Ineffective esophageal motility: Characterization and outcomes across pediatric neurogastroenterology and motility centers in the United States.

OBJECTIVES: Ineffective esophageal motility (IEM) on high-resolution manometry (HRM) is not consistently associated with specific clinical syndromes or outcomes. We evaluated the prevalence, clinical features, management, and outcomes of pediatric IEM patients across the United States. METHODS: Clinical and manometric characteristics of children undergoing esophageal HRM during 2021-2022 were collected from 12 pediatric motility centers. Clinical presentation, test results, management strategies, and outcomes were compared between children with IEM and normal HRM. RESULTS: Of 236 children (median age 15 years, 63.6% female, 79.2% Caucasian), 62 (23.6%) patients had IEM, and 174 (73.7%) patients had normal HRM, with similar demographics, medical history, clinical presentation, and median symptom duration. Reflux monitoring was performed more often for IEM patients (25.8% vs. 8.6%, p = 0.002), but other adjunctive testing was similar. Among 101 patients with follow-up, symptomatic cohorts declined in both groups in relation to the initial presentation (p > 0.107 for each comparison) with management targeting symptoms, particularly acid suppression. Though prokinetics were used more often and behavioral therapy less often in IEM (p ≤ 0.015 for each comparison), symptom outcomes were similar between IEM and normal HRM. Despite a higher proportion with residual dysphagia on follow-up in IEM (64.0% vs. 39.1%, p = 0.043), an alternate mechanism for dysphagia was identified more often in IEM (68.8%) compared to normal HRM (27.8%, p = 0.017). CONCLUSIONS: IEM is a descriptive manometric pattern rather than a clinical diagnosis requiring specific intervention in children. Management based on clinical presentation provides consistent symptom outcomes.

A methodological pipeline for the preclinical evaluation of novel topical agents for the treatment of CRS.

KEY POINTS: Novel topical therapeutics require extensive pre-clinical testing to assess efficacy and safety. Antibiofilm or immunosuppressant agents can utilize ex vivo models to measure ciliotoxicity. Agents that are found to be effective and non-toxic ex vivo warrant further investigation in vivo.

Optimization of spermatozoa analysis in mice: A comprehensive protocol.

Sperm quality is critical to predict reproductive alterations caused by immunological factors or toxicant agents. Yet, no detailed protocol has been published focusing on analyses of sperm parameters in mice. Our aim was to evaluate the most efficient diluent for mice sperm analyses and to optimize the sperm morphology classification, through the comparison of different staining methods. The diluents assessed were PBS (baseline), HTF, DMEM, 1 % BSA in PBS and 9 % skimmed powdered milk diluted in PBS. Spermatozoa were evaluated for vitality, motility, and morphology, smears were stained with Papanicolaou, HE, Giemsa, and Rapid staining. Sperm vitality and total motility reached better scores in milk based and DMEM diluents. HE raised up as an effective option since its combination with any of the diluents we tested, resulted in a fair staining, which was appropriated to evaluate mice spermatozoa. Finally, based on WHO manual, we have updated the current morphological classification for mice sperm, since we have detailed the head defects as well as included midpiece and tail defects on it. Taken together, we presented a useful, low cost, and reliable method to assess sperm morphology that could be employed worldwide by laboratories dedicated to study reproductive biology on mice model.

Approaches to nutrition and feeding in congenital diaphragmatic hernia.

In patients with congenital diaphragmatic hernia1, nutrition can represent a challenge both in the short and long term. Its failure to resolve can have a significant impact on multiple aspects of the lives of patients with congenital diaphragmatic hernia (CDH), ranging from lung function to neurodevelopment. In this review, we will describe the causes of nutritional problems in patients with CDH, their consequences, and possible strategies to address them.

Genomic stress in diseases stemming from defects in the second brain.

This review discusses the less-explored realm of DNA damage and repair within the enteric nervous system (ENS), often referred to as the "second brain." While the central nervous system has been extensively studied for its DNA repair mechanisms and associated neuropathologies, the ENS, which can autonomously coordinate gastrointestinal function, experiences unique challenges and vulnerabilities related to its genome integrity. The susceptibility of the ENS to DNA damage is exacerbated by its limited protective barriers, resulting in not only endogenous genotoxic exposures, such as oxidative stress, but also exogenous threats, such as ingested environmental contaminants, local inflammatory responses, and gut dysbiosis. Here, we discuss the evidence for DNA repair defects in enteric neuropathies, most notably, the reported relationship between inherited mutations in RAD21 and LIG3 with chronic intestinal pseudo-obstruction and mitochondrial gastrointestinal encephalomyopathy disorders, respectively. We also introduce the lesser-recognized gastrointestinal complications in DNA repair syndromes, including conditions like Cockayne syndrome. The review concludes by pointing out the potential role of DNA repair defects in not only congenital disorders but also aging-related gut dysfunction, as well as the crucial need for further research to establish direct causal links between DNA damage accumulation and ENS-specific pathologic phenotypes.

