Clinical trial: Effects of treatment with a vibrating capsule in patients with severe chronic constipation.

BACKGROUND: There is little information on the effectiveness of therapies for severe chronic constipation. In a phase 3 trial, we previously demonstrated that a vibrating capsule was significantly more efficacious than a placebo in chronic constipation. AIM: To examine the effects of a vibrating capsule and placebo on symptoms and health-related quality of life (HRQoL) in patients with severe chronic constipation. METHODS: We performed a post hoc analysis of phase 3, multicentre, randomised, double-blind, and placebo-controlled 8-week clinical trial of a vibrating capsule to specifically assess outcomes among subjects who reported 0 complete spontaneous bowel movements (CSBMs) during the 2-week baseline period. We assessed effects of treatment on bowel symptoms, patient satisfaction, and HRQoL. CSBM responders were defined as subjects with increases of ≥1 or ≥2 or ≥3 weekly CSBMs (CSBM1 or CSBM2, CSBM3, respectively) over baseline for ≥6 out of 8 weeks of treatment. RESULTS: The severe chronic constipation subgroup comprised 175 (56%) of the 312 subjects. Significantly more subjects with severe chronic constipation who received the vibrating capsule than those who received the placebo were CSBM1 (44.9% vs. 20.9%, p = 0.007), CSBM2 (29.2% vs. 11.6%, p = 0.004), and CSBM3 (19.10% vs 6.98%, p = 0.017) responders. Straining effort, stool consistency, patient satisfaction, and HRQoL significantly improved in the severe chronic constipation subgroup. A mild vibrating sensation was reported in 10%. CONCLUSION: The vibrating capsule significantly improved constipation-related symptoms and HRQoL in patients with severe constipation, affirming its efficacy and safety across the spectrum of chronic constipation.

Review article: advances in the diagnosis and management of anorectal motility disorders.

BACKGROUND: Anorectal motility disorders such as dyssynergic defecation (DD), faecal incontinence (FI) and anorectal pain affect 40% of the population and are a frequent reason for gastroenterology consultation. They significantly affect the quality of life and lead to psychological distress. Lack of understanding of these problems compounded by a lack of availability and knowledge of diagnostic tools in most medical centres and/or trained physicians has significantly hampered this field. AIMS: To discuss the latest advances in pathophysiology, diagnostic tests and therapeutic options for these disorders using an evidence-based approach. METHODS: We reviewed the published literature over the past 20 years on DD, FI and anorectal pain and distilled these into a narrative review. RESULTS: A detailed history, prospective stool diary and digital rectal exam, together with diagnostic tests such as anorectal manometry, balloon expulsion test, translumbosacral anorectal magnetic stimulation test for assessing neuropathy, defecography and anal ultrasound, can provide detailed mechanistic and structural information. Such knowledge can pave the way for a meaningful and pathophysiologic-based management approach. This could include biofeedback therapy for DD or FI, sensory training for rectal hyposensitivity or sensory adaptation training for rectal hypersensitivity or sphincter bulking agents or neuromodulation therapies. These treatments are effective and safe. CONCLUSIONS: Anorectal motility disorders are common, but either less well recognized or poorly managed by most gastroenterologists. Equipped with the practical and up-to-date knowledge provided in this review, physicians could provide improved health care for these patients.

The role of a social determinants of health summary measure on the association between cancer history status and colorectal cancer screening utilization among screening eligible adults.

Objective: We sought to examine the influence of social needs on the relationship between cancer history and colorectal cancer (CRC) screening utilization among adults in the United States. Methods: We conducted a cross-sectional analysis using data from the 2022 Behavioral Risk Factor Surveillance System. Our outcome of interest was utilization of guideline-concordant CRC screening and exposures of interest were cancer history/levels of social needs. Multivariable logistic regression was performed to examine the association. Results: Among 74,743 eligible adults, a majority did not have a personal history of cancer (87.9 %), had at least one social need (58.4 %), and had undergone CRC screening (72.2 %). In multivariable analysis, a history of cancer was positively associated with use of CRC screening (OR = 1.59, 95 %CI, 1.35 - 1.87). Having at least one social need was associated with lower likelihood of being screened (one social need: OR = 0.85 95 %CI, 0.76 - 0.95; two + social needs: OR = 0.77, 95 % CI, 0.69 - 0.87). When exploring the effects of social needs, adults without a history of cancer who reported at least one need were 12-20 % less likely to be screened for CRC. Conclusions: A personal history of cancer was associated with greater utilization of CRC screening, whilst having at least one social need had lower screening use. Having social needs plays an important role in reducing screening uptake among adults without a history of cancer. Integrated care that considers both cancer history and social needs may have implications for improved adherence of CRC screening recommendations.

Predicting Response to Neuromodulators or Prokinetics in Patients with Suspected Gastroparesis Using Machine Learning: the "BIDnD" Model.

INTRODUCTION: Pharmacologic therapies for symptoms of gastroparesis have limited efficacy and it is difficult to predict which patients will respond. In this study, we implemented a machine-learning model to predict the response to prokinetics and/or neuromodulators in patients with gastroparesis-like symptoms. METHODS: Subjects with suspected gastroparesis underwent simultaneous gastric emptying scintigraphy (GES) and wireless motility capsule (WMC) and were followed for 6 months. Subjects were included if they were started on neuromodulators and/or prokinetics. Subjects were considered responders if their Gastroparesis Cardinal Symptom Index (GCSI) at 6 months decreased by ≥1 from baseline. A machine-learning model was trained using lasso regression, ridge regression or random forest. Five-fold cross-validation was used to train the models and the area under the receiver operator characteristic curve (AUC-ROC) was calculated using the test set. RESULTS: Of the 150 patients enrolled, 123 patients received either a prokinetic and/or a neuromodulator. Of the 123, 45 were considered responders and 78 were non-responders. A ridge regression model with the variables: BMI, Infectious prodrome, delayed GES, no diabetes (BIDnD), had the highest AUC-ROC of 0.72. The model performed well for subjects on prokinetics without neuromodulators (AUC-ROC of 0.83) but poorly for those on neuromodulators without prokinetics. A separate model with GET, duodenal MI, no diabetes, and functional dyspepsia performed better (AUC-ROC of 0.75). DISCUSSION: This machine learning model has an acceptable accuracy in predicting those who will respond to neuromodulators and/or prokinetics. If validated, our model provides valuable data in predicting treatment outcomes in patients with gastroparesis-like symptoms.

Comparison of Insulin Sensitivity in Subclinical and Overt Hypothyroidism.

OBJECTIVE: To assess the association of thyroid hormone levels with insulin sensitivity in patients with subclinical (SCH) and overt hypothyroidism (OH). MATERIALS AND METHODS: The present cross-sectional case-control study observed the association of thyroid hormone levels with insulin sensitivity in patients with SCH and OH as compared to their age-matched controls with euthyroidism (ET). Thyroid profile status, fasting blood sugar and triglyceride level, and basic anthropometric measurements were noted. Fasting insulin level (FIL) was analyzed using serum. Body mass index (BMI) and quantitative insulin sensitivity check index (QUICKI) were calculated. RESULTS: Insulin levels were found to be significantly increased (p = 0.038) in patients with SCH as well as those with OH when compared with compared with age-matched ET controls. insulin sensitivity index (ISI) was comparable among the subjects of the three groups. CONCLUSION: Subclinical hypothyroidism (SCH) and OH had high insulin levels but without statistically significant association between thyroid-stimulating hormone (TSH) levels and QUICKI.

Unraveling the cognitive implications among individuals with co-occurring chronic periodontitis and type 2 diabetes mellitus: a cross-sectional study.

OBJECTIVES: Chronic periodontitis and type 2 diabetes mellitus (T2DM) are associated with cognitive decline when examined individually. To gain deeper insight into the combined effects of these conditions on cognitive decline, the present study aimed to examine the cognitive status of individuals with co-occurring T2DM and chronic periodontitis. METHODS: We recruited 220 participants categorized into four groups: Group I, healthy subjects; Group II, individuals with chronic periodontitis; Group III, individuals with T2DM; and Group IV, individuals with both T2DM and chronic periodontitis. Medical histories were recorded for all participants, followed by periodontal examination and evaluation of cognitive status using the Montreal Cognitive Assessment (MoCA) scale. Finger dexterity was assessed using the nine-hole peg test. RESULTS: A statistically significant increase in the proportion of mild cognitive impairment (MCI) was observed between groups I and IV (p<0.001). Logistic regression analysis revealed that, among the parameters assessed in this study, the adjusted odds ratio (OR) was significant for age, finger dexterity scores, and co-occurrence of T2DM and periodontitis. CONCLUSIONS: The findings of this study suggest that the co-occurrence of chronic periodontitis and T2DM can have a detrimental effect on the cognitive abilities of an individual. Subsequent research should include longitudinal monitoring of the cognitive status in patients with concurrent conditions during treatment to gain deeper prognostic insights into the relationship between these co-occurring conditions and cognitive decline.

Capsules for the Diagnosis and Treatment of Gastrointestinal Motility Disorders- A Game Changer.

PURPOSE OF REVIEW: Over the last few decades, there have been remarkable strides in endoscopy and radiological imaging that have advanced gastroenterology. However, the management of neurogastroenterological disorders has lagged behind, in part handicapped by the use of catheter-based manometry that is both non-physiological and uncomfortable. The advent of capsule technology has been a game changer for both diagnostic and therapeutic applications. RECENT FINDINGS: Here, we discuss several capsule devices that are available or under investigation. There are three technologies that are FDA approved. Wireless motility capsule measures pH and pressure and provides clinically impactful information regarding gastric, small intestine and colonic transit, without radiation that has been demonstrated to guide management of gastroparesis, dyspepsia and constipation. Wireless ambulatory pH monitoring capsule is currently the gold standard for assessing gastroesophageal acid reflux. In the therapeutics arena, an orally ingested vibrating capsule has been recently FDA approved for the treatment of chronic constipation, supported by a robust phase 3 clinical trial which showed significant improvement in constipation symptoms and quality of life. There are several capsules currently under investigation. Smart capsule bacterial detection system and Capscan® are capsules that can sample fluid in the small or large bowel and provide microbiome analysis for detection of small intestinal bacterial (SIBO) or fungal overgrowth (SIFO). Another investigational gas sensing capsule analyzing hydrogen, CO2, volatile fatty acids and capsule orientation, can measure regional gut transit time and luminal gas concentrations and assess gastroparesis, constipation or SIBO. Therapeutically, other vibrating capsules are in development. Innovations in capsule technology are poised to transform our ability to investigate gut function physiologically, and non-invasively deliver targeted treatment(s), thereby providing both accurate diagnostic information and luminally-directed, safe therapy.

Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

BACKGROUND: Bloating is a bothersome symptom in irritable bowel syndrome with constipation (IBS-C). AIM: To evaluate plecanatide efficacy in patients with IBS-C stratified by bloating intensity. METHODS: Pooled phase 3 data (2 randomized, controlled IBS-C trials) from adults treated with plecanatide 3 mg or placebo for 12 weeks were analyzed. Patients were stratified post-hoc by baseline bloating severity (11-point scale: mild [≤ 5] and moderate-to-severe [> 5]). Assessments included change from baseline in bloating, abdominal pain, and complete spontaneous bowel movement (CSBM) frequency. Abdominal pain and bloating composite responders were defined as patients with ≥ 30% improvement from baseline in both bloating and abdominal pain at Week 12. RESULTS: At baseline, 1104/1436 patients with IBS-C (76.9%) reported moderate-to-severe bloating. In the moderate-to-severe bloating subgroup, plecanatide significantly reduced bloating severity versus placebo (least-squares mean change [LSMC]: - 1.7 vs - 1.3; P = 0.002), reduced abdominal pain (- 1.7 vs - 1.3; P = 0.006), and increased CSBM frequency (1.4 vs 0.8; P < 0.0001). In the mild bloating subgroup, significant improvements were observed with plecanatide versus placebo for abdominal pain (LSMC: - 1.3 vs - 1.0; P = 0.046) and CSBM frequency (2.0 vs 1.2; P = 0.003) but not bloating (- 0.9 vs - 0.8; P = 0.28). A significantly greater percentage of patients were abdominal pain and bloating composite responders with plecanatide versus placebo (moderate-to-severe bloating: 33.6% vs 26.8% [P = 0.02]; mild bloating: 38.4% vs 27.2% [P = 0.03]). CONCLUSION: Plecanatide treatment improved IBS-C abdominal and bowel symptoms, including in those who present with moderate-to-severe bloating.

Understanding Health Care Provider Burnout When Caring for Patients With Refractory Epilepsy in the United States.

Background and Objectives: Among health care providers (HCPs), neurologists have one of the highest rates of burnout in the United States, compromising the quality and accessibility of patient care. Patients with refractory epilepsy are especially challenging to treat. This study aims to understand the burnout level in neurologists treating patients with refractory epilepsy and identify key contributing factors. Methods: US board-certified pediatric/adult neurologists who devote ≥50% of their time to clinical practice and treat ≥10 unique patients with refractory epilepsy annually were invited to take a noninterventional quantitative survey, designed to capture key elements of the HCP's background, burnout level, current practice, burden domains, and satisfaction with current antiseizure medications (ASMs). Burnout in 3 domains (emotional exhaustion, depersonalization, and personal accomplishment) was assessed by the validated Maslach Burnout Inventory-Human Services Survey. Results: From March 11, 2022, to April 10, 2022, a total of 138 neurology-specialist HCPs participated in the survey, divided between adult epileptologists (n = 44), adult neurologists (n = 41), pediatric epileptologists (n = 36), and pediatric neurologists (n = 17). Of participating HCPs, 61% experienced at least some burnout (≥1 of 3 burnout domains categorized as high), and 4% experienced high burnout (3 of 3 burnout domains categorized as high). High burnout levels were driven by high pediatric and inpatient caseloads and unexpected pediatric patient reluctance to transition to adult care. HCPs with high burnout had a higher yearly caseload of patients with refractory epilepsy. Most HCPs (approximately 90%) indicated that patients with refractory epilepsy were more difficult to manage than those with nonrefractory epilepsy. The proportion of HCPs satisfied or extremely satisfied with ASMs was lower for patients with refractory epilepsy (20%) than that for patients with nonrefractory epilepsy (73%). Dissatisfaction was mostly due to workload and latency of the insurance approval process, out-of-pocket costs, and poor efficacy, safety, and tolerability. For 32% of HCPs, stopping practicing or moving to another practice within 5 years was probable or very probable. Discussion: Some burnout is common among HCPs who treat patients with refractory epilepsy. However, management of refractory epilepsy is challenging, and satisfaction with available ASMs is low. Thus, addressing these contributing factors may help to alleviate HCP burnout.

Prokinetics-safety and efficacy: The European Society of Neurogastroenterology and Motility/The American Neurogastroenterology and Motility Society expert review.

BACKGROUND: Prokinetics are a class of pharmacological drugs designed to improve gastrointestinal (GI) motility, either regionally or across the whole gut. Each drug has its merits and drawbacks, and based on current evidence as high-quality studies are limited, we have no clear recommendation on one class or other. However, there remains a large unmet need for both regionally selective and/or globally acting prokinetic drugs that work primarily intraluminally and are safe and without systemic side effects. PURPOSE: Here, we describe the strengths and weaknesses of six classes of prokinetic drugs, including their pharmacokinetic properties, efficacy, safety and tolerability and potential indications.

Intrinsic factors responsible for brittle versus ductile nature of refractory high-entropy alloys.

Refractory high-entropy alloys (RHEAs) are of interest for ultrahigh-temperature applications. To overcome their drawbacks - low-temperature brittleness and poor creep strength at high temperatures - improved fundamental understanding is needed. Using experiments, theory, and modeling, we investigated prototypical body-centered cubic (BCC) RHEAs, TiZrHfNbTa and VNbMoTaW. The former is compressible to 77 K, whereas the latter is not below 298 K. Hexagonal close-packed (HCP) elements in TiZrHfNbTa lower its dislocation core energy, increase lattice distortion, and lower its shear modulus relative to VNbMoTaW whose elements are all BCC. Screw dislocations dominate TiZrHfNbTa plasticity, but equal numbers of edges and screws exist in VNbTaMoW. Dislocation cores are compact in VNbTaMoW and extended in TiZrHfNbTa, and different macroscopic slip planes are activated in the two RHEAs, which we attribute to the concentration of HCP elements. Our findings demonstrate how ductility and strength can be controlled through the ratio of HCP to BCC elements in RHEAs.

Comparative profiles of lubiprostone, linaclotide, and elobixibat for chronic constipation: a systematic literature review with meta-analysis and number needed to treat/harm.

OBJECTIVE: To comprehensively evaluate the efficacy, safety, patient symptoms, and quality-of-life (QoL) of lubiprostone, linaclotide, and elobixibat as treatment for chronic constipation (CC). DESIGN: Systematic literature review (SLR) and meta-analysis (MA). Literature searches were conducted on PubMed and Embase using the Ovid platform. METHODS: SLR including randomized controlled trials (RCTs) and observational studies was conducted to identify the overall efficacy and safety of lubiprostone, linaclotide, and elobixibat. Thereafter, MA was performed using only RCTs. The number needed to treat (NNT) and number needed to harm (NNH) analyses were additionally conducted. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was efficacy regarding change in spontaneous bowel movements. Secondary outcomes included safety, constipation-related symptoms, and QoL. RESULTS: Twenty-four studies met the inclusion criteria for the SLR: 17 RCTs, 4 observational studies, and 3 single-arm trials. Feasibility assessment for the MA resulted in 14 studies available for safety data analysis, and 8 available for efficacy analysis, respectively. Three drugs showed similar efficacy in the MA and NNT analysis. However, the NNH analysis revealed distinct safety profiles: lubiprostone, linaclotide, and elobixibat were linked to the highest risk of nausea, diarrhea, and abdominal pain, respectively. CONCLUSION: The current study provides an updated overview of the efficacy, safety, patient symptoms, and QoL of the three drugs with different mechanisms of action for CC treatment.The findings could help physicians adopt an individualized approach for treating patients with CC in clinical practice.

Benefits of Prokinetics, Gastroparesis Diet, or Neuromodulators Alone or in Combination for Symptoms of Gastroparesis.

BACKGROUND & AIMS: Prokinetics have limited effectiveness for treating symptoms of gastroparesis. Thus, alternative or adjunct therapies, such as gastroparesis diets or neuromodulators, are often prescribed. Their therapeutic benefits alone or in combination remain unclear. METHODS: One hundred and twenty-nine patients with symptoms of gastroparesis underwent wireless motility capsule gastric emptying time and gastric emptying scintigraphy. Based on test results, changes in therapy were recommended. Changes in Gastroparesis Cardinal Symptom Index (GCSI) and individual symptom scores over 6 months were related to recommendations for prokinetics, gastroparesis diet, or neuromodulators given as solo new therapies or in dual combinations. Multivariate analyses were performed to adjust for gastric emptying and other variables. RESULTS: In the whole group regardless of therapy, GCSI scores decreased by 0.53 points (interquartile range, -1.25 to 0.05; P < .0001) over 6 months. GCSI did not decrease for prokinetics as solo new therapy (P = .95). Conversely, neuromodulators as solo therapy decreased GCSI scores (P = .04) and all individual symptoms except nausea/vomiting (P = .86). Prokinetics combined with gastroparesis diets or neuromodulators improved GCSI scores (P ≤ .04) and most individual symptoms. Adjusting for gastric emptying time on multivariate analyses showed greater GCSI decreases for nondelayed emptying for neuromodulators as solo new therapy (P = .01). Gastric emptying scintigraphy, gender, diabetes, and functional dyspepsia did not influence responses to any treatment. CONCLUSIONS: