Emory University

Dysregulated neutrophil recruitment drives many pulmonary diseases, but most preclinical screening methods are unsuited to evaluate pulmonary neutrophilia, limiting progress toward therapeutics. Namely, high-throughput therapeutic assays typically exclude critical neutrophilic pathophysiology, including blood-to-lung recruitment, dysfunctional activation, and resulting impacts on the air-blood barrier. To meet the conflicting demands of physiological complexity and high throughput, we developed an assay of 96-well leukocyte recruitment in an air-blood barrier array (L-ABBA-96) that enables in vivo-like neutrophil recruitment compatible with downstream phenotyping by automated flow cytometry. We modeled acute respiratory distress syndrome (ARDS) with neutrophil recruitment to 20 ng/mL epithelial-side interleukin 8 and found a dose-dependent reduction in recruitment with physiologic doses of baricitinib, a JAK1/2 inhibitor recently Food and Drug Administration-approved for severe Coronavirus Disease 2019 ARDS. Additionally, neutrophil recruitment to patient-derived cystic fibrosis sputum supernatant induced disease-mimetic recruitment and activation of healthy donor neutrophils and upregulated endothelial e-selectin. Compared to 24-well assays, the L-ABBA-96 reduces required patient sample volumes by 25 times per well and quadruples throughput per plate. Compared to microfluidic assays, the L-ABBA-96 recruits two orders of magnitude more neutrophils per well, enabling downstream flow cytometry and other standard biochemical assays. This novel pairing of high-throughput in vitro modeling of organ-level lung function with parallel high-throughput leukocyte phenotyping substantially advances opportunities for pathophysiological studies, personalized medicine, and drug testing applications.

Aims The PANORAMA‐HF trial demonstrated significant N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) reductions in paediatric patients with left ventricular systolic dysfunction with sacubitril/valsartan or enalapril treatment over 52 weeks. This post hoc analysis aims to correlate changes in NT‐proBNP levels with clinical outcomes in PANORAMA‐HF patients receiving either sacubitril/valsartan or enalapril. Additionally, NT‐proBNP reductions in the paediatric population were compared with a subset of adult heart failure with reduced ejection fraction (HFrEF) patients from the PARADIGM‐HF trial. Methods and results This post hoc analysis utilized data from Part 2 of the PANORAMA‐HF trial. Associations between baseline NT‐proBNP levels, changes post‐baseline and the risk of HF clinical events in paediatric patients on sacubitril/valsartan or enalapril were assessed. The paediatric HF population from PANORAMA‐HF was categorized into age groups (AG): AG1 (aged 6 to <18 years), AG2a (aged 2 to <6 years) and AG3a (aged 1 month to <2 years). The Cox proportional hazard model evaluated the relationship between NT‐proBNP and clinical outcomes. Analysis of 361 paediatric patients (sacubitril/valsartan, n = 179; enalapril, n = 182) demonstrated overall higher baseline NT‐proBNP levels in younger AGs. At Week 52, both treatment groups exhibited reduced NT‐proBNP levels across all AGs. Reductions were comparable between sacubitril/valsartan and enalapril, with a numerically greater reduction observed in adult patients versus children. Strong associations between NT‐proBNP levels and HF clinical outcomes were observed in paediatric populations in PANORAMA‐HF and in adult DCM patients with HFrEF in PARADIGM‐HF. Doubling of NT‐proBNP levels was associated with a ≥1.7‐fold increased risk of HF clinical events, while halving of the levels correlated with a 52% reduction in the risk of clinical events. Conclusions This is the first prospective, randomized large‐scale study to demonstrate a strong correlation between NT‐proBNP levels and risks of HF clinical events in paediatric patients with HF.