Extending the emission peak tail of indole cyanine for deep-near-infrared bioimaging.

We propose a novel strategy for tailoring the structure of fluorescent molecules to achieve emission at the tail end of the NIR-II window. The favorable spectroscopic properties and low cytotoxicity of YNs make them powerful tools for bioimaging. Notably, YN-4 exhibits a brightness 2.5 times greater than YN-3, 6 times that of IR-783, and 5 times that of ICG. This enhanced brightness enabled high-resolution imaging of mouse thoracic and abdominal cavities, tumor vasculature, and real-time monitoring of gastrointestinal motility using YN-4. Furthermore, covalent grafting of glucose onto the YN-Glu scaffold significantly improved tumor-targeting capability and facilitated tracking of glucose metabolism. This work aims to extend the application of fluorescent molecule imaging beyond the NIR-IIa window.

The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells.

Cancer stem cells (CSCs) play an important role in metastasis development, tumor recurrence, and treatment resistance, and are essential for the eradication of cancer. Currently, therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape, which leads to enhanced aggressive behaviors compared with CSCs that have never been treated. However, the underlying mechanisms regulating the therapeutic escape remain unknown. To this end, we established a model to isolate the therapeutic escaped CSCs (TSCSCs) from breast CSCs and performed the transcription profile to reveal the mechanism. Mechanistically, we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway, resulting in TSCSCs exhibiting enhanced motility and metastasis. Notably, blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo, which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition (EMT)-related proteins vimentin and N-cadherin. The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.

Safety and feasibility of early drinking water after general anesthesia recovery in patients undergoing daytime surgery.

BACKGROUND: Patients who are recovering from general anesthesia commonly exhibit symptoms such as dry lips, throat irritation, and thirst, prompting a desire to drink water in the post-anesthesia care unit (PACU). In this study, we aimed to evaluate the therapeutic effects and any potential complications of administering varying quantities of water to such patients. The primary objectives are to assess the safety and feasibility of early water intake after general anesthesia, specifically in the context of daytime surgery. METHODS: A total of 200 nongastrointestinal patients who underwent outpatient surgery were randomly assigned to four groups: Group A (drinking < 1 ml/kg), Group B (drinking 1-2 ml/kg), Group C (drinking > 2 ml/kg), and Group D (no water intake). We monitored changes in the assessment parameters before and after water consumption, as well as the incidence of post-drinking nausea and vomiting, and compared these outcomes among the four groups. RESULTS: Water intake led to a significant reduction in thirst, oropharyngeal discomfort, and pain scores and a notable increase in the gastric antrum motility index (MI), exhibiting statistical significance compared to the values before drinking (p < 0.05). Remarkably, higher water consumption correlated with enhanced gastrointestinal peristalsis. There was a significant difference in the antral MI among groups B, C, and A (p < 0.05). The occurrence of nausea and vomiting did not significantly differ among groups A, B, C, and D (p > 0.05). Early water consumption enhanced patient satisfaction with medical care, significantly varying from Group D (p < 0.05). CONCLUSION: Non-gastrointestinal surgical patients who passed pre-drinking water assessments post GA(general anesthesia)recovery could safely ingest moderate amounts of water in the PACU. Early water intake is both safe and feasible, effectively fostering swift postoperative recovery.

A cyclic di-GMP-binding adaptor protein interacts with a N5-glutamine methyltransferase to regulate the pathogenesis in Xanthomonas citri subsp. citri.

The second messenger cyclic diguanylate monophosphate (c-di-GMP) regulates a wide range of bacterial behaviours through diverse mechanisms and binding receptors. Single-domain PilZ proteins, the most widespread and abundant known c-di-GMP receptors in bacteria, act as trans-acting adaptor proteins that enable c-di-GMP to control signalling pathways with high specificity. This study identifies a single-domain PilZ protein, XAC3402 (renamed N5MapZ), from the phytopathogen Xanthomonas citri subsp. citri (Xcc), which modulates Xcc virulence by directly interacting with the methyltransferase HemK. Through yeast two-hybrid, co-immunoprecipitation and immunofluorescent staining, we demonstrated that N5MapZ and HemK interact directly under both in vitro and in vivo conditions, with the strength of the protein-protein interaction decreasing at high c-di-GMP concentrations. This finding distinguishes N5MapZ from other characterized single-domain PilZ proteins, as it was previously known that c-di-GMP enhances the interaction between those single-domain PilZs and their protein partners. This observation is further supported by the fact that the c-di-GMP binding-defective mutant N5MapZR10A can interact with HemK to inhibit the methylation of the class 1 translation termination release factor PrfA. Additionally, we found that HemK plays an important role in Xcc pathogenesis, as the deletion of hemK leads to extensive phenotypic changes, including reduced virulence in citrus plants, decreased motility, production of extracellular enzymes and stress tolerance. Gene expression analysis has revealed that c-di-GMP and the HemK-mediated pathway regulate the expression of multiple virulence effector proteins, uncovering a novel regulatory mechanism through which c-di-GMP regulates Xcc virulence by mediating PrfA methylation via the single-domain PilZ adaptor protein N5MapZ.

ER and SOCE Ca2+ signals are not required for directed cell migration in human iPSC-derived microglia.

The central nervous system (CNS) is constantly surveilled by microglia, highly motile and dynamic cells deputed to act as the first line of immune defense in the brain and spinal cord. Alterations in the homeostasis of the CNS are detected by microglia that respond by extending their processes or - following major injuries - by migrating toward the affected area. Understanding the mechanisms controlling directed cell migration of microglia is crucial to dissect their responses to neuroinflammation and injury. We used a combination of pharmacological and genetic approaches to explore the involvement of calcium (Ca2+) signaling in the directed migration of human induced pluripotent stem cell (iPSC)-derived microglia challenged with a purinergic stimulus. This approach mimics cues originating from injury of the CNS. Unexpectedly, simultaneous imaging of microglia migration and intracellular Ca2+ changes revealed that this phenomenon does not require Ca2+ signals generated from the endoplasmic reticulum (ER) and store-operated Ca2+ entry (SOCE) pathways. Instead, we find evidence that human microglial chemotaxis to purinergic signals is mediated by cyclic AMP in a Ca2+-independent manner. These results challenge prevailing notions, with important implications in neurological conditions characterized by perturbation in Ca2+ homeostasis.

Influence of Age, Obesity, Smoking, Sleep duration, and Sleep Quality on Concentration, Morphology, and Sperm Motility: A Cross-Sectional Study.

BACKGROUND: Age, smoking, sleep duration, sleep quality, and obesity are risk factors that can affect the amount of sperm concentration, morphology, and motility. The aim of this study is to assess the lifestyle effects: of age, smoking, sleep duration, sleep quality, and obesity on the amount of concentration, morphology, and motility of sperm. MATERIALS AND METHODS: The study utilized an analytical observational approach with a cross-sectional design. The study subjects comprised 70 male partners of infertile couples admitted to the Sekar Fertility Clinic at the Dr. Moewardi General Hospital between March and August 2022. The study assessed variables including age, body mass index (BMI), smoking status, sleep duration, sleep quality, sperm concentration, sperm morphology, and sperm motility. Furthermore, the data were analyzed using univariate, bivariate, and multivariate methods with SPSS 25 software. RESULTS: The research findings demonstrate that obesity is significantly associated with abnormal sperm concentration [odds ratio (OR)=40.07, confidence interval (CI)=3.90-411.67, P=0.002]. Furthermore, moderate or heavy smoking is significantly associated with abnormal sperm concentration (OR=17.45, CI=1.83-166.15, P=0.013) and sleep quality with severe disorders (OR=5.73, CI=1.12-29.21, P=0.036). Moreover, obesity is significantly associated with abnormal sperm motility (OR=12.97, CI=2.66-63.15, P=0.002), while moderate or heavy smoking (OR=5.89, CI=1.23- 28.20, P=0.026) and poor sleep duration (OR=6.21, CI=1.43-26.92, P=0.015) also exhibit significant associations with abnormal sperm motility. However, no significant findings were observed regarding sperm morphology. CONCLUSION: The findings of this study indicate that obesity, moderate or heavy smoking, and sleep quality have statistically significant effects on sperm concentration, while obesity, moderate or heavy smoking, and sleep duration have statistically significant effects on sperm motility. However, no statistically significant influence was observed on sperm morphology. Further research with larger sample sizes and more diverse populations is needed to validate these findings and explore other potential factors that may impact male fertility.

Brown Seaweed Byproduct Extracts Improve Intestinal Motility and Auto-Inflammation in Mice with Loperamide-Induced Constipation.

Sargassum fusiforme and Sargassum fulvellum are types of brown algae used for their nutritional value and medicinal properties, including anti-inflammatory, antioxidant, and anticancer effects. Despite their importance in various industries, many seaweed byproducts containing dietary fiber and polysaccharides are discarded in landfills. These byproducts can be recycled and repurposed for different applications. In this study, we investigated the impact of S. fusiforme food processing byproducts (MbP-SFF) and S. fulvellum food processing byproducts (MbP-SFV) on improving intestinal motility and reducing inflammation in mice with constipation induced by loperamide. To evaluate this, mice were orally administered 500 mg/kg/day of the byproducts once daily for 8 days. Constipation was induced by 5 mg/kg/day of loperamide for two days after oral administration for 6 days. Each sample contained approximately 70% carbohydrates. MbP-SFF had 52.0% mannuronic acid and 18.8% guluronic acid, while MbP-SFV had 36.9% mannuronic acid and 32.9% guluronic acid. These byproducts enhanced fecal excretion and intestinal motility by modulating inflammatory responses. Furthermore, they restored the balance of the gut microbiota disrupted by loperamide, increasing beneficial Bifidobacterium and reducing harmful Staphylococcus aureus. Overall, MbP-SFF and MbP-SFV improved intestinal motility and inflammation by influencing the gut microbiota and inflammatory responses in a loperamide-induced mouse model. These byproducts show potential as ingredients in functional foods aimed at enhancing gut health, potentially reducing waste disposal costs and addressing environmental concerns associated with their utilization.

Cpne1 deficiency preserves sperm motility under Ca2+ channel blockade.

Calcium ions (Ca2+) play crucial roles in sperm motility and fertilization. The copine (CPNE) family comprises several Ca2+-dependent phospholipid-binding proteins. Of these, CPNE1 is extensively expressed in mammalian tissues; however, its precise role in testicular development and spermatogenesis is yet to be fully characterized. In this study, we used proteomics to analyze testicular biopsies and found that levels of CPNE1 were significantly reduced in patients with non-obstructive azoospermia (defective spermatogenesis) compared to those in patients with obstructive azoospermia (physiological spermatogenesis). In mice, CPNE1 is expressed at various stages of germ cell development and is associated with the Golgi apparatus. Ultimately, CPNE1 is expressed in the flagella of mature sperms. To further examine the role of CPNE1, we developed a Cpne1 knockout mouse model. Analysis showed that the loss of Cpne1 did not impair testicular development, spermatogenesis, or sperm morphology and motility in physiological conditions. When treated with gadolinium (III) chloride or 2-aminoethoxydiphenyl borate, known inhibitors of store-operated Ca2+ entry, Ca2+ signals and sperm motility were significantly compromised in wild-type mice; however, both mechanisms were conserved in KO mice. These results suggested that CPNE1 is dispensable for testicular development, spermatogenesis or sperm motility in physiological conditions. In addition, CPNE1 may represent a target of Ca2+ channel inhibitors and may therefore be implicated in the regulation of Ca2+ signaling and sperm motility.

Compressed intracellular motility via non-uniform temporal sampling in dynamic optical coherence tomography.

Significance: Optical coherence tomography has great utility for capturing dynamic processes, but such applications are particularly data-intensive. Samples such as biological tissues exhibit temporal features at varying time scales, which makes data reduction challenging. Aim: We propose a method for capturing short- and long-term correlations of a sample in a compressed way using non-uniform temporal sampling to reduce scan time and memory overhead. Approach: The proposed method separates the relative contributions of white noise, fluctuating features, and stationary features. The method is demonstrated on mammary epithelial cell spheroids in three-dimensional culture for capturing intracellular motility without loss of signal integrity. Results: Results show that the spatial patterns of motility are preserved and that hypothesis tests of spheroids treated with blebbistatin, a motor protein inhibitor, are unchanged with up to eightfold compression. Conclusions: The ability to measure short- and long-term correlations compressively will enable new applications in (3+1)D imaging and high-throughput screening.

Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.

BACKGROUND & AIMS: Restricted gastric motor functions contribute to aging-associated under-nutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC, gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC. METHODS: klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg i.p. BID for 3 weeks). Gastric ICC were analyzed by western blotting (WB) and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line. RESULTS: In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC. CONCLUSIONS: Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.

Filopodia: integrating cellular functions with theoretical models.

Filopodia, widely distributed on cell surfaces, are distinguished by their dynamic extensions, playing pivotal roles in a myriad of biological processes. Their functions span from mechanosensing and guidance to cell-cell communication during cellular organization in the early embryo. Filopodia have significant roles in pathogenic processes, such as cancer invasion and viral dissemination. Molecular mapping of the filopodome has revealed generic components essential for filopodia functions. In parallel, recent insights into biophysical mechanisms governing filopodia dynamics have provided the foundation for broader investigations of filopodia's biological functions. We highlight recent discoveries of engagement of filopodia in various stages of development and pathogenesis and present an overview of intricate molecular and physical features of these cellular structures across a spectrum of cellular activities.

Aqp4a and Trpv4 mediate regulatory cell volume increase for swimming maintenance of marine fish spermatozoa.

Volume regulation is essential for cell homeostasis and physiological function. Amongst the sensory molecules that have been associated with volume regulation is the transient receptor potential vanilloid 4 (TRPV4), which is a non-selective cation channel that in conjunction with aquaporins, typically controls regulatory volume decrease (RVD). Here we show that the interaction between orthologous AQP4 (Aqp4a) and TRPV4 (Trpv4) is important for regulatory volume increase (RVI) in post-activated marine fish spermatozoa under high osmotic stress. Based upon electrophysiological, volumetric, and in vivo and ex vivo functional experiments using the pharmacological and immunological inhibition of Aqp4a and Trpv4 our model suggests that upon ejaculation and exposure to the hypertonic seawater, spermatozoon shrinkage is initially mediated by water efflux through Aqp1aa in the flagellar tail. The shrinkage results in an increase in intracellular Ca2+ concentration, and the activation of sperm motility and a Na+/K+/2Cl- (NKCC1) cotransporter. The activity of NKCC1 is required for the initiation of cell swelling, which secondarily activates the Aqp4a-Trpv4 complex to facilitate the influx of water via Aqp4a-M43 and Ca2+ via Trpv4 and L-type channels for the mediation of RVI. The inhibitory experiments show that blocking of each of these events prevents either shrinkage or RVI. Our data thus reveal that post-activated marine fish spermatozoa are capable of initiating RVI under a high hypertonic stress, which is essential for the maintenance of sperm motility.

Mucin-induced surface dispersal of Staphylococcus aureus and Staphylococcus epidermidis via quorum-sensing dependent and independent mechanisms.

Nasopharyngeal carriage of staphylococci spreads potentially pathogenic strains into (peri)oral regions and increases the chance of cross-infections. Some laboratory strains can also move rapidly on hydrated agar surfaces, but the biological relevance of these observations is not clear. Using soft-agar [0.3% (wt/vol)] plate assays, we demonstrate the rapid surface dispersal of (peri)oral isolates of Staphylococcus aureus and Staphylococcus epidermidis and closely related laboratory strains in the presence of mucin glycoproteins. Mucin-induced dispersal was a stepwise process initiated by the passive spreading of the growing colonies followed by their rapid branching (dendrites) from the colony edge. Although most spreading strains used mucin as a growth substrate, dispersal was primarily dependent on the lubricating and hydrating properties of the mucins. Using S. aureus JE2 as a genetically tractable representative, we demonstrate that mucin-induced dendritic dispersal, but not colony spreading, is facilitated by the secretion of surfactant-active phenol-soluble modulins (PSMs) in a process regulated by the agr quorum-sensing system. Furthermore, the dendritic dispersal of S. aureus JE2 colonies was further stimulated in the presence of surfactant-active supernatants recovered from the most robust (peri)oral spreaders of S. aureus and S. epidermidis. These findings suggest complementary roles for lubricating mucins and staphylococcal PSMs in the active dispersal of potentially pathogenic strains from perioral to respiratory mucosae, where gel-forming, hydrating mucins abound. They also highlight the impact that interspecies interactions have on the co-dispersal of S. aureus with other perioral bacteria, heightening the risk of polymicrobial infections and the severity of the clinical outcomes. IMPORTANCE: Despite lacking classical motility machinery, nasopharyngeal staphylococci spread rapidly in (peri)oral and respiratory mucosa and cause cross-infections. We describe laboratory conditions for the reproducible study of staphylococcal dispersal on mucosa-like surfaces and the identification of two dispersal stages (colony spreading and dendritic expansion) stimulated by mucin glycoproteins. The mucin type mattered as dispersal required the surfactant activity and hydration provided by some mucin glycoproteins. While colony spreading was a passive mode of dispersal lubricated by the mucins, the more rapid and invasive form of dendritic expansion of Staphylococcus aureus and Staphylococcus epidermidis required additional lubrication by surfactant-active peptides (phenol-soluble modulins) secreted at high cell densities through quorum sensing. These results highlight a hitherto unknown role for gel-forming mucins in the dispersal of staphylococcal strains associated with cross-infections and point at perioral regions as overlooked sources of carriage and infection by staphylococci.

[Click phenomenon in acquired Jaensch-Brown syndrome and trigger finger/thumb: the Notta syndrome]. / "Klick"-Phänomen beim erworbenen Jaensch-Brown-Syndrom und schnellenden Finger/Daumen: dem Notta-Syndrom.

CLINICAL FEATURES: The click phenomenon occurs when an acquired mechanical restriction of the elevation in adduction of the eye or of the extension of the finger/thumb, is forcefully overcome. The common cause is a nodule either of the superior oblique tendon posterior to the trochlea in the case of a Jaensch-Brown syndrome or of the digital flexor tendon anterior to the A1 annular pulley in the case of a trigger finger. Both locations share similar anatomical conditions for the development of the nodule and the pathomechanism of the click. RESULTS: From these identical findings in the eye and the hand in small children it can be assumed that the results from the studies of the hand in newborns and infants with a trigger thumb/finger are also applicable to the situation of the eye. 1. This motility disorder is not congenital. This is most likely due to an incomplete development at the time of birth of the sliding factors needed for a free passage of the tendon through the trochlea and the A1 annular pulley. 2. A distinction must be made between stages 0-3: stage 0 = no more restriction of the motility and no click phenomenon; stage 1 = forced active extension/elevation possible; stage 2 = only passive extension/elevation, each with a click phenomenon; stage 3 = no extension/elevation possible and no click phenomenon. 3. In most cases in early childhood there is a spontaneous complete recovery (75% after 6-7 years). In the eye this spontaneous course can only limitedly be shortened with motility exercises in combination with segmental occlusion. CONCLUSION: The click phenomenon is a symptom of stages 1 and 2 of an acquired mechanical restriction of the elevation in adduction of the eye or the extension of the finger/thumb. It should not be called a syndrome.

Impact of Esophageal Motility on Microbiome Alterations in Symptomatic Gastroesophageal Reflux Disease Patients With Negative Endoscopy: Exploring the Role of Ineffective Esophageal Motility and Contraction Reserve.

Background/Aims: Ineffective esophageal motility (IEM) is common in patients with gastroesophageal reflux disease (GERD) and can be associated with poor esophageal contraction reserve on multiple rapid swallows. Alterations in the esophageal microbiome have been reported in GERD, but the relationship to presence or absence of contraction reserve in IEM patients has not been evaluated. We aim to investigate whether contraction reserve influences esophageal microbiome alterations in patients with GERD and IEM. Methods: We prospectively enrolled GERD patients with normal endoscopy and evaluated esophageal motility and contraction reserve with multiple rapid swallows during high-resolution manometry. The esophageal mucosa was biopsied for DNA extraction and 16S ribosomal RNA gene V3-V4 (Illumina)/full-length (Pacbio) amplicon sequencing analysis. Results: Among the 56 recruited patients, 20 had normal motility (NM), 19 had IEM with contraction reserve (IEM-R), and 17 had IEM without contraction reserve (IEM-NR). Esophageal microbiome analysis showed a significant decrease in microbial richness in patients with IEM-NR when compared to NM. The beta diversity revealed different microbiome profiles between patients with NM or IEM-R and IEM-NR (P = 0.037). Several esophageal bacterial taxa were characteristic in patients with IEM-NR, including reduced Prevotella spp. and Veillonella dispar, and enriched Fusobacterium nucleatum. In a microbiome-based random forest model for predicting IEM-NR, an area under the receiver operating characteristic curve of 0.81 was yielded. Conclusions: In symptomatic GERD patients with normal endoscopic findings, the esophageal microbiome differs based on contraction reserve among IEM. Absent contraction reserve appears to alter the physiology and microbiota of the esophagus.