current study. CONCLUSION: Serum host inflammatory biomarkers may be useful in predicting relapse in TB patients prior to the initiation of treatment. Our findings have implications for tailored patient management and require prospective evaluation in larger studies.

Cardiovascular and mortality benefits of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists as third-step glucose-lowering medicine in patients with type 2 diabetes: a retrospective cohort analysis.

INTRODUCTION: Studies have found that sodium-glucose cotransporter 2 inhibitors (SGLT2) and glucagon-like peptide 1 receptor agonists (GLP1) have cardiovascular benefits for patients with type 2 diabetes (DM2) and atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF). The literature does not provide evidence specifically for patients with these conditions who are adding one of these medicines to two glucose-lowering medications (ie, as "third-step" therapy). We explored the effects of different third-step medications on cardiovascular outcomes in patients with diabetes and these comorbid conditions. Specifically, we compared third-step SGLT2 or GLP1 to third-step dipeptidyl peptidase-4 inhibitors (DPP4), insulin, or thiazolidinediones (TZD). RESEARCH DESIGN AND METHODS: We assembled a retrospective cohort of adults at five Kaiser Permanente sites with DM2 and ASCVD, CKD, or HF, initiating third-step treatment between 2016 and 2020. Propensity score weighted Poisson models were used to calculate adjusted rate ratios (ARRs) for all-cause mortality, incident major adverse cardiovascular event (MACE), and incident HF hospitalization in patients initiating SGLT2 or GLP1 compared with DPP4, insulin, or TZD. RESULTS: We identified 27 542 patients initiating third-step treatment with one or more of these conditions (19 958 with ASCVD, 14 577 with CKD, and 3919 with HF). ARRs for GLP1 and SGLT2 versus DPP4, insulin, and TZD in the patient subgroups ranged between 0.22 and 0.55 for all-cause mortality, 0.38 and 0.81 for MACE, and 0.46 and 1.05 for HF hospitalization. Many ARRs were statistically significant, and all significant ARRs showed a benefit (ARR <1) for GLP1 or SGLT2 when compared with DPP4, insulin, or TZD. CONCLUSIONS: Third-step SGLT2 and GLP1 are generally associated with a benefit for these outcomes in these patient groups when compared with third-step DPP4, insulin, or TZD. Our results add to evidence of a cardiovascular benefit of SGLT2 and GLP1 and could inform clinical guidelines for choosing third-step diabetes treatment.

Identification of Selective Imidazopyridine CSF1R Inhibitors.

Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure-activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat.

Considering the associations of adverse and positive childhood experiences with health behaviors and outcomes among emerging adults.

Childhood is a sensitive period of development during which early life experiences can facilitate either positive or negative health trajectories across subsequent developmental periods. Previous research has established strong links between adverse childhood experiences (ACEs) and adverse health outcomes (e.g., sleep-related problems, pain, substance use). Despite this, less is known about positive childhood experiences (PCEs) and how they may buffer the effects of ACEs on health outcomes. The current study investigated whether PCEs moderate the associations between ACEs and health behavior and health-related outcomes (i.e., cannabis use, alcohol use, sleep disturbance, sleep-related impairment, pain intensity, and pain interference) in a sample of at-risk emerging adults. Participants (N = 165) were undergraduate college students (18-25 years of age) who reported frequent alcohol and/or cannabis use (≥3 times in the past week). A significant positive association was found between ACEs and cannabis use. There were also significant negative associations found between PCEs and pain interference and intensity. PCEs did not moderate any of the associations between ACEs and health behavior and health-related outcomes (i.e., cannabis use, alcohol use, sleep disturbance, sleep-related impairment, pain intensity, and pain interference). Findings suggest that PCEs may be unlikely to serve as a strong enough protective factor during early life to decrease risk for suboptimal health and health behaviors during emerging adulthood among individuals who report a greater accumulation of ACEs. Longitudinal research is needed to identify additional related risk and protective factors during early life to further support health and health behavior during this transitional period of development and beyond.

Modeling Allosteric Mechanisms of Eukaryotic Type II Topoisomerases.

Type II topoisomerases (TopoIIs) are ubiquitous enzymes that are involved in crucial nuclear processes such as genome organization, chromosome segregation, and other DNA metabolic processes. These enzymes function as large, homodimeric complexes that undergo a complex cycle of binding and hydrolysis of two ATP molecules in their ATPase domains, which regulates the capture and passage of one DNA double-helix through a second, cleaved DNA molecule. This process requires the transmission of information about the state of the bound nucleotide over vast ranges in the TopoII complex. How this information is transmitted at the molecular level to regulate TopoII functions and how protein substitutions disrupt these mechanisms remains largely unknown. Here, we employed extensive microsecond scale molecular dynamics simulations of the yeast TopoII enzyme in multiple nucleotide-bound states and with amino acid substitutions near both the N- and C-terminals of the complex. Simulation results indicate that the ATPase domains are remarkably flexible on the sub-microsecond timescale and that these dynamics are modulated by the identity of the bound nucleotides and both local and distant amino acid substitutions. Network analyses point towards specific allosteric networks that transmit information about the hydrolysis cycle throughout the complex, which include residues in both the protein and the bound DNA molecule. Amino acid substitutions weaken many of these pathways. Together, our results provide molecular-level details on how the TopoII catalytic cycle is controlled through nucleotide binding and hydrolysis and how mutations may disrupt this process.

A prospective study of posttransplant cyclophosphamide for unrelated donor peripheral blood stem cell transplant with special attention to graft content and the impact of a higher γδ T cell dose.

Posttransplant cyclophosphamide (PtCy) has been shown to decrease post-hematopoietic stem cell transplant acute and chronic graft-versus-host disease (GVHD). In this study, PtCy was used in 44 patients along with mycophenolate and tacrolimus with HLA matched (29) and mismatched (15) unrelated donors to determine the impact of graft content on outcome; thus, all patients had flow cytometric analysis of their graft content including the number of B cells, NK cells, and various T cell subsets. Higher γδ T cell dose was associated with the development of acute GVHD (p = .0038). For PtCy, further studies of the cell product along with further graft manipulation, such as selective γδ T cell depletion, could potentially improve outcomes.

Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs.

Unique characteristics of the J-domain proximal regions of Hsp70 cochaperone Apj1 in prion propagation/elimination and its overlap with Sis1 function.

J-domain proteins (JDPs) are obligate cochaperones of Hsp70s. The Class A JDP Apj1 of the yeast cytosol has an unusually complex region between the N-terminal J-domain and the substrate binding region-often called the Grich or GF region in Class A and B JDPs because of its typical abundance of glycine. The N-terminal 161-residue Apj1 fragment is known to be sufficient for Apj1 function in prion curing, driven by the overexpression of Hsp104. Further analyzing the N-terminal segment of Apj1, we found that a 90-residue fragment that includes the 70-residue J-domain and the adjacent 12-residue glutamine/alanine (Q/A) segment is sufficient for curing. Furthermore, the 121-residue fragment that includes the Grich region was sufficient to not only sustain the growth of cells lacking the essential Class B JDP Sis1 but also enabled the maintenance of several prions normally dependent on Sis1 for propagation. A J-domain from another cytosolic JDP could substitute for the Sis1-related functions but not for Apj1 in prion curing. Together, these results separate the functions of JDPs in prion biology and underscore the diverse functionality of multi-domain cytosolic JDPs in yeast.

Massively parallel dissection of RNA in RNA-protein interactions in vivo.

Many of the biological functions performed by RNA are mediated by RNA-binding proteins (RBPs), and understanding the molecular basis of these interactions is fundamental to biology. Here, we present massively parallel RNA assay combined with immunoprecipitation (MPRNA-IP) for in vivo high-throughput dissection of RNA-protein interactions and describe statistical models for identifying RNA domains and parsing the structural contributions of RNA. By using custom pools of tens of thousands of RNA sequences containing systematically designed truncations and mutations, MPRNA-IP is able to identify RNA domains, sequences, and secondary structures necessary and sufficient for protein binding in a single experiment. We show that this approach is successful for multiple RNAs of interest, including the long noncoding RNA NORAD, bacteriophage MS2 RNA, and human telomerase RNA, and we use it to interrogate the hitherto unknown sequence or structural RNA-binding preferences of the DNA-looping factor CTCF. By integrating systematic mutation analysis with crosslinking immunoprecipitation, MPRNA-IP provides a novel high-throughput way to elucidate RNA-based mechanisms behind RNA-protein interactions in vivo.

Promoting Healthy Adolescent Romantic Relationships: Results of a Multisite, Two-group Parallel Randomized Clinical Trial.

PURPOSE: To examine the impact of About Us, an innovative healthy relationships intervention that promotes positive adolescent romantic relationships and the use of effective contraceptives, on improving behavior, attitudes, and intentions related to sexual intercourse, relationship communication, and conflict resolution at 3- and 9-month follow-up, compared to services as usual. METHODS: This was a multi-site, two-group, parallel, randomized-controlled trial with an intervention/comparison allocation ratio of 3:2 conducted at seven high schools in California between February 2018 and May 2021. RESULTS: Overall, our study did not find statistically significant evidence of improved behavior, attitudes, and intentions related to sexual intercourse, relationship communication, and conflict resolution among participants (14-18 years old) randomized to the intervention group (n = 316) compared to services as usual (n = 217) during follow-up (group x time; p > .05). Exploratory within group analyses showed that, compared to baseline, at the 3-month follow-up, the prevalence of reporting having had sex increased in the control group relative to intervention group (+19% vs. +9%, p < .01). Our sub-group analyses showed that changes in condom use intentions scores differed across school sites (group x time x school; p < .01); mixed (positive and negative) trends were observed for intervention effect, and schools with positive intervention effect trends tended to have greater program participation. DISCUSSION: About Us did not show statistically significant positive impacts on primary or secondary outcomes as anticipated. Our exploratory findings show evidence of some promising trends of intervention effects at the school-level, suggesting a need for better tailored intervention components and/or delivery to address the unique environmental contexts of participants. Overall, the context of study implementation was negatively affected by the COVID-19 pandemic and challenges related to using a non-classroom delivery intervention approach. Combined, these factors may have contributed to the study null findings. Moreover, it is difficult to know (or determine) the intervention's impact under more ideal conditions (i.e., no COVID pandemic).

Examining the Associations Between Substance Misuse and Suicide Bereavement.

Focusing on the understudied question of substance misuse among suicide bereaved adults we investigated patterns of binge drinking and non-prescribed drug use among a recently bereaved sample (n = 1,132). Comparing our respondents to the non-bereaved, those in the 2022 National Survey of Drug Use and Health (n = 71,369), we did not find heightened problematical substance misuses among our respondents. With t-tests and multiple regression analyses we examined whether binge drinkers and non-prescribed drug users had heightened levels of grief difficulties, PTSD, self-blaming and depression compared to others not bingeing or using non-prescribed drugs. Results showed binge drinkers had more of all these grieving problems when important confounding variables were also considered. Analysis of the demographic correlates of bingeing showed them dimly aware of their own additional grieving and substance misusing problems. Since 75% indicated being under the care of counseling professionals, this represents an important opportunity for psycho-educational helping.

Lung adenocarcinomas without driver genes converge to common adaptive strategies through diverse genetic, epigenetic, and niche construction evolutionary pathways.

Somatic evolution selects cancer cell phenotypes that maximize survival and proliferation in dynamic environments. Although cancer cells are molecularly heterogeneous, we hypothesized convergent adaptive strategies to common host selection forces can be inferred from patterns of epigenetic and genetic evolutionary selection in similar tumors. We systematically investigated gene mutations and expression changes in lung adenocarcinomas with no common driver genes (n = 313). Although 13,461 genes were mutated in at least one sample, only 376 non-synonymous mutations evidenced positive evolutionary selection with conservation of 224 genes, while 1736 and 2430 genes exhibited ≥ two-fold increased and ≥ 50% decreased expression, respectively. Mutations under positive selection are more frequent in genes with significantly altered expression suggesting they often "hardwire" pre-existing epigenetically driven adaptations. Conserved genes averaged 16-fold higher expression in normal lung tissue compared to those with selected mutations demonstrating pathways necessary for both normal cell function and optimal cancer cell fitness. The convergent LUAD phenotype exhibits loss of differentiated functions and cell-cell interactions governing tissue organization. Conservation with increased expression is found in genes associated with cell cycle, DNA repair, p53 pathway, epigenetic modifiers, and glucose metabolism. No canonical driver gene pathways exhibit strong positive selection, but extensive down-regulation of membrane ion channels suggests decreased transmembrane potential may generate persistent proliferative signals. NCD LUADs perform niche construction generating a stiff, immunosuppressive microenvironment through selection of specific collagens and proteases. NCD LUADs evolve to a convergent phenotype through a network of interconnected genetic, epigenetic, and ecological pathways.

Modeling a hot, dry future: Substantial range reductions in suitable environment projected under climate change for a semiarid riparian predator guild.

An understanding of species-environmental relationships is invaluable for effective conservation and management under anthropogenic climate change, especially for biodiversity hotspots such as riparian habitats. Species distribution models (SDMs) assess present species-environmental relationships which can project potential suitable environments through space and time. An understanding of environmental factors associated with distributions can guide conservation management strategies under a changing climate. We generated 260 ensemble SDMs for five species of Thamnophis gartersnakes (n = 347)-an important riparian predator guild-in a semiarid and biogeographically diverse region under impact from climate change (Arizona, United States). We modeled present species-environmental relationships and projected changes to suitable environment under 12 future climate scenarios per species, including the most and least optimistic greenhouse gas emission pathways, through 2100. We found that Thamnophis likely advanced northward since the turn of the 20th century and overwinter temperature and seasonal precipitation best explained present distributions. Future ranges of suitable environment for Thamnophis are projected to decrease by ca. -37.1% on average. We found that species already threatened with extinction or those with warm trailing-edge populations likely face the greatest loss of suitable environment, including near or complete loss of suitable environment. Future climate scenarios suggest an upward advance of suitable environment around montane areas for some low to mid-elevation species, which may create pressures to ascend. The most suitable environmental areas projected here can be used to identify potential safe zones to prioritize conservation refuges, including applicable critical habitat designations. By bounding the climate pathway extremes to, we reduce SDM uncertainties and provide valuable information to help conservation practitioners mitigate climate-induced threats to species. Implementing informed conservation actions is paramount for sustaining biodiversity in important aridland riparian systems as the climate warms and dries.

Potency of a small molecule that targets the molluscum contagiosum virus processivity factor increases when conjugated to a tripeptide.

We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity.

Weight management using meal replacements and cardiometabolic risk reduction in individuals with pre-diabetes and features of metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.

This review synthesized the evidence from randomized controlled trials comparing the effect of meal replacements (MRs) as part of a weight loss intervention with conventional food-based weight loss diets on cardiometabolic risk in individuals with pre-diabetes and features of metabolic syndrome. MEDLINE, EMBASE, and Cochrane Library were searched through January 16, 2024. Data were pooled using the generic inverse variance method and expressed as mean difference [95% confidence intervals]. The overall certainty of the evidence was assessed using GRADE. Ten trials (n = 1254) met the eligibility criteria. MRs led to greater reductions in body weight (-1.38 kg [-1.81, -0.95]), body mass index (BMI, -0.56 kg/m2 [-0.78, -0.34]), waist circumference (-1.17 cm [-1.93, -0.41]), HbA1c (-0.11% [-0.22, 0.00]), LDL-c (-0.18 mmol/L [-0.28, -0.08]), non-HDL-c (-0.17 mmol/L [-0.33, -0.01]), and systolic blood pressure (-2.22 mmHg [-4.20, -0.23]). The overall certainty of the evidence was low to moderate owing to imprecision and/or inconsistency. The available evidence suggests that incorporating MRs into a weight loss intervention leads to small important reductions in body weight, BMI, LDL-c, non-HDL-c, and systolic blood pressure, and trivial reductions in waist circumference and HbA1c, beyond that seen with conventional food-based weight loss diets.

Bicycling for Rehabilitation of Persons With Parkinson Disease: A Scoping Review.

BACKGROUND AND PURPOSE: Exercise is beneficial for persons with Parkinson disease (PwPD). The overarching purpose of this scoping review was to provide guidance to clinicians and scientists regarding current evidence for bicycling exercise for PwPD. A scoping review was conducted to examine the heterogeneous literature on stationary bicycling for PwPD to reduce motor symptoms and body function structure impairments, improve activities and motor performance, and reduce disease severity. METHODS: The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines were followed. PubMed, CINAHL, and PEDro were searched from inception to January 23, 2023. Articles reporting original data on relevant outcome measures were included. Search results were screened and articles were extracted. Data were analyzed quantitatively with percentages of significant and clinically meaningful findings and qualitatively to extract themes. RESULTS: Bicycling was categorized using bicycle types (assisted, nonassisted) and training modes (speed, aerobic, force). A high percentage of the 34 studies showed statistical significance for reducing motor symptoms (83%), body function structure impairments (78%), disease severity (82%), and improving activities (gait 72%, balance 60%). Clinically meaningful findings were achieved in 71% of the studies for reduction in disease severity and in 50% for improving gait. DISCUSSION AND CONCLUSIONS: The literature on bicycling for PwPD has evolved from speed to aerobic studies. The terminology describing types of bicycling was simplified. Of all the outcomes reported, reduction of disease severity achieved the highest frequency of clinical meaningful improvements. Bicycling was comparable with other forms of aerobic training for walking speed and endurance. Opportunities for translation to practice and research are presented. VIDEO ABSTRACT AVAILABLE: for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A462).

Diversity and molecular evolution of non-visual opsin genes across environmental, developmental, and morphological adaptations in frogs.

Non-visual opsins are transmembrane proteins expressed in the eyes and other tissues of many animals. When paired with a light-sensitive chromophore, non-visual opsins form photopigments involved in various non-visual, light-detection functions including circadian rhythm regulation, light-seeking behaviors, and seasonal responses. Here we investigate the molecular evolution of non-visual opsin genes in anuran amphibians (frogs and toads). We test several evolutionary hypotheses including the predicted loss of non-visual opsins due to nocturnal ancestry and potential functional differences in non-visual opsins resulting from environmental light variation across diverse anuran ecologies. Using whole-eye transcriptomes of 81 species, combined with genomes, multi-tissue transcriptomes, and independently annotated genes from an additional 21 species, we identify which non-visual opsins are present in anuran genomes and those that are also expressed in the eyes, compare selective constraint among genes, and test for potential adaptive evolution by comparing selection between discrete ecological classes. At the genomic level, we recovered all 18 ancestral vertebrate non-visual opsins, indicating that anurans demonstrate the lowest documented amount of opsin gene loss among ancestrally nocturnal tetrapods. We consistently found expression of 14 non-visual opsins in anuran eyes and detected positive selection in a subset of these genes. We also found shifts in selective constraint acting on non-visual opsins in frogs with differing activity periods, habitats, distributions, life histories, and pupil shapes, which may reflect functional adaptation. Although many non-visual opsins remain poorly understood, these findings provide insight into the diversity and evolution of these genes across anurans, filling an important gap in our understanding of vertebrate opsins and setting the stage for future research on their functional evolution across taxa.