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Background and Aims: Indocyanine Green Fluorescence (ICG-F)- guided surgery is becoming an increasingly helpful tool in pediatric surgical care. This consensus statement investigates the utility of ICG-F in various pediatric surgical applications, primarily focusing on its evidence base, safety, indications, use across different surgical specialties and dosing strategies. The aim is to establish an international consensus for ICG-F use in pediatric surgery., Methods: An international panel of 15 pediatric surgeons from 9 countries was assembled. The structured process consisted of a rapid scoping review, iterative discussion sessions, mixed-methods studies with key stakeholders, and voting rounds on individual statements to create draft consensus statements., Results: 100 articles were identified during the review and summarized by application. Based on this condensed evidence, consensus statements were generated after 3 iterative rounds of anonymous voting. Key areas of agreement were quality of evidence, the safety of ICG, pediatric surgical indications, utilization per surgical specialty, and dosing of ICG., Conclusion: This consensus statement aims to guide healthcare professionals in managing ICG-F use in pediatric surgical cases based on the best available evidence, key stakeholder consultation, and expert opinions. Despite ICG-F's promising potential, the need for higher-quality evidence, prospective trials, and safety studies is underscored. The consensus also provides a framework for pediatric surgeons to utilize ICG-F effectively., Level of Evidence: III., Competing Interests: Conflict of interest All authors have no disclosures or conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective : To examine the relationship between body mass index (BMI) and genotype among pre-symptomatic carriers of different pathogenic variants associated with amyotrophic lateral sclerosis. Methods : C9orf72+ carriers, SOD1+ carriers, and pathogenic variant negative controls (Gene-Negatives) were included from 3 largely independent cohorts: ALS Families Project (ALS-Families); Dominantly inherited ALS (DIALS); and Pre-symptomatic Familial ALS ( Pre-fALS ). First reported ( ALS-Families ) or measured ( DIALS and Pre-fALS ) weight and height were used to calculate BMI. Age at weight measurement, self-reported sex (male vs. female), and highest education (high school or below vs. college education vs . graduate school or above) were extracted. The associations between BMI and genotype in each cohort were examined with multivariable linear regression models, adjusted for age, sex, and education. Results : A total of 223 C9orf72+ carriers, 135 SOD1+ carriers, and 191 Gene-Negatives were included, deriving from ALS-Families ( n  = 114, median age 46, 37% male), DIALS ( n  = 221, median age 46, 30% male), and Pre-fALS ( n  = 214, median age 44, 39% male). Adjusting for age, sex, and education, the mean BMI of C9orf72+ carriers was lower than Gene-Negatives by 2.4 units (95% confidence interval [CI] = 0.3-4.6, p  = 0.02) in ALS-Families ; 2.7 units (95% CI = 0.9-4.4, p  = 0.003) in DIALS ; and 1.9 units (95% CI = 0.5-4.2, p  = 0.12) in Pre-fALS . There were no significant differences in BMI between SOD1+ carriers and Gene-Negatives in any of the 3 cohorts. Conclusions : Compared to Gene-Negatives, average BMI is lower in asymptomatic C9orf72+ carriers across 3 cohorts while no significant difference was found between Gene-Negatives and SOD1+ carriers.

Seemingly simple bacteria mount intricate adaptive responses when exposed to physical stress or nutrient limitation, and the activation of these responses is governed by complex signal transduction networks. Upon entry into the stationary growth phase, the soil bacterium Bacillus subtilis may develop natural competence, form biofilms or stress-resistant cells, or ultimately trigger a cellular differentiation program leading to spore formation. Master regulators, such as Spo0A, ComK, SinR, and SigB, constantly monitor the bacterium's environment and then determine appropriate adaptive responses. Here, we show that exposure of B. subtilis to visible light and other stresses triggers a general stress response-dependent block in competence development. SigB serves as an "emergency system" to silence inappropriate expression of an alternative developmental program in the face of unfavorable conditions. In particular, we document a stress-dependent molecular mechanism that prevents accumulation of the central competence regulator ComK via expression of a SigB-driven antisense RNA ( as-comK , S365) which is part of a noncontiguous operon., Importance: Bacillus subtilis exhibits a large number of different specific and general adaptation reactions, which need to be well balanced to sustain survival under largely unfavorable conditions. Under specific conditions, natural competence develops, which enables B. subtilis to actively take up exogenous DNA to integrate it into its own genome. In contrast to this specific adaptation, the general stress response is induced by a variety of exogenous stress and starvation stimuli, providing comprehensive protection and enabling survival of vegetative B. subtilis cells. In the present work, we reveal the molecular basis for the interconnection of these two important responses in the regulatory network. We describe that the master regulator of the general stress response SigB is activated by physiological stress stimuli, including daylight and ethanol stress, leading to the inactivation of the competence master regulator ComK by transcriptional anti-sense regulation, showing a strict hierarchy of adaptational responses under severe stress.

CD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naïve MS patients and control participants. A small subset of highly expanded and activated CD8+ T cells were enriched in the CSF in MS that displayed high activation, cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. These findings shed vital insight into the role of CD8+ T cells in MS and pave the way towards disease biomarkers and therapeutic targets.

Background: Suspected false positive norovirus results occurred after introduction of the BioFire® FilmArray® Gastrointestinal panel (BF-GIP) into 6 laboratory sites, in British Columbia, Canada., Objectives: The primary objective was to investigate suspected false positive results by performing additional molecular assays and whole genome sequencing (WGS). The second objective was to determine if melting curve review could predict false positive results., Study Design: From February 2023 to May 2024, the proportion of potential false positive norovirus results from the BF-GIP was calculated based on confirmatory testing using alternate molecular method. A subset of 65 norovirus BF-GIP positive specimens, including 35 negatives and 30 positives on additional molecular assays, underwent WGS. Melting curves appearances from 150 specimens were reviewed., Results: Overall, 215/784 (27.4 %) BF-GIP norovirus results were suspected to be false positives. When using WGS, 64/65 results were in agreement with confirmatory testing. Notably, 35 specimens negative on confirmatory testing and suspected to be BF-GIP norovirus false positive results were undetectable by WGS. Melting curves did not accurately predict false positives, since 20/72 (27.8 %) had typical appearances upon review., Conclusions: BF-GIP produces false positive results for norovirus, which cannot be predicted by melting curve review., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Autophagy is an evolutionarily ancient catabolic pathway and has recently emerged as an integral part of the innate immune system. While the core machinery of autophagy is well defined, the physiological regulation of autophagy is less understood. Here, we identify a C-terminal fragment of human hemoglobin A (HBA1, amino acids 111-132) in human bone marrow as a fast-acting non-inflammatory inhibitor of autophagy initiation. It is proteolytically released from full-length HBA1 by cathepsin E, trypsin or pepsin. Biochemical characterization revealed that HBA1(111-132) has an in vitro stability of 52 min in human plasma and adopts a flexible monomeric conformation in solution. Structure-activity relationship studies revealed that the C-terminal 13 amino acids of HBA1(120-132) are sufficient to inhibit autophagy, two charged amino acids (D127, K128) mediate solubility, and two serines (S125, S132) are required for function. Successful viruses like human immunodeficiency virus 1 (HIV-1) evolved strategies to subvert autophagy for virion production. Our results show that HBA1(120-132) reduced virus yields of lab-adapted and primary HIV-1. Summarizing, our data identifies naturally occurring HBA1(111-132) as a physiological, non-inflammatory antagonist of autophagy. Optimized derivatives of HBA1(111-132) may offer perspectives to restrict autophagy-dependent viruses., (© 2024. The Author(s).)

Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. Our structure-activity relationship study investigates the conjugation of EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction and receptor affinity. Molecular dynamic simulations revealed that the lipid moieties stabilize the peptide-receptor interaction through hydrophobic contacts at the receptor's N-terminus, anchoring the lipopeptide within the CXCR4 binding pocket and maintaining essential receptor interactions. Accordingly, lipidation resulted in increased receptor affinities and antagonistic activities. Additionally, by interacting with human serum albumin lipidated EPI-X4 derivatives displayed sustained stability in human plasma and extended circulation times in vivo. Selected candidates showed significant therapeutic potential in human retinoblastoma cells in vitro and in ovo, with our lead derivative exhibiting higher efficacies compared to its non-lipidated counterpart. This study not only elucidates the optimization trajectory for EPI-X4 derivatives but also underscores the intricate interplay between stability and efficacy, crucial for delineating their translational potential in clinical applications., Competing Interests: Declaration of competing interest M.H, M.W.H.H., A.H.A., L.S., F.K., E.SG., and J.M. are coinventors of pending and issued patents that claim to use EPI-X4 (ALB408–423) and derivatives for the therapy of CXCR4-associated diseases., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Principal component analysis (PCA) and partial least squares regression (PLS) were combined in this study to identify key material descriptors determining tabletability in direct compression and roller compaction. An extensive material library including 119 material descriptors and tablet tensile strengths of 44 powders and roller compacted materials with varying drug loads was generated to systematically elucidate the impact of different material descriptors, raw API and filler properties as well as process route on tabletability. A PCA model was created which highlighted correlations between different powder descriptors and respective characterization methods and, thus, can enable reduction of analyses to save resources to a certain extent. Subsequently, PLS models were established to identify key material attributes for tabletability such as density and particle size but also surface energy, work of cohesion and wall friction, which were for the first time demonstrated by PLS as highly relevant for tabletability in roller compaction and direct compression. Further, PLS based on extensive material characterization enabled the prediction of tabletability of materials unknown to the model. Thus, this study highlighted how PCA and PLS are useful tools to elucidate the correlations between powder and tabletability, which will enable more robust prediction of manufacturability in formulation development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR-ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR-ABL1-transformed mouse pre-B cells, as the deletion of CXCR4 induces death in these cells. To investigate whether CXCR4 inhibition also effectively blocks BCR-ABL1-transformed cell growth in vitro, in this study, we explored an array of peptide-based inhibitors of CXCR4. The inhibitors were optimized derivatives of EPI-X4, an endogenous peptide antagonist of CXCR4. We observed that among all the candidates, EPI-X4 JM#170 (referred to as JM#170) effectively induced cell death in BCR-ABL1-transformed mouse B cells but had little effect on untransformed wild-type B cells. Importantly, AMD3100, a small molecule inhibitor of CXCR4, did not show this effect. Treatment with JM#170 induced transient JNK phosphorylation in BCR-ABL1-transformed cells, which in turn activated the intrinsic apoptotic pathway by inducing cJun , Bim , and Bax gene expressions. Combinatorial treatment of JM#170 with ABL1 kinase inhibitor Imatinib exerted a stronger killing effect on BCR-ABL1-transformed cells even at a lower dose of Imatinib. Surprisingly, JM#170 actively killed Sup-B15 cells, a BCR-ABL1 + human ALL cell line, but had no effect on the BCR-ABL1 - 697 cell line. This suggests that the inhibitory effect of JM#170 is specific for BCR-ABL1 + ALL. Taken together, JM#170 emerges as a potent novel drug against Ph + ALL.

Purpose: Technological advancements allowing for the analysis of low-volume samples have led to the investigation of human tear fluid and aqueous humor (AH) as potential biomarker sources. However, acquiring AH samples poses significant challenges, making human tear fluid a more accessible alternative. This study aims to compare the protein compositions of these two biofluids to evaluate their suitability for biomarker discovery., Methods: Paired tear and AH samples were collected from 20 patients undergoing cataract surgery. Tear samples were collected using Schirmer strips prior to surgery, and AH samples were collected from the anterior chamber immediately after corneal incision. Proteins were extracted and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: A total of 481 proteins were identified in greater than 50% of the tear samples, and 191 proteins were detected in greater than 50% of the AH samples. Of these proteins, 82 were found to be common between the two biofluids, with ALB, LTF, TF, LCN1, and IGKC being the most abundant., Conclusion: Although tear fluid and the AH are functionally independent and physically separated, many of the proteins detected in AH were also detected in tears. This direct comparison of the proteomic content of tear fluid and AH may aid in further investigation of tear fluid as a source of readily accessible biomarkers for various human diseases., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The aim of this study was to investigate the 2-year postoperative efficacy of the XEN45 Gel Stent by evaluating the reduction of intraocular pressure (IOP) and the need for eye pressure-lowering medications in a multicenter setting in Switzerland., Methods: Patients with various types of glaucoma who received a XEN45 Gel Stent with or without combined phacoemulsification cataract surgery at five hospitals in Switzerland were retrospectively enrolled. Pre- and postoperative IOP, the number of antiglaucoma medications, and the need of subsequent interventions to control IOP were assessed. The success rate was defined as a ≥ 20% reduction of IOP 2 years postoperatively without the need for subsequent glaucoma surgery., Results: A total of 345 eyes were included: 44.3% with primary open-angle, 42.0% pseudoexfoliation, and 13.7% with other types of glaucoma. Of these, 206 patients were followed for 2 years. Preoperatively, the mean IOP was 26.3 ± 8.9 mmHg and the mean number of antiglaucoma medications administered was 3.0 ± 1.3. Two years postoperatively, the success rate was 66.0% (95% confidence interval 59.3-72.1%), the IOP had dropped by 43.8% to 14.8 ± 5.7 mmHg, and the number of medications was reduced by a mean of 2.0 ± 1.7 per day. Postoperative complications and the need for interventions remained low., Conclusion: The XEN45 Gel Stent successfully reduced IOP and the number of antiglaucoma drugs in most patients at 2 years postoperatively., (© 2024. The Author(s).)

Objectives: To describe the course of symptoms reported by patients with symptoms attributed to Lyme borreliosis (LB) without being subsequently diagnosed with LB., Methods: We performed a prospective cohort study with patients presenting at the outpatient clinic of two clinical LB centres. The primary outcome was the prevalence of persistent symptoms, which were defined as clinically relevant fatigue (CIS, subscale fatigue), pain (SF-36, subscale bodily pain), and cognitive impairment (CFQ) for ≥ 6 months and onset < 6 months over the first year of follow-up. Outcomes were compared with a longitudinal cohort of confirmed LB patients and a general population cohort. Prevalences were standardised to the distribution of pre-defined confounders in the confirmed LB cohort., Results: Participants (n = 123) reported mostly fatigue, arthralgia, myalgia, and paraesthesia as symptoms. The primary outcome could be determined for 74.8% (92/123) of participants. The standardised prevalence of persistent symptoms in our participants was 58.6%, which was higher than in patients with confirmed LB at baseline (27.2%, p < 0.0001) and the population cohort (21.2%, p < 0.0001). Participants reported overall improvement of fatigue (p < 0.0001) and pain (p < 0.0001) but not for cognitive impairment (p = 0.062) during the follow-up, though symptom severity at the end of follow-up remained greater compared to confirmed LB patients (various comparisons p < 0.05)., Conclusion: Patients with symptoms attributed to LB who present at clinical LB centres without physician-confirmed LB more often report persistent symptoms and report more severe symptoms compared to confirmed LB patients and a population cohort., (© 2024. The Author(s).)

In proteomics, fast, efficient, and highly reproducible sample preparation is of utmost importance, particularly in view of fast scanning mass spectrometers enabling analyses of large sample series. To address this need, we have developed the web application MassSpecPreppy that operates on the open science OT-2 liquid handling robot from Opentrons. This platform can prepare up to 96 samples at once, performing tasks like BCA protein concentration determination, sample digestion with normalization, reduction/alkylation and peptide elution into vials or loading specified peptide amounts onto Evotips in an automated and flexible manner. The performance of the developed workflows using MassSpecPreppy was compared with standard manual sample preparation workflows. The BCA assay experiments revealed an average recovery of 101.3% (SD: ± 7.82%) for the MassSpecPreppy workflow, while the manual workflow had a recovery of 96.3% (SD: ± 9.73%). The species mix used in the evaluation experiments showed that 94.5% of protein groups for OT-2 digestion and 95% for manual digestion passed the significance thresholds with comparable peptide level coefficient of variations. These results demonstrate that MassSpecPreppy is a versatile and scalable platform for automated sample preparation, producing injection-ready samples for proteomics research., (© 2023 The Authors. PROTEOMICS published by Wiley‐VCH GmbH.)

Introduction: HIV pre-exposure prophylaxis (PrEP) is effective at reducing HIV transmission. However, PrEP uptake is low for racial and ethnic minorities and women, especially in the Southern US Health care clinicians should be prepared to identify all patients eligible for PrEP, provide counseling, and prescribe PrEP., Methods: Retrospective analysis of persons newly diagnosed with HIV was conducted at a large public health system from January 2015 to June 2021. Interactions with the health system in the 5 years preceding HIV diagnosis were analyzed, and missed opportunities for HIV prevention interventions, including PrEP and condom use counseling, were identified., Results: We identified 454 patients with a new HIV diagnosis with previous health system interactions. 166(36.6%) had at least 1 identifiable indication for PrEP: 42(9.3%) bacterial STI, 63(13.9%) inconsistent condom use, or 82(18%) injection drug use before HIV diagnosis. Only 7(1.5%) of patients were counseled on PrEP. Most patients (308; 67.8%) had no documented condom use history in the EHR before diagnosis, a surrogate marker for obtaining a sexual history. Patients who exclusively interacted with the emergency care setting did not receive PrEP education and were less likely to receive condom use counseling., Conclusion: Missed opportunities to offer HIV prevention before diagnosis were common among patients newly diagnosed with HIV. Most patients did not have sexual history documented in the chart before their HIV diagnosis. Educational interventions are needed to ensure that clinicians are prepared to identify those eligible and discuss the benefits of PrEP., Competing Interests: Conflict of interest: None., (© Copyright 2024 by the American Board of Family Medicine.)

With the advent of serial X-ray crystallography on microfocus beamlines at free-electron laser and synchrotron facilities, the demand for protein microcrystals has significantly risen in recent years. However, by in vitro crystallization extensive efforts are usually required to purify proteins and produce sufficiently homogeneous microcrystals. Here, we present InCellCryst, an advanced pipeline for producing homogeneous microcrystals directly within living insect cells. Our baculovirus-based cloning system enables the production of crystals from completely native proteins as well as the screening of different cellular compartments to maximize chances for protein crystallization. By optimizing cloning procedures, recombinant virus production, crystallization and crystal detection, X-ray diffraction data can be collected 24 days after the start of target gene cloning. Furthermore, improved strategies for serial synchrotron diffraction data collection directly from crystals within living cells abolish the need to purify the recombinant protein or the associated microcrystals., (© 2024. The Author(s).)

Rare-variants (RVs) genetic association studies enable researchers to uncover the variation in phenotypic traits left unexplained by common variation. Traditional single-variant analysis lacks power; thus, researchers have developed various methods to aggregate the effects of RVs across genomic regions to study their collective impact. Some existing methods utilize a static delineation of genomic regions, often resulting in suboptimal effect aggregation, as neutral subregions within the test region will result in an attenuation of signal. Other methods use varying windows to search for signals but often result in long regions containing many neutral RVs. To pinpoint short genomic regions enriched for disease-associated RVs, we developed a novel method, DYNamic Aggregation TEsting (DYNATE). DYNATE dynamically and hierarchically aggregates smaller genomic regions into larger ones and performs multiple testing for disease associations with a controlled weighted false discovery rate. DYNATE's main advantage lies in its strong ability to identify short genomic regions highly enriched for disease-associated RVs. Extensive numerical simulations demonstrate the superior performance of DYNATE under various scenarios compared with existing methods. We applied DYNATE to an amyotrophic lateral sclerosis study and identified a new gene, EPG5, harboring possibly pathogenic mutations., (© 2023 Wiley Periodicals LLC.)

The aqueous humor (AH) is a low-viscosity biofluid that continuously circulates from the posterior chamber to the anterior chamber of the eye. Recent advances in high-resolution mass-spectrometry workflows have facilitated the study of proteomic content in small-volume biofluids like AH, highlighting the potential clinical implications of the AH proteome. Nevertheless, in-depth investigations into the role of AH proteins in ocular diseases have encountered challenges due to limited accessibility to these workflows, difficulties in large-scale AH sample collection and the absence of a reference AH proteomic database. In response to these obstacles, and to promote further research on the involvement of AH proteins in ocular physiology and pathology, we have developed the web-based Aqueous Humor Proteomics Database (AHP DB). The current version of AHP DB contains proteomic data from 307 human AH samples, which were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The database offers comprehensive information on 1683 proteins identified in the AH samples. Furthermore, relevant clinical data are provided for each analyzed sample. Researchers also have the option to download these datasets individually for offline use, rendering it a valuable resource for the scientific community. Database URL: https://ahp.augusta.edu/., (© The Author(s) 2024. Published by Oxford University Press.)

Proteolysis targeting chimeras (PROTACs) are a promising class of pharmaceutical agents with a unique mode of action. PROTACs enable the targeting of a broad variety of structures including transcription factors and other "undruggable" targets. The poor solubility and slow dissolution of PROTACs currently limit the extensive use of their potential. Up to date, only very limited drug delivery options have been examined to address this challenge. Therefore, we explored the potential of amorphous solid dispersions (ASDs) by spray drying a model PROTAC with different polymers. The resulting formulations were assessed in terms of purity, solid state, dissolution performance, and stability. A strong increase in supersaturation compared to the physical mixture was provided, although in both systems the PROTAC molecule itself was already in the amorphous state. Evaluation of the reasons for the superiority of the ASD formulations revealed that the major factor was the homogeneous, molecular distribution of the active pharmaceutical ingredient (API) in the polymer matrix, as well as improved wettability of the formulation containing Soluplus compared to the physical mixture. The manufactured formulations were stable over a minimum of 8 weeks when protected from light and humidity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Meike Harms reports financial support was provided by Merck KGaA. Nicole Hofmann reports financial support was provided by Merck KGaA., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Although the mechanical properties of paracetamol and MCC are extensively described in literature, there still is a need for a better understanding of the material properties impacting them. Thus, this study systematically analyzed material properties of paracetamol-MCC blends to elucidate their influence on the mechanical tablet properties in roller compaction and direct compression with special focus on surface properties., Methods: Multiple material characteristics of binary mixtures of paracetamol and MCC with varying drug loads were analyzed, with particular emphasis on specific surface area and surface energy. Subsequently, mechanical tablet properties of the materials in direct compression and after roller compaction were examined., Results: It was demonstrated that the impact of the initial material properties on mechanical tablet properties prevailed over the impact of processing route for paracetamol-MCC blends, underlining the importance of material characterization for tabletability of oral solid dosage forms. By applying bivariate as well as multivariate analysis, key material properties influencing the tabletability of paracetamol, MCC and its mixtures such as surface area, surface energy, effective angle of internal friction and density descriptors were identified., Conclusions: This study highlighted the importance of comprehensive assessment of different material characteristics leading to a deeper understanding of underlying factors impacting mechanical tablet properties in direct compression and after roller compaction by the example of paracetamol-MCC mixtures with varying drug loads. Furthermore, it was shown that multivariate analysis could be a valuable extension to common bivariate analysis to reveal underlying correlations of material properties., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: The authors declare no conflict of interest.

EPI-X4, a natural peptide CXCR4 antagonist, shows potential for treating inflammation and cancer, but its short plasma stability limits its clinical application. We aimed to improve the plasma stability of EPI-X4 analogues without compromising CXCR4 antagonism. Our findings revealed that only the peptide N-terminus is prone to degradation. Consequently, incorporating d-amino acids or acetyl groups in this region enhanced peptide stability in plasma. Notably, EPI-X4 leads 5 , 27 , and 28 not only retained their CXCR4 binding and antagonism but also remained stable in plasma for over 8 h. Molecular dynamic simulations showed that these modified analogues bind similarly to CXCR4 as the original peptide. To further increase their systemic half-lives, we conjugated these stabilized analogues with large polymers and albumin binders. These advances highlight the potential of the optimized EPI-X4 analogues as promising CXCR4-targeted therapeutics and set the stage for more detailed preclinical assessments.

The development of minimally invasive glaucoma surgeries (MIGSs) was intended to provide safe and modestly efficacious modalities for early intervention of mild-to-moderate glaucoma, with minimal trauma and rapid recovery. They were mainly ab interno procedures that reduce intraocular pressure by facilitating the aqueous outflow by bypassing the trabecular meshwork resistance, reinforcing the uveoscleral flow via the supraciliary space, and reducing aqueous production by the ciliary body. While the cumulating evidence helps shape the role of the available MIGS, the exponential new development and advancement in this field has expanded the territory of MIGS. Apart from developing subconjunctival MIGS filtration devices (Xen gel stent and PRESERFLO MicroShunt), there is a tendency to revisit the "traditional" MIGS for alternative use and to modify the procedures with consideration of the fundamental aqueous outflow physiology. Combined MIGS has also been suggested, based on the theory that their different mechanisms may provide additive or synergistic effects. The advancement of laser procedures is also promising and could supplement unmet needs along the glaucoma treatment algorithm. This review examines the broad array of MIGS, updates the recent findings, discusses their potential alternative applications, and explores future challenges., Competing Interests: J.E.D. and A.H. are employees of Sight Sciences, Inc. T.W.S. is a consultant and an investigator for Glaukos, as well as other canal device conflicting companies such as Alcon Surgical, Ivantis, Sight Science, Vialase, Elios, Belkin Vision, and New World Medical. The remaining authors have no funding or conflicts of interest to declare., (Copyright © 2023 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Background: Respiratory mucosal host defense relies on the production of secretory IgA (sIgA) antibodies, but we currently lack a fundamental understanding of how sIgA is induced by contact with microbes and how such immune responses may vary between humans. Defense of the nasal mucosal barrier through sIgA is critical to protect from infection and to maintain homeostasis of the microbiome, which influences respiratory disorders and hosts opportunistic pathogens., Methods: We applied IgA-seq analysis to nasal microbiota samples from male and female healthy volunteers, to identify which bacterial genera and species are targeted by sIgA on the level of the individual host. Furthermore, we used nasal sIgA from the same individuals in sIgA deposition experiments to validate the IgA-seq outcomes., Conclusions: We observed that the amount of sIgA secreted into the nasal mucosa by the host varied substantially and was negatively correlated with the bacterial density, suggesting that nasal sIgA limits the overall bacterial capacity to colonize. The interaction between mucosal sIgA antibodies and the nasal microbiota was highly individual with no obvious differences between potentially invasive and non-invasive bacterial species. Importantly, we could show that for the clinically relevant opportunistic pathogen and frequent nasal resident Staphylococcus aureus, sIgA reactivity was in part the result of epitope-independent interaction of sIgA with the antibody-binding protein SpA through binding of sIgA Fab regions. This study thereby offers a first comprehensive insight into the targeting of the nasal microbiota by sIgA antibodies. It thereby helps to better understand the shaping and homeostasis of the nasal microbiome by the host and may guide the development of effective mucosal vaccines against bacterial pathogens. Video Abstract., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: A new monthly virtual education curriculum on sexual healthcare was launched in 2021. This is an analysis of the pilot education series designed to increase primary care providers' knowledge of sexual health best practices including taking thorough sexual histories, STI screening and treatment, and PrEP prescribing., Methods: A Sexual Health Curriculum Series was developed as part of a quality improvement initiative at a large urban safety-net hospital in Dallas County, Texas. Didactic sessions were administered to primary care providers and staff via a virtual meeting platform once a month from May 2021 to April 2022., Results: A total of 52 participants completed the pre-series survey, and 21 participants filled out the final post-series survey. 70% of respondents who completed the post-series survey reported that they learned new information that was incorporated into their practice. The average percentage correct on individual pre-session surveys was 60% compared to 63% on individual post-session surveys (p = 0.03)., Conclusion: Sexual health education is an important tool to help primary care providers adhere to sexual health best practices. There is a need for ongoing implementation of innovative strategies to improve knowledge and adherence to sexual health best practices. A sexual health curriculum may be effective in helping primary providers recognize patients at increased risk and apply evidence-based guidelines to their practices., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Syncope management is fraught with unnecessary tests and frequent failure to establish a diagnosis. We evaluated the potential of implementing the 2018 European Society of Cardiology (ESC) Syncope Guidelines regarding diagnostic yield, accuracy and costs., Methods: A multicentre pre-post study in five Dutch hospitals comparing two groups of syncope patients visiting the emergency department: one before intervention (usual care; from March 2017 to February 2019) and one afterwards (from October 2017 to September 2019). The intervention consisted of the simultaneous implementation of the ESC Syncope Guidelines with quick referral routes to a syncope unit when indicated. The primary objective was to compare diagnostic accuracy using logistic regression analysis accounting for the study site. Secondary outcome measures included diagnostic yield, syncope-related healthcare and societal costs. One-year follow-up data were used to define a gold standard reference diagnosis by applying ESC criteria or, if not possible, evaluation by an expert committee. We determined the accuracy by comparing the treating physician's diagnosis with the reference diagnosis., Results: We included 521 patients (usual care, n = 275; syncope guidelines intervention, n = 246). The syncope guidelines intervention resulted in a higher diagnostic accuracy in the syncope guidelines group than in the usual care group (86% vs.69%; risk ratio 1.15; 95% CI 1.07 to 1.23) and a higher diagnostic yield (89% vs. 76%, 95% CI of the difference 6 to 19%). Syncope-related healthcare costs did not differ between the groups, yet the syncope guideline implementation resulted in lower total syncope-related societal costs compared to usual care (saving €908 per patient; 95% CI €34 to €1782)., Conclusions: ESC Syncope Guidelines implementation in the emergency department with quick referral routes to a syncope unit improved diagnostic yield and accuracy and lowered societal costs., Trial Registration: Netherlands Trial Register, NTR6268., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Viral infections pose a significant threat to human health, and effective antiviral strategies are urgently needed. Antiviral peptides have emerged as a promising class of therapeutic agents due to their unique properties and mechanisms of action. While effective on their own, combining antiviral peptides may allow us to enhance their potency and to prevent viral resistance. Here, we developed an orthogonal chemical strategy to prepare a heterodimeric peptide conjugate assembled on a protein-based nanoplatform. Specifically, we combined the optimized version of two peptides inhibiting HIV-1 by distinct mechanisms. Virus-inhibitory peptide (VIRIP) is a 20 amino acid fragment of α1-antitrypsin that inhibits HIV-1 by targeting the gp41 fusion peptide. Endogenous peptide inhibitor of CXCR4 (EPI-X4) is a 16-residue fragment of human serum albumin that prevents HIV-1 entry by binding to the viral CXCR4 co-receptor. Optimized forms of both peptides are assembled on supramolecular nanoplatforms through the streptavidin-biotin interaction. We show that the construct consisting of the two different peptides (SAv-VIR-102C9-EPI-X4 JM#173-C) shows increased activity against CCR5- and CXCR4-tropic HIV-1 variants. Our results are a proof of concept that peptides with different modes of action can be assembled on nanoplatforms to enhance their antiviral activity.

This study discovers the complement protein profile in the aqueous humor (AH) of human subjects and investigates its association with primary open-angle glaucoma (POAG) pathogenesis. Among the 32 complement proteins identified, 22 were highly abundant and detected in more than 50% of AH samples. The most predominant active complement proteins in the AH are C3, C4B, C4A, CFB, CFD, and C9. Additionally, the most prevalent complement regulators and receptors include CLU, SERPING1, F2, CFH, CFI, and VTN. Significant alterations in complement proteins were observed in individuals with POAG compared to those with cataracts. Specifically, complement protein F2 was upregulated, while C8G, C6, and CFH were downregulated in POAG samples. Stratification of the samples by race and sex revealed distinct alterations of complement proteins in patients with POAG. In the African American cohort, five complement proteins (C4A, C4B, F2, C7, and C3) were upregulated in POAG compared to cataract patients. In the Caucasian cohort, eight complement proteins (C3, SERPING1, CFI, CLU, CFHR1, C8G, C6, and CFH) were downregulated in the POAG samples compared to the cataract samples. Within the male cohort, three complement proteins (CLU, C6, and CFH) were downregulated in POAG patients compared to those with cataracts. Whereas, within the female cohort, two complement proteins (C4B and F2) were upregulated and one (C8G) downregulated in the POAG samples when compared to cataracts. Discerning these changes in the AH complement protein profile will assist in the development of tailored therapies to modulate the complement system for managing ocular disorders. These insights may also lead to novel biomarkers for diagnosing and monitoring disease progression.

Background: Although ICG-FA may be valuable in assessing anastomotic perfusion, reliable data on its use in pediatric gastrointestinal surgery is lacking. This systematic review analyzes whether ICG is useful for intestinal perfusion assessment in pediatric gastrointestinal surgery and safe to use in neonates., Methods: Systematic searches of PubMed, EMBASE & MEDLINE and CENTRAL were performed (last conducted December 6, 2021). The main inclusion criteria were (1) use of ICG for intestinal perfusion assessment and (2) use of ICG in young infants. Exclusion criteria were lack of an English or Dutch full-text and MINORS quality score <60%. Data was presented in overview tables. The usefulness in pediatric gastrointestinal surgery was assessed by surgical outcome. Safety of ICG in neonates was assessed by complication or adverse event occurrence., Results: Regarding intestinal perfusion assessment, four studies were included, reporting 45 patients (median age 1.5 years). ICG was considered useful for anastomotic blood flow evaluation and intraoperative determination of resection length. Regarding ICG safety in neonates, eight studies were included, reporting 46 infants (median age 24.9 days), of which 18 neonates. All but one studies reported the absence of complications or adverse events. Two studies reported subcutaneous dye retention, which fully disappeared within two weeks., Conclusion: Although the number of available studies is small, ICG might be useful for intraoperative intestinal perfusion assessment, perhaps even more than conventional clinical assessment. Furthermore, its safety profile looks promising in neonates. Larger prospective studies are necessary to confirm these assumptions and seem warranted given the safety profile., Levels of Evidence: Since this is a systematic review, a Level of Evidence for clinical studies cannot be determined for this manuscript., Competing Interests: Declaration of Competing Interest One of the authors is a representative at Stryker Endoscopy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction/Aims . Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods . The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK ® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results . In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion . We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

The peptide fragment of human serum albumin that was identified as an inhibitor of C-X-C motif chemokine receptor 4 (CXCR4), termed EPI-X4, was investigated as a scaffold for the development of CXCR4-targeting radio-theragnostics. Derivatives of its truncated version JM#21 (ILRWSRKLPCVS) were conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and tested in Jurkat and Ghost-CXCR4 cells. Ligand- 1 , - 2 , - 5 , - 6 , - 7 , - 8 , and - 9 were selected for radiolabeling. Molecular modeling indicated that 177 Lu-DOTA incorporation C-terminally did not interfere with the CXCR4 binding. Lipophilicity, in vitro plasma stability, and cellular uptake hinted 177 Lu- 7 as superior. In Jurkat xenografts, all radioligands showed >90% washout from the body within an hour, with the exception of 177 Lu- 7 and 177 Lu- 9 . 177 Lu- 7 demonstrated best CXCR4-tumor targeting. Ex vivo biodistribution and single-photon emission computed tomography (SPECT)/positron emission tomography (PET)/CT imaging of 177 Lu- 7 / 68 Ga- 7 showed the same distribution profile for both radioligands, characterized by very low uptake in all nontargeted organs except the kidneys. The data support the feasibility of CXCR4-targeting with EPI-X4-based radioligands and designate ligand- 7 as a lead candidate for further optimization.

Semen is an important vector for sexual HIV-1 transmission. Although CXCR4-tropic (X4) HIV-1 may be present in semen, almost exclusively CCR5-tropic (R5) HIV-1 causes systemic infection after sexual intercourse. To identify factors that may limit sexual X4-HIV-1 transmission, we generated a seminal fluid-derived compound library and screened it for antiviral agents. We identified four adjacent fractions that blocked X4-HIV-1 but not R5-HIV-1 and found that they all contained spermine and spermidine, abundant polyamines in semen. We showed that spermine, which is present in semen at concentrations up to 14 mM, binds CXCR4 and selectively inhibits cell-free and cell-associated X4-HIV-1 infection of cell lines and primary target cells at micromolar concentrations. Our findings suggest that seminal spermine restricts sexual X4-HIV-1 transmission.

Mountain regions are fragile ecosystems and often host remarkably rich biodiversity, and thus they are especially under threat from ongoing global changes. Located in the Eastern Alps, Trentino-South Tyrol is bioculturally diverse but an understudied region from an ethnobotanical perspective. We explored the ethnomedicinal knowledge of the area from a cross-cultural and diachronic perspective by conducting semi-structured interviews with 22 local inhabitants from Val di Sole (Trentino) and 30 from Überetsch-Unterland (South Tyrol). Additionally, we compared the results with ethnobotanical studies conducted in Trentino and South Tyrol over 25 years ago. The historical comparison revealed that about 75% of the plants currently in use were also used in the past in each study region. We argue that the adoption of "new" medicinal species could have occurred through printed and social media and other bibliographical sources but may also be due to limitations in conducting the comparison (i.e., different taxonomic levels and different methodologies). The inhabitants of Val di Sole and Überetsch-Unterland have shared most medicinal plants over the past few decades, yet the most used species diverge (perhaps due to differences in local landscapes), and in South Tyrol, people appear to use a higher number of medicinal plants, possibly because of the borderland nature of the area.

Purpose of Review: It was not until the nineteen nineties that there was scientific evidence for the primary treatment concept of glaucoma, lowering intraocular pressure. The treatment concept of lowering intraocular pressure is now proven by randomized controlled clinical trials (landmark studies). This review provides an overview of the follow-up studies to these landmark studies from the last 18 months., Recent Findings: The 20-year data of the ocular hypertension treatment study showed a 49% incidence of primary open-angle glaucoma. The data of this landmark study was used for developing different machine learning algorithms. Bilateral disease, disc hemorrhages, and higher intraocular pressure (IOP) were risk factors for visual field deterioration in the United Kingdom Glaucoma Treatment Study. The Advanced Glaucoma Intervention Trial and the Collaborative Initial Glaucoma Treatment Study identified demographic factors, comorbidity, and clinical variables associated with visual field damage. Analysis was performed on Chinese subsets from the Laser in Glaucoma and Ocular Hypertension Study (LiGHT). Looking at all the follow-up studies to the tube shunt landmark studies, preoperative IOP, neovascular glaucoma, Ahmed implantation, and younger age were predictors of failure. A follow-up study to the Effectiveness in Angle-Closure Glaucoma in Lens Extraction Study showed that patients were ten times more likely to maintain a drop-free target IOP after lens extraction than after laser iridotomy. A superior location for iridotomy results in significantly more significant angle widening than temporal or nasal locations, as shown by a follow-up study to the Zhongshan Angle Closure Prevention Trial using OCT and gonioscopy., Summary: The number of published follow-up studies to the landmark studies in glaucoma show the ongoing development of clinical questions in management of glaucoma., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To provide expert consensus and evidence-based current guidelines on treatment technique, postoperative care, expected outcomes and retreatment for MicroPulse Transscleral Laser Treatment (TLT)., Methods: A comprehensive search of PubMed led to the identification and analysis of 61 studies on MicroPulse TLT. To provide guidance in areas where there was not enough available literature, a three-round Delphi method was conducted involving 10 international experts in MicroPulse TLT., Results: The response rate was 70% in the first round, 70% in the second round, and 80% in the third round of the Delphi method. Once all responses were aggregated, a live meeting was held with 90% attendance, and consensus was achieved on each of the findings detailed in this manuscript., Conclusion: Used within appropriate treatment parameters, with proper technique and patient selection, MicroPulse TLT is a safe and effective treatment for many types and severities of glaucoma. MicroPulse TLT represents a useful addition to the glaucoma armamentarium., Competing Interests: The following authors have received grant support (S), lecture fees (L), or consulting fees (C) from Iridex Corporation: Jella An (S, L); Jacob W Brubaker (S, L); Ronald MPC de Crom (S, L); Brian A Francis (S, L); Michael Giovingo (S, L); Tomas M Grippo (C, S, L); Brian Jerkins (S); Robert Noecker (C, S, L); Nathan Radcliffe (S); Marc Toeteberg-Harms (S, L). Prof. Dr. Marc Töteberg-Harms also reports speaker’s honorarium from Allergan, MLase AG, ELIOS, ELT Sight, Novartis/Alcon, Santen, Heidelberg Engineering, and Glaukos; honorarium for Advisory Board Activity from Reichert, outside the submitted work. Dr Michael Giovingo also reports grants from Santen, outside the submitted work. Dr Jella An also reports personal fees from Alcon, New World Medical, Aerie, Sight Sciences; grants from Abbvie, outside the submitted work. Dr Nathan Radcliffe also reports personal fees from Alderya, Avellino, Aerie Pharmaceuticals; Alcon Vision, Alimera Sciences, Allergan/AbbVie, Bausch + Lomb, Beaver-Visitec International, Belkin, CATS, Carl Zeiss Meditec, CATS, Dompe, Ellex, ELIOS Vision Inc, Equinox, Eyepoint Pharmaceuticals, Glaukos, Iridex, IrisVision, Kala Pharmaceuticals, Lumenis, New World Medical, Novartis, Ocular Science, Ocular Therapeutix, Omeros, Reichert, Santen, Shire, Sight Sciences, Spyglass, Tarsus, Thea, TearClear and ViaLase, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Grippo et al.)

Background and Objectives: Prospective, deeply phenotyped research cohorts monitoring individuals with chronic neurologic conditions, such as multiple sclerosis (MS), depend on continued participant engagement. The COVID-19 pandemic restricted in-clinic research activities, threatening this longitudinal engagement, but also forced adoption of televideo-enabled care. This offered a natural experiment in which to analyze key dimensions of remote research: (1) comparison of remote vs in-clinic visit costs from multiple perspectives and (2) comparison of the remote with in-clinic measures in cross-sectional and longitudinal disability evaluations., Methods: Between March 2020 and December 2021, 207 MS cohort participants underwent hybrid in-clinic and virtual research visits; 96 contributed 100 "matched visits," that is, in-clinic (Neurostatus-Expanded Disability Status Scale [NS-EDSS]) and remote (televideo-enabled EDSS [tele-EDSS]; electronic patient-reported EDSS [ePR-EDSS]) evaluations. Clinical, demographic, and socioeconomic characteristics of participants were collected., Results: The costs of remote visits were lower than in-clinic visits for research investigators (facilities, personnel, parking, participant compensation) but also for participants (travel, caregiver time) and carbon footprint ( p < 0.05 for each). Median cohort EDSS was similar between the 3 modalities (NS-EDSS: 2, tele-EDSS: 1.5, ePR-EDSS: 2, range 0.6.5); the remote evaluations were each noninferior to the NS-EDSS within ±0.5 EDSS point (TOST for noninferiority, p < 0.01 for each). Furthermore, year to year, the % of participants with worsening/stable/improved EDSS scores was similar, whether each annual evaluation used NS-EDSS or whether it switched from NS-EDSS to tele-EDSS., Discussion: Altogether, the current findings suggest that remote evaluations can reduce the costs of research participation for patients, while providing a reasonable evaluation of disability trajectory longitudinally. This could inform the design of remote research that is more inclusive of diverse participants., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Advanced derivatives of the E ndogenous P eptide I nhibitor of C X CR 4 (EPI-X4) have shown therapeutic efficacy upon topical administration in animal models of asthma and dermatitis. Here, we studied the plasma stability of the EPI-X4 lead compounds WSC02 and JM#21, using mass spectrometry to monitor the chemical integrity of the peptides and a functional fluorescence-based assay to determine peptide function in a CXCR4-antibody competition assay. Although mass spectrometry revealed very rapid disappearance of both peptides in human plasma within seconds, the functional assay revealed a significantly higher half-life of 9 min for EPI-X4 WSC02 and 6 min for EPI-X4 JM#21. Further analyses demonstrated that EPI-X4 WSC02 and EPI-X4 JM#21 interact with low molecular weight plasma components and serum albumin. Albumin binding is mediated by the formation of a disulfide bridge between Cys10 in the EPI-X4 peptides and Cys34 in albumin. These covalently linked albumin-peptide complexes have a higher stability in plasma as compared with the non-bound peptides and retain the ability to bind and antagonize CXCR4. Remarkably, chemically synthesized albumin-EPI-X4 conjugates coupled by non-breakable bonds have a drastically increased plasma stability of over 2 h. Thus, covalent coupling of EPI-X4 to albumin in vitro before administration or in vivo post administration may significantly increase the pharmacokinetic properties of this new class of CXCR4 antagonists.

Angle-closure glaucoma is a rare form of glaucoma characterized by a narrow or an occlusion of the anterior chamber angle and subsequently an obstruction of the outflow of aqueous humor resulting in an increase in intraocular pressure. Symptoms can include severe eye pain and/or headache, blurred vision, a medium-sized and rigid pupil, conjunctival hyperemia, and nausea. Treatment options include pressure-lowering topical and systemic medications as well as surgical interventions, especially cataract surgery and laser iridotomy. Besides parasympathomimetics (pilocarpine), all topical antiglaucoma medications can principally be used (beta-receptor antagonists, carbonic anhydrase inhibitors, alpha‑2 selective adrenergic antagonists, prostaglandins and prostaglandin analogues). Carbonic anhydrase inhibitors and osmotic agents (e.g., mannitol) can be systemically used., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The relevance of the polymorphic form, particle size, and processing of mannitol for the mechanical properties of solid oral dosage forms was examined. Thus, particle and powder properties of spray granulated β D-mannitol, β D-mannitol, and δ D-mannitol were assessed in this study with regards to their manufacturability. D-mannitol is a commonly used excipient in pharmaceutical formulations, especially in oral solid dosage forms, and can be crystallized as three polymorphic forms, of which β is the thermodynamically most stable form and δ is a kinetically stabilized polymorph. A systematic analysis of the powders as starting materials and their respective roller compacted granules is presented to elucidate the multidimensional effects of powder and granules characteristics such as polymorphic form, particle size, and preprocessing on the resulting tablets' mechanical properties. In direct compression and after roller compaction, δ polymorph displayed superior tableting properties over β mannitol, but was outperformed by spray granulated β mannitol. This could be primarily correlated to the higher specific surface area, leading to higher bonding area and more interparticle bonds within the tablet. Hence, it was shown that surface characteristics and preprocessing can prevail over the impact of polymorphism on manufacturability for oral solid dosage forms.