Background Pakistan has been an endemic country for dengue virus since 1994, with a significant increase in cases reported in 2022 largely due to heavy rainfall and flooding. All four serotypes of the dengue virus (DENV) are present in Pakistan, with DENV 1 and DENV 2 being the most prevalent. The current study aims to explore the clinical presentations and features of dengue fever in a tertiary care hospital. Methodology We enrolled and studied 349 cases of suspected and confirmed dengue presenting for care at the Aga Khan University Hospital in Karachi between June 2021 and November 2023. Collected data on cases included clinical symptoms and laboratory results including qRT-PCR and serotype characterization. Findings The majority of subjects enrolled (75%) had mild disease without warning signs, while 11% exhibited warning signs, 1.4% had severe dengue, and 12.6% had no dengue diagnosis. Patients with severe dengue (SD) had significantly higher levels of liver enzymes (AST and ALT) compared to those with non-severe dengue (NSD) (AST; p = 0.024 and ALT; p = 0.047). Additionally, a higher grade of thrombocytopenia was significantly associated with hospitalization (p = 0.0008), and prolonged illness (p = 0.03). Both Platelet (p < 0.0001) and WBC counts (p = 0.001) were significantly lower in dengue PCR-positive patients in comparison to Dengue PCR-negative. Among those tested for dengue serotypes, DENV 1 (34%) and DENV 2 (45%) emerged as the predominant serotypes, with mixed infections accounting for 17%. The sensitivity of q-RT PCR was found to be 87.25% and the specificity of 68.35%. qRT-PCR detected 43.5% of cases with viral fever initially screened negative by IgM or NS1. Conclusion The epidemiology of dengue fever during a widespread outbreak in 2022 showed a predominance of DENV 1 and DENV 2 serotypes with milder phenotype of viral illness. Screening with rapid tests requires further confirmation by molecular assay in cases with dengue and dengue-like illness. The sensitivity of q-RT PCR using gold standard.

Muscle mechanoreflex is crucial to cardiac vagal modulation during exercise and can be activated during passive calf stretch. Herein, we aimed to determine whether cardiac vagal modulation following a single session of passive stretch is linked to interindividual cardiac vagal responses at the onset of passive calf muscle stretching in healthy young adults. Twenty‐four volunteers (10 women) completed the experimental conditions in a randomised order over different days: a time‐control condition and five sets of 1 min of unilateral passive stretching of the calf, with 15 s of rest between each stretching trial. Heart rate and systolic and diastolic blood pressure were continuously measured on a beat‐to‐beat basis before, immediately following, and at 15 and 30 min after the passive stretching intervention. Interindividual variations in cardiac vagal inhibition during the passive stretching session were identified, classifying volunteers into responder (n = 16) and non‐responder (n = 8) groups. The onset of passive muscle stretching elicited an immediate reduction in cardiac vagal modulation (P = 0.026) and an increase in heart rate (P = 0.009) for the responders only. Cardiac vagal modulation significantly increased following 30 min of passive stretching (P = 0.010 vs. rest) for the responders only. During time control, all cardiac vagal variables were unchanged for both groups. In summary, our findings demonstrate that a single session of passive calf muscle stretching can enhance cardiac vagal modulation, but this effect is dependent on interindividual responses at the onset of stretching. These results highlight the role of muscle mechanoreflex activation in cardiac autonomic regulation and suggest that passive stretching may have potential cardiovascular benefits, particularly for individuals who exhibit a mechanoreflex‐mediated response.

Objective Valid and reliable measurement of early childhood development (ECD) is critical for monitoring and evaluating ECD-related policies and programmes. Although ECD tools developed in high-income countries may be applicable to low- and middle-income countries (LMICs), directly applying them in LMICs can be problematic without psychometric evidence for new cultures and contexts. Our objective was to systematically appraise available evidence on the psychometric properties of tools used to measure ECD in LMIC. Design A systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Data sources MEDLINE, Embase, PubMed, PsycInfo, SciELO and BVS were searched from inception to February 2025. Eligibility criteria We included studies that examined the reliability, validity, and measurement invariance of tools assessing ECD in children 0–6 years of age living in LMICs. Data extraction and synthesis Each study was independently screened by two researchers and data extracted by one randomly assigned researcher. Risk of bias was assessed using a checklist developed by the study team assessing bias due to training/administration, selective reporting and missing data. Results were synthesised narratively by country, location, age group at assessment and developmental domain. Results A total of 160 articles covering 117 tools met inclusion criteria. Most reported psychometric properties were internal consistency reliability (n=117, 64%), concurrent validity (n=81, 45%), convergent validity (n=74, 41%), test–retest reliability (n=73, 40%) and structural validity (n=72, 40%). Measurement invariance was least commonly reported (n=16, 9%). Most articles came from Brazil, China, India and South Africa. Most psychometric evidence was from urban (n=92, 51%) or urban–rural (n=41, 23%) contexts. Study samples focused on children aged 6–17.9 or 48–59.9 months. The most assessed developmental domains were language (n=111, 61%), motor (n=104, 57%) and cognitive (n=82, 45%). Bias due to missing data was most common. Conclusions Psychometric evidence is fragmented, limited and heterogeneous. More rigorous psychometric analyses, especially on measurement invariance, are needed to establish the quality and accuracy of ECD tools for use in LMICs. PROSPERO registration number CRD42022372305.

Background Despite well-established criteria for genetic testing to rule out hereditary cancer syndromes (HCSs), most pathogenic variant (PV) carriers are not being tested. Thus, mechanisms that allow for better identification and a streamlined process for testing need to be implemented. The main purpose was to develop a self-updating, guideline-driven tool integrated with the electronic health record (EHR) to prospectively identify at-risk individuals and facilitate outreach and diagnosis. Methods National Comprehensive Cancer Network/American College of Medical Genetics criteria for genetic testing were translated into three distinct rule-based conditional logic statements in the EHR from 218 rules that serially evaluate each aspect of individual criteria, which together roll up into a logic statement of ‘at-risk’. The rules evaluate personal or family history, determine age at onset and categorise family relationships. This tool is applied to a system-wide registry of active patients. Results Out of 1 325 545 individuals, 59 377 (4.48%) were identified as at-risk and thus constitute the At-Risk Cancer Genetic Syndrome Identification (ARCAGEN-ID) registry. Of those, only 12 377 (20.9%) had previously been evaluated, and 2506 had a PV. ARCAGEN-ID appropriately included 96.2% of cases. ARCAGEN-ID individuals not previously evaluated were more often included based on family history criteria (79.8% vs 49.3%), and less often because of both personal and family history of cancer (13% vs 41%) (p<0.001). Conclusions This study is the first to use an EHR-based registry for the automatic and prospective identification of individuals eligible for genetic testing based on current criteria for all major HCS. By streamlining the identification process, this approach has the potential to dramatically increase diagnostic rates and improve cancer-related survival.

Background Few studies showed associations of childhood allergic diseases with epigenetic aging using traditional clocks trained mainly on adults. Tracking DNA methylation variation early in life has suggested poor performance of these clocks in children. Therefore, we aim to elucidate the association between allergic diseases and epigenetic age using a pediatric clock. Methods We used data from the German LISA birth cohort study at six (N = 234) and ten (N = 227) years. DNA methylation was measured in blood using the Infinium Methylation EPIC BeadChip. We calculated epigenetic age using the pediatric clock developed by Wu et al. (Aging 2019) (median absolute error = 0.04 years, Spearman correlation with chronological age r = 0.75). Linear mixed models were used to examine longitudinal associations of epigenetic age acceleration with doctor‐diagnosed asthma, rhinitis, and eczema, or a combination thereof (“any allergy”) as well as aeroallergen sensitization. Replication was performed in BAMSE at the 8‐year follow‐up (N = 625) using linear models. Additionally, epigenetic age in adults from KORA F4 was estimated using Horvath's clocks and associations with allergic diseases were tested applying linear models. Results Having any allergy was significantly associated with a mean epigenetic age acceleration of 0.34 years (95% CI = [0.06; 0.63]) using Wu's clock in LISA. Associations with consistent effect directions were found for allergic rhinitis, asthma, and eczema. No associations with aeroallergen sensitization were observed. In BAMSE, an inverse association of epigenetic age acceleration with eczema was found (−0.52 years, 95% CI = [−0.97; −0.07]). In KORA, hay fever was significantly associated with accelerated epigenetic age when using the Horvath pan‐tissue clock (1.05 years, 95% CI = [0.21; 1.89]). Conclusions We found an increase in epigenetic age in children with allergic diseases from LISA. Our results suggest that epigenetic age acceleration seems to be related to the persistent burden of allergic diseases, but not to non‐symptomatic aeroallergen sensitization.

Background Prenatal exposure to maternal asthma may influence DNA methylation patterns in offspring, potentially affecting their susceptibility to later diseases including asthma. Objective To investigate the relationship between parental asthma and newborn blood DNA methylation. Methods Epigenome-wide association analyses were conducted in 13 cohorts on 7433 newborns with blood methylation data from the Illumina450K or EPIC array. We used fixed effects meta-analyses to identify differentially methylated CpGs (DMCs) and comb-p to identify differentially methylated regions (DMRs) associated with maternal asthma during pregnancy and maternal asthma ever. Paternal asthma was analyzed for comparison. Models were adjusted for covariates and cell-type composition. We examined whether implicated sites related to gene expression analyses in publicly available data for childhood blood and adult lung. Results We identified 27 CpGs associated with maternal asthma during pregnancy at False Discovery Rate < 0.05 but none for maternal asthma ever. Two distinct CpGs were associated with paternal asthma. We observed 5 DMRs associated with maternal asthma during pregnancy 3 associated with maternal asthma ever and 13 DMRs associated with paternal asthma. Gene expression analysis using data in blood from 832 children and lung from 424 adults showed associations between identified DMCs using maternal asthma and expression of several genes, including HLA genes and HOXA5, previously implicated in asthma or lung function. Conclusion Parental asthma, especially maternal asthma during pregnancy, may be associated with alterations in newborn DNA methylation. These findings might shed light on underlying mechanisms for asthma susceptibility.

Background Advancements in novel peptides significantly affect cancer diagnosis by targeting cancer-specific markers, thereby improving imaging modalities, such as positron emission tomography combined with computed tomography (PET/CT) for more accurate tumor detection. This systematic review and meta-analysis aimed to assess the diagnostic accuracy of [18F] Fluorodeoxyglucose (FDG) and ⁶⁸Ga-fibroblast activation protein inhibitor (FAPI- 46) PET/CT for early cancer detection. Methods A comprehensive search was conducted in Scopus, MEDLINE, Web of Science, and Embase databases up to March 28, 2024, using MeSH keywords. Titles and abstracts were screened to identify studies on hybrid [68Ga] FAPI- 46 and [18F] FDG, followed by a detailed full-text evaluation. Only cohort or cross-sectional studies published in English, focusing on the clinical diagnosis of cancer patients, were included, while reviews, case reports, conference proceedings, and abstracts were excluded. Random-effects meta-analysis was used for the estimation of pooled specificity and sensitivity with 95% confidence intervals (CIs). In addition, the heterogeneity was assessed across studies and subgroup meta-analyses for the detection rate via Stata. Results Among the 615 retrieved studies, nine articles were incorporated in the present systematic review, with five (n = 144 patients) eligible for meta-analysis. For [68Ga] FAPI- 46, the pooled sensitivity and specificity compared with immunohistopathology were 0.96 (95% CI 0.84, 0.99) and 0.92 (95% CI 0.53, 0.99), respectively, with a positive likelihood ratio (LR +) of 4.41 (95% CI 1.64, 11.79) and a negative likelihood ratio (LR −) of 3.07 (95% CI 1.01, 9.37). For [18F] FDG, pooled sensitivity and specificity compared with immunohistopathology were 0.73 (95% CI 0.34, 0.93) and 0.83 (95% CI 0.57, 0.95), with an LR + of 12.73 (95% CI 1.43, 113.45) and an LR − of 0.32 (95% CI 0.11, 0.17). The pooled odds ratio for the detection rate on a per-lesion basis was 1.73 (95% CI 0.99, 3.02) for [68Ga] FAPI- 46 compared with [18F] FDG. The pooled weighted mean differences in the standardized uptake value (SUVmax) for primary tumor uptake and the tumor-to-background ratio (TBR) in [68Ga] FAPI- 46 vs. 18F-FDG were 4.40 (95% CI − 0.7, 9.5) and 6.18 (95% CI 1.74, 10.61), respectively. Moderate to high heterogeneity was noted because of the variations in patient selection, interpretation criteria, and scanning procedures. Conclusions This study revealed that [68Ga] FAPI- 46 outperforms [18F] FDG in cancer diagnosis, with higher sensitivity (0.96 vs. 0.73) and specificity (0.92 vs. 0.83). [Ga] FAPI- 46 improved tumor detection with higher SUVmax and TBR. While FDG had a higher LR +, its lower LR − highlighted more false negatives. Accordingly, [68Ga] FAPI- 46 exhibited superior accuracy and reliability than FDG in cancer diagnosis. Systematic review registration PROSPERO CRD 42023472270. Graphical Abstract

Background Dopamine dysregulation syndrome (DDS) is a debilitating complication of Parkinson's disease (PD) dopamine replacement therapy (DRT) in which patients pathologically and/or compulsively use dopaminergic drugs to treat motor symptoms. Studies examining DDS outcomes following deep brain stimulation (DBS) are limited and have focused on subthalamic targeting. Cases Here, we present DDS outcomes in six patients from the Emory Movement Disorders clinic who underwent unilateral or bilateral DBS implantation of the globus pallidus internus (GPi). Despite motor improvements and/or initial reductions in DRT dosing, all six patients continued to meet clinical criteria for DDS 6 months post‐surgery, displaying persistent pathological medication use, mood disturbances, and social impairment. Anxiety surrounding levodopa use was the most persistent DDS feature following surgery. Conclusion These results indicate that pallidal DBS is not a suitable treatment for DDS and its associated symptoms.

Purpose/Background Examining a patient's family history of medication response is a commonly used method to inform treatment selection. Though widely recommended, there are no published reviews that assess the validity of this approach when treating patients with affective disorders. Methods/Procedures All published studies in the form of case-control or randomized controlled trials that enrolled probands with either bipolar I or II depression or major depression and were written in English were included. Studies must have also included biological relatives and must have included at least 2 families. The authors compared the methodology of each trial to a hierarchy of study designs best suited to demonstrate the predictive ability of a family history of response to a medication. Findings/Results All studies involved only a small number of participants and none of the publications included in this review used a study design that reached the highest level of study quality needed to prove the link between 2 family members' likelihood of response to a medicine. Two studies had some elements of a level I study while the remaining studies were classified at level II or III of the study hierarchy. Implications/Conclusions Although small studies suggest that a family history of drug response can predict outcome in mood disorder patients, the designs of these studies do not confirm this in a definitive manner.

Psoriasis is a systemic immune disease with severe inflammation and skin thickening. Roflumilast (ROF) blocks cAMP hydrolysis, and paclitaxel (PTX) inhibits cell proliferation; both are effective in topical psoriasis treatment. However, the combination of ROF and PTX has not been reported. This study explored their synergistic mechanism and formulated a ROF-PTX oleogel with strong skin adhesion, low viscosity, enhanced skin penetration, and increased retention. The oleogel, prepared via direct gelation with jojoba oil as oil phase, PPG-15 as solvent, Transcutol as solubilizer, and hydrogenated castor oil as oleogelator. It showed 78.9% holding oil capacity and a viscosity of 0.4049 Pa·s, indicating excellent stability and adhesion. In the imiquimod-induced psoriasis model, the ROF:PTX (1:1) oleogel reduced Baker scores and splenic indices more effectively than ROF or PTX alone. Histological studies suggested that the combination was superior in reducing inflammation and skin thickening. The ROF:PTX (1:1) oleogel group exhibited lower Baker scores and epidermal thickness, demonstrating superior therapeutic efficacy. The H-SCORE revealed a 2.95-fold reduction in IL-17 levels compared to the model group, highlighting the potential of the ROF and PTX combination as an effective psoriasis treatment strategy.

Internalized homophobia (IH) negatively impacts the mental health of adolescent sexual minority men (ASMM), while self-esteem is posited to bolster their mental health. In a repeated-measures study with 599 ASMM (Mean age = 16.2 [SD = 1.3]; 75.6% racial and ethnic minorities), longitudinal structural equation models investigated the relationships among IH, self-esteem, and mental health (depression and anxiety), as well as the mediating role of self-esteem. Higher self-esteem at earlier time points was significantly associated with lower anxiety and depressive symptoms. The hypothesized mediation pathways were not statistically significant. Subgroup analyses revealed that the protective effect of self-esteem against anxiety was significant for racial and ethnic minority ASMM but not for their non-Hispanic White counterparts. These findings highlight the need for tailored interventions that address the unique experiences of ASMM from diverse racial and ethnic backgrounds.

This paper provides a comprehensive overview of fine-tuning techniques for Large Language Models (LLMs), a critical component in advancing natural language processing. It synthesizes recent progress in instruction fine-tuning, multitask learning, federated learning, and pedagogical alignment, highlighting their effectiveness, challenges, and potential applications. The survey also delves into technical aspects such as model specialization, evaluation metrics, and heterogeneous client management in federated settings. Moreover, it addresses open issues including societal implications and ethical considerations. Key findings emphasize the significance of tailored fine-tuning approaches for enhancing LLM adaptability, the value of comprehensive evaluation protocols, and the impact of informed instruction selection. This work contributes to the field by analyzing current trends, summarizing technical advancements, and outlining future directions. It aims to support researchers and practitioners in navigating the complexities of LLM fine-tuning and in developing more robust, generalizable, and responsible NLP systems across diverse domains.