Epidemiology and Burden of Peripheral Artery Disease in People With Type 2 Diabetes: A Systematic Literature Review.

Type 2 diabetes (T2D) and lower-extremity peripheral artery disease (PAD) are growing global health problems associated with considerable cardiovascular (CV) and limb-related morbidity and mortality, poor quality of life and high healthcare resource use and costs. Diabetes is a well-known risk factor for PAD, and the occurrence of PAD in people with T2D further increases the risk of long-term complications. As the available evidence is primarily focused on the overall PAD population, we undertook a systematic review to describe the burden of comorbid PAD in people with T2D. The MEDLINE, Embase and Cochrane Library databases were searched for studies including people with T2D and comorbid PAD published from 2012 to November 2021, with no restriction on PAD definition, study design or country. Hand searching of conference proceedings, reference lists of included publications and relevant identified reviews and global burden of disease reports complemented the searches. We identified 86 eligible studies, mostly observational and conducted in Asia and Europe, presenting data on the epidemiology (n = 62) and on the clinical (n = 29), humanistic (n = 12) and economic burden (n = 12) of PAD in people with T2D. The most common definition of PAD relied on ankle-brachial index values ≤ 0.9 (alone or with other parameters). Incidence and prevalence varied substantially across studies; nonetheless, four large multinational randomised controlled trials found that 12.5%-22% of people with T2D had comorbid PAD. The presence of PAD in people with T2D was a major cause of lower-limb and CV complications and of all-cause and CV mortality. Overall, PAD was associated with poor quality of life, and with substantial healthcare resource use and costs. To our knowledge, this systematic review provides the most comprehensive overview of the evidence on the burden of PAD in people with T2D to date. In this population, there is an urgent unmet need for disease-modifying agents to improve outcomes.

Building on Strong Foundations: Deploying Enhanced Replicating Effective Programs for evidence-based prevention curriculum adaptation.

Schools frequently adopt new interventions for each new public health issue, but this is both time- and resource-intensive. Adversity exposure is an example of a pervasive public health issue that emerged during Coronavirus Disease 2019 (COVID-19) with notable consequences, including an elevated risk of developing substance use disorders and mental illnesses. Adapting existing, universal, evidence-based interventions, such as the Michigan Model for HealthTM (MMH), by incorporating trauma-sensitive content is a promising approach to meet this need. We examined critical steps in promoting MMH adaptability as part of the Enhanced REP (Replicating Effective Programs) implementation strategy during the COVID-19 pandemic. We share usability testing from the 2020 to 2021 school year and describe how we apply the results to inform the group randomized trial pilot study. We applied key steps from implementation adaptation frameworks to integrate trauma-sensitive content as COVID-19 unfolded, documenting the process through field notes. We conducted initial usability testing with two teachers via interviews and used a rapid qualitative analysis approach. We conducted member checking by sharing the information with two health coordinators to validate results and inform additional curriculum refinement. We developed an adapted MMH curriculum to include trauma-sensitive content, with adaptations primarily centered on adding content, tailoring content, substituting content, and repeating/reinforcing elements across units. We designed adaptations to retain the core functional elements of MMH. Building foundational relationships and infrastructure supports opportunities to user-test intervention materials for Enhanced REP that enhance utility and relevance for populations that would most benefit. Enhanced REP is a promising strategy to use an existing evidence-based intervention to meet better the needs of youth exposed to adversity. Building on the foundations of existing evidence-based interventions, is vital to implementation success and achieving desired public health outcomes.

Schools frequently adopt new interventions for each new public health issue that may or may not be evidence-based. Concentrating efforts on supporting the effective implementation of existing, widely adopted evidence-based interventions (EBIs) in schools is an efficient and effective way to achieve their public health impact and reduce implementer overload. We systematically adapted an EBI, the Michigan Model for HealthTM, to incorporate trauma-sensitive content and pilot-tested the materials with two health teachers using pre-/post-interviews to gather feedback for refinement. The implementation support professionals­regional school health coordinators­provided further insight and validation of teacher feedback on adaptations. The adaptations developed focused on maintaining the core functions that make the curriculum effective. We learned that the foundational relationships and implementation infrastructure were central to testing intervention materials in a way that would enhance utility and relevance for the student population that would most benefit. Leveraging available infrastructure and existing collaborations are vital to implementation success and achieving desired public health outcomes.

Comparing Two Training Modalities Supporting the Adoption of the SEEK Approach in Pediatric Primary Care 6/30/24.

OBJECTIVE: To compare the impact of two common continuing medical education training modalities - independent online training (IND) and a Maintenance of Certification-4 activity (MOC) - on primary care professionals' (PCPs') thinking and practice behavior regarding the Safe Environment for Every Kid (SEEK) approach. This was part of an implementation science study scaling up the evidence-based practice, SEEK. METHODS: This is a longitudinal, multi-site, mixed methods, cluster randomized controlled trial comparing 21 pediatric primary care practices across the U.S. randomized to one of two training modalities. Two hundred and ten PCPs completed surveys up to 4 times over a two-year period to assess their thinking and practice regarding SEEK; a subset was interviewed up to 3 times. RESULTS: Training led to significant and sustained improvements in PCPs' thinking and behavior related to SEEK, with no significant differences between the IND and MOC groups. PCPs mostly viewed their training positively, but several described shortcomings. PCP characteristics, such as age and sex, did not moderate the impact of the training, nor did the presence of a behavioral health professional. CONCLUSIONS: The lack of significant differences between the training modalities favors the simpler IND modality. This was despite the MOC training employing key principles of adult education. Of note, MOC-4 credits are required for pediatric board certification. More research is needed to optimize continuing medical education and to tailor approaches for different learners.

Unsupervised Exercise in Interstitial Lung Disease: A Delphi Study to Develop a Consensus Preparticipation Screening Tool for Lymphangioleiomyomatosis.

BACKGROUND: Little research is available to provide practical guidance to health care providers for exercise preparticipation screening and referral of patients with interstitial lung diseases (ILD), including lymphangioleiomyomatosis (LAM), to participate in remote, unsupervised exercise programs. RESEARCH QUESTION: What exercise preparticipation screening steps are essential to determine whether a patient with LAM is medically appropriate to participate in a remote, unsupervised exercise program? STUDY DESIGN AND METHODS: Sixteen experts in LAM and ILD participated in a two-round modified Delphi study, ranking their level of agreement for ten statements related to unsupervised exercise training in LAM, with an a priori definition of consensus. Additionally, 60 patients with LAM completed a survey of the perceived risks and benefits of remote exercise training in LAM. RESULTS: Seven of the 10 statements reached consensus among experts. Experts agreed that an in-person clinical exercise test is indicated to screen for exercise-induced hypoxemia and prescribe supplemental oxygen therapy as indicated prior to initiating a remote exercise program. Patients with recent pneumothorax should wait to start an exercise program for at least 4 weeks until after resolution of pneumothorax and clearance by a physician. Patients with high cardiovascular risk for event during exercise, severe resting pulmonary hypertension, or risk for falls may be more appropriate for referral to a rehabilitation center. A LAM-specific remote exercise preparticipation screening tool was developed from the consensus statements and agreed upon by the panelists. INTERPRETATION: A modified Delphi study approach was useful to develop disease-specific recommendations for safety and preparticipation screening prior to unsupervised, remotely administered exercise in LAM. The primary product of this study is a clinical decision aid for providers to use when medically screening patients prior to participation in the newly launched LAMFit remote exercise program. FUNDING: This work was funded by an Established Investigator Award (LAM0130PB07-18) to MBB from The LAM Foundation.

Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes.

Research demonstrates the important role of genetic factors in attention-deficit/hyperactivity disorder (ADHD). DNA sequencing of families provides a powerful approach for identifying de novo (spontaneous) variants, leading to the discovery of hundreds of clinically informative risk genes for other childhood neurodevelopmental disorders. This approach has yet to be extensively leveraged in ADHD. We conduct whole-exome DNA sequencing in 152 families, comprising a child with ADHD and both biological parents, and demonstrate a significant enrichment of rare and ultra-rare de novo gene-damaging mutations in ADHD cases compared to unaffected controls. Combining these results with a large independent case-control DNA sequencing cohort (3206 ADHD cases and 5002 controls), we identify lysine demethylase 5B (KDM5B) as a high-confidence risk gene for ADHD and estimate that 1057 genes contribute to ADHD risk. Using our list of genes harboring ultra-rare de novo damaging variants, we show that these genes overlap with previously reported risk genes for other neuropsychiatric conditions and are enriched in several canonical biological pathways, suggesting early neurodevelopmental underpinnings of ADHD. This work provides insight into the biology of ADHD and demonstrates the discovery potential of DNA sequencing in larger parent-child trio cohorts.

Health professionals involved in diabetic foot and their tasks in a country without podiatrists: From a Japanese Nationwide Survey.

Although there are no podiatrists in 85% of countries worldwide, how diabetic foot is managed in those countries is still unknown. We sought to identify the health professionals involved in diabetic foot and their tasks in Japan, where no podiatrists exist. This cross-sectional study used the Japanese Nationwide Survey on Foot Ulcer Management dataset, consisting of 249 medical doctors and 680 allied health professionals. The types of health professionals involved in the diabetic foot were identified, and the tasks performed by each professional were compared within subgroups (medical doctors and allied health professionals). We found that the primary medical doctors involved in diabetic foot care in Japan were plastic surgeons (33.5%), dermatologists (21%), cardiovascular/vascular surgeons (15.2%), and cardiologists (12.1%). Nurses were the main allied health professionals (80%), and the rest consisted of prosthetists/orthotists (7.6%), physical/occupational therapists (5.9%), and clinical engineering technologists (3.6%). Medical doctors performed tasks related to their specialties significantly more than others (p < 0.001); however, they also engaged in tasks outside of their specialty, such as plastic surgeons performing preventive foot care (72%). Among allied health professionals, clinical engineering technologists performed more vascular assessments (p < 0.001), and half were engaged in wound management, preventive foot care, and self-foot care education. In conclusion, the type and proportion of health professionals in our study differed from those in countries with podiatrists, and many performed tasks outside their specialties. This is the first nationwide cross-sectional study of diabetic foot care in a country without podiatrists and is unique in examining multiple specialists/professionals in one study.

Risk of new-onset diabetes and efficacy of pharmacological weight loss therapy.

AIMS: To develop a clinical risk model to identify individuals at higher risk of developing new-onset diabetes and who might benefit more from weight loss pharmacotherapy. MATERIALS AND METHODS: A total of 21 143 patients without type 2 diabetes at baseline from two TIMI clinical trials of stable cardiovascular patients were divided into a derivation (~2/3) and validation (~1/3) cohort. The primary outcome was new-onset diabetes. Twenty-seven candidate risk variables were considered, and variable selection was performed using multivariable Cox regression. The final model was evaluated for discrimination and calibration, and for its ability to identify patients who experienced a larger benefit from the weight loss medication lorcaserin in terms of risk of new-onset diabetes. RESULTS: During a median (interquartile range) follow-up of 2.3 (1.8-2.7) years, new-onset diabetes occurred in 1013 patients (7.7%). The final model included five independent predictors (glycated haemoglobin, fasting glucose, age, body mass index, and triglycerides/high-density lipoprotein). The clinical risk model showed good discrimination (Harrell's C-indices 0.802, 95% confidence interval [CI] 0.788-0.817 and 0.807, 95% CI 0.788-0.826) in the derivation and validation cohorts. The calibration plot demonstrated adequate calibration (2.5-year area under the curve was 81.2 [79.1-83.5]). While hazard ratios for new-onset diabetes with a weight-loss therapy were comparable across risk groups (annual risks of <1%, 1%-5%, and >5%), there was a sixfold gradient in absolute risk reduction from lowest to highest risk group (p = 0.027). CONCLUSIONS: The developed clinical risk model effectively predicts new-onset diabetes, with potential implications for personalized patient care and therapeutic decision making.

Weight, habitual fibre intake, and microbiome composition predict tolerance to fructan supplementation.

Fructans are commonly used as dietary fibre supplements for their ability to promote the growth of beneficial gut microbes. However, fructan consumption has been associated with various dosage-dependent side effects. We characterised side effects in an exploratory analysis of a randomised trial in healthy adults (n = 40) who consumed 18 g/day inulin or placebo. We found that individuals weighing more or habitually consuming higher fibre exhibited the best tolerance. Furthermore, we identified associations between gut microbiome composition and host tolerance. Specifically, higher levels of Christensenellaceae R-7 group were associated with gastrointestinal discomfort, and a machine-learning-based approach successfully predicted high levels of flatulence, with [Ruminococcus] torques group and (Oscillospiraceae) UCG-002 sp. identified as key predictive taxa. These data reveal trends that can help guide personalised recommendations for initial inulin dosage. Our results support prior ecological findings indicating that fibre supplementation has the greatest impact on individuals whose baseline fibre intake is lowest.

Clinical outcomes in people with diabetes-related foot infections: Analysis from a limb preservation service infection database.

BACKGROUND: Diabetes-related foot infections are common and represent a significant clinical challenge. There are scant data about outcomes from large cohorts. The purpose of this study was to report clinical outcomes from a large cohort of people with diabetes-related foot infections. METHODS: A tertiary referral hospital limb preservation service database was established in 2018, and all new episodes of foot infections were captured prospectively using an electronic database (REDCap). People with foot infections between January 2018 and May 2023, for whom complete data were available on infection episodes, were included. Infection outcomes were compared between skin and soft tissue infections (SST-DFI) and osteomyelitis (OM) using chi-square tests. RESULTS: Data extraction identified 647 complete DFI episodes in 397 patients. The data set was divided into two cohorts identifying each infection episode and its severity as either SST-DFI (N = 326, 50%) or OM (N = 321, 50%). Most infection presentations were classified as being moderate (PEDIS 3 = 327, 51%), with 36% mild (PEDIS 2 = 239) and 13% severe (PEDIS 4 = 81). Infection resolution occurred in 69% (n = 449) of episodes with failure in 31% (n = 198). Infection failures were more common with OM than SST-DFI (OM = 140, 71% vs. SST-DFI = 58, 29%, p < 0.00001). In patients with SST-DFI a greater number of infection failures were observed in the presence of peripheral arterial disease (PAD) compared to the patients without PAD (failure occurred in 30% (31/103) of episodes with PAD and 12% (27/223) of episodes without PAD; p < 0.001). In contrast, the number of observed infection failures in OM episodes were similar in patients with and without PAD (failure occurred in 45% (57/128) of episodes with PAD and 55% (83/193) of episodes without PAD; p = 0.78). CONCLUSIONS: This study provides important epidemiological data on the risk of poor outcomes for DFI and factors associated with poor outcomes in an Australian setting. It highlights the association of PAD and treatment failure, reinforcing the need for early intervention to improve PAD in patients with DFI. Future randomised trials should assess the benefits of revascularisation and surgery in people with DFI and particularly those with OM where outcomes are worse.

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells.

Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include on-target off-tumor toxicities, which have inspired efforts to optimize CARs for improved tumor antigen selectivity and overall safety. We recently developed a CAR T cell therapy targeting prostate stem cell antigen (PSCA) for prostate and pancreatic cancers, showing improved preclinical antitumor activity and T cell persistence by optimizing the intracellular co-stimulatory domain. Similar studies were undertaken to optimize HER2-directed CAR T cells with modifications to the intracellular co-stimulatory domain for selective targeting of breast cancer brain metastasis. In the present study, we evaluate various nonsignaling extracellular spacers in these CARs to further improve tumor antigen selectivity. Our findings suggest that length and structure of the extracellular spacer can dictate the ability of CARs to selectively target tumor cells with high antigen density, while sparing cells with low antigen density. This study contributes to CAR construct design considerations and expands our knowledge of tuning solid tumor CAR T cell therapies for improved safety and efficacy.

Use of concept mapping to inform a participatory engagement approach for implementation of evidence-based HPV vaccination strategies in safety-net clinics.

BACKGROUND: Multiple evidence-based strategies (EBS) for promoting HPV vaccination exist. However, adolescent HPV vaccination rates remain below target levels in communities at high risk for HPV-associated cancers and served by safety-net clinics. Participatory engaged approaches are needed to leverage the expertise of community and clinical partners in selecting EBS relevant to their local context. We engaged concept mapping as a method to inform the adoption and adaptation of EBS that seeks to empower implementation partners to prioritize, select, and ultimately implement context-relevant EBS for HPV vaccination. METHODS: Using 38 EBS statements generated from qualitative interviews and national HPV vaccine advocacy sources, we conducted a modified concept mapping activity with partners internal to safety-net clinics and external community members in two study sites of a larger implementation study (Greater Los Angeles and New Jersey), to sort EBS into clusters and rate each EBS by importance and feasibility for increasing HPV vaccination within safety-net clinics. Concept mapping findings (EBS statement ratings, ladder graphs and go-zones) were shared with leaders from a large federally qualified health center (FQHC) system (focusing on three clinic sites), to select and implement EBS over 12 months. RESULTS: Concept mapping participants (n=23) sorted and rated statements, resulting in an eight-cluster solution: 1) Community education and outreach; 2) Advocacy and policy; 3) Data access/quality improvement monitoring; 4) Provider tracking/audit and feedback; 5) Provider recommendation/communication; 6) Expanding vaccine access; 7) Reducing missed opportunities; and 8) Nurse/staff workflow and training. The FQHC partner then selected to intervene on eight of 17 EBS statements in the "go-zone" for action, with three from "reducing missed opportunities," two from "nurse/staff workflow and training," and one each from "provider tracking/audit and feedback," "provider recommendation/communication," and "expanding vaccine access," which the research team addressed through the implementation of three multi-level intervention strategies (e.g., physician communication training, staff training and workflow assessment, audit and feedback of clinic processes). CONCLUSIONS: Concept mapping provided a powerful participatory approach to identify multilevel EBS for HPV vaccination relevant to the local safety-net clinic context, particularly when several strategies exist, and prioritization is necessary. This study demonstrates how a clinic system benefited directly from the ratings and prioritization of EBS by multilevel clinic and community partners within the broader safety-net clinic context to identify and adapt prioritized solutions needed to advance HPV vaccine equity.

Bayesian phylogenetic analysis of Philippine languages supports a rapid migration of Malayo-Polynesian languages.

The Philippines are central to understanding the expansion of the Austronesian language family from its homeland in Taiwan. It remains unknown to what extent the distribution of Malayo-Polynesian languages has been shaped by back migrations and language leveling events following the initial Out-of-Taiwan expansion. Other aspects of language history, including the effect of language switching from non-Austronesian languages, also remain poorly understood. Here we apply Bayesian phylogenetic methods to a core-vocabulary dataset of Philippine languages. Our analysis strongly supports a sister group relationship between the Sangiric and Minahasan groups of northern Sulawesi on one hand, and the rest of the Philippine languages on the other, which is incompatible with a simple North-to-South dispersal from Taiwan. We find a pervasive geographical signal in our results, suggesting a dominant role for cultural diffusion in the evolution of Philippine languages. However, we do find some support for a later migration of Gorontalo-Mongondow languages to northern Sulawesi from the Philippines. Subsequent diffusion processes between languages in Sulawesi appear to have led to conflicting data and a highly unstable phylogenetic position for Gorontalo-Mongondow. In the Philippines, language switching to Austronesian in 'Negrito' groups appears to have occurred at different time-points throughout the Philippines, and based on our analysis, there is no discernible effect of language switching on the basic vocabulary.

Assessment of the pathogen genomics landscape highlights disparities and challenges for effective AMR Surveillance and outbreak response in the East African community.

The East African Community (EAC) grapples with many challenges in tackling infectious disease threats and antimicrobial resistance (AMR), underscoring the importance of regional and robust pathogen genomics capacities. However, a significant disparity exists among EAC Partner States in harnessing bacterial pathogen sequencing and data analysis capabilities for effective AMR surveillance and outbreak response. This study assesses the current landscape and challenges associated with pathogen next-generation sequencing (NGS) within EAC, explicitly focusing on World Health Organization (WHO) AMR-priority pathogens. The assessment adopts a comprehensive approach, integrating a questionnaire-based survey amongst National Public Health Laboratories (NPHLs) with an analysis of publicly available metadata on bacterial pathogens isolated in the EAC countries. In addition to the heavy reliance on third-party organizations for bacterial NGS, the findings reveal a significant disparity among EAC member States in leveraging bacterial pathogen sequencing and data analysis. Approximately 97% (n = 4,462) of publicly available high-quality bacterial genome assemblies of samples collected in the EAC were processed and analyzed by external organizations, mainly in Europe and North America. Tanzania led in-country sequencing efforts, followed by Kenya and Uganda. The other EAC countries had no publicly available samples or had all their samples sequenced and analyzed outside the region. Insufficient local NGS sequencing facilities, limited bioinformatics expertise, lack of adequate computing resources, and inadequate data-sharing mechanisms are among the most pressing challenges that hinder the EAC's NPHLs from effectively leveraging pathogen genomics data. These insights emphasized the need to strengthen microbial pathogen sequencing and data analysis capabilities within the EAC to empower these laboratories to conduct pathogen sequencing and data analysis independently. Substantial investments in equipment, technology, and capacity-building initiatives are crucial for supporting regional preparedness against infectious disease outbreaks and mitigating the impact of AMR burden. In addition, collaborative efforts should be developed to narrow the gap, remedy regional imbalances, and harmonize NGS data standards. Supporting regional collaboration, strengthening in-country genomics capabilities, and investing in long-term training programs will ultimately improve pathogen data generation and foster a robust NGS-driven AMR surveillance and outbreak response in the EAC, thereby supporting global health initiatives.

Interplay between particle size and microbial ecology in the gut microbiome.

Physical particles can serve as critical abiotic factors that structure the ecology of microbial communities. For non-human vertebrate gut microbiomes, fecal particle size (FPS) has been known to be shaped by chewing efficiency and diet. However, little is known about what drives FPS in the human gut. Here, we analyzed FPS by laser diffraction across a total of 76 individuals and found FPS to be strongly individualized. Surprisingly, a behavioral intervention with 41 volunteers designed to increase chewing efficiency did not impact FPS. Dietary patterns could also not be associated with FPS. Instead, we found evidence that mammalian and human gut microbiomes shaped FPS. Fecal samples from germ-free and antibiotic-treated mice exhibited increased FPS relative to colonized mice. In humans, markers of longer transit time were correlated with smaller FPS. Gut microbiota diversity and composition were also associated with FPS. Finally, ex vivo culture experiments using human fecal microbiota from distinct donors showed that differences in microbiota community composition can drive variation in particle size. Together, our results support an ecological model in which the human gut microbiome plays a key role in reducing the size of food particles during digestion, and that the microbiomes of individuals vary in this capacity. These new insights also suggest FPS in humans to be governed by processes beyond those found in other mammals and emphasize the importance of gut microbiota in shaping their own abiotic environment.

Effectiveness of IVIG on Non-Length-Dependent Skin Biopsies in Small Fiber Neuropathy With Plexin D1, Trisulfated Heparin Disaccharide, and Fibroblast Growth Factor Receptor 3 Autoantibodies.

OBJECTIVES: To demonstrate treatment efficacy on composite and non-length-dependent (NLD) punch biopsy specimens from intravenous immunoglobulin (IVIG) in pure small-fiber neuropathy (SFN) with trisulfated heparin disaccharide (TS-HDS), fibroblast growth factor-3 (FGFR-3), or Plexin D1 antibodies. SFN has an increasing prevalence, and over 30% of cases may be immune-mediated. TS-HDS, FGFR-3, and Plexin D1 autoantibodies have been shown to be present in 44%-55% of cryptogenic SFN cases, suggesting an immune mechanism. Reports have shown IVIG to be effective for this condition, but some controversy exists based on length-dependent (LD) post-IVIG treatment data in a recent trial. METHODS: In a retrospective review, all pure SFN cases tested for the 3 antibodies from January 2021 to May 2022 were tabulated, and patients who underwent IVIG treatment were separated and analyzed for changes in epidermal nerve fiber density (ENFD) on skin biopsy, as well as SFN-specific questionnaire and pain scores. RESULTS: Ninety-one patients with pure SFN had antibody testing. Sixty of these (66%) were seropositive, and 31 (34%) were seronegative. Seventeen seropositive patients (13 female patients, 4 male patients, 6 FGFR-3, 2 TS-HDS, 4 Plexin D1, 2 with all 3 antibodies, 1 with FGFR-3 and Plexin D1, 1 with FGFR-3 and TS-HDS, and 1 with TS-HDS and Plexin D1) underwent IVIG treatment. Of these, 2 patients stopped treatment due to side effects, and the remaining 15 completed at least 6 months of IVIG. Of these, 12 had a post-IVIG skin biopsy, and of these, 11 (92%) had a 55.1% improved mean composite ENFD (P = 0.01). NLD-ENFD specimens improved by 42.3% (P = 0.02), and LD-ENFD specimens improved by 99.7% (P = 0.01). Composite ENFD in Plexin D1-SFN patients improved by 139% (P = 0.04). In addition, 14 patients had questionnaires pre-IVIG/post-IVIG, and average pain decreased by 2.7 (P = 0.002). CONCLUSIONS: IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1-SFN, as well as significantly improved pain. NLD-ENFD should be examined as well as LD-ENFD to see this effect. Further randomized controlled trials looking at NLD-ENFD as well as LD-ENFD improvement, along with pain and SFN-specific questionnaires, are needed to confirm these findings.

Comparison of Wild-Type and High-risk PNPLA3 variants in a Human Biomimetic Liver Microphysiology System for Metabolic Dysfunction-associated Steatotic Liver Disease Precision Therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide health epidemic with a global occurrence of approximately 30%. The pathogenesis of MASLD is a complex, multisystem disorder driven by multiple factors including genetics, lifestyle, and the environment. Patient heterogeneity presents challenges for developing MASLD therapeutics, creation of patient cohorts for clinical trials and optimization of therapeutic strategies for specific patient cohorts. Implementing pre-clinical experimental models for drug development creates a significant challenge as simple in vitro systems and animal models do not fully recapitulate critical steps in the pathogenesis and the complexity of MASLD progression. To address this, we implemented a precision medicine strategy that couples the use of our liver acinus microphysiology system (LAMPS) constructed with patient-derived primary cells. We investigated the MASLD-associated genetic variant PNPLA3 rs738409 (I148M variant) in primary hepatocytes, as it is associated with MASLD progression. We constructed LAMPS with genotyped wild type and variant PNPLA3 hepatocytes together with key non-parenchymal cells and quantified the reproducibility of the model. We altered media components to mimic blood chemistries, including insulin, glucose, free fatty acids, and immune activating molecules to reflect normal fasting (NF), early metabolic syndrome (EMS) and late metabolic syndrome (LMS) conditions. Finally, we investigated the response to treatment with resmetirom, an approved drug for metabolic syndrome-associated steatohepatitis (MASH), the progressive form of MASLD. This study using primary cells serves as a benchmark for studies using patient biomimetic twins constructed with patient iPSC-derived liver cells using a panel of reproducible metrics. We observed increased steatosis, immune activation, stellate cell activation and secretion of pro-fibrotic markers in the PNPLA3 GG variant compared to wild type CC LAMPS, consistent with the clinical characterization of this variant. We also observed greater resmetirom efficacy in PNPLA3 wild type CC LAMPS compared to the GG variant in multiple MASLD metrics including steatosis, stellate cell activation and the secretion of pro-fibrotic markers. In conclusion, our study demonstrates the capability of the LAMPS platform for the development of MASLD precision therapeutics, enrichment of patient cohorts for clinical trials, and optimization of therapeutic strategies for patient subgroups with different clinical traits and disease stages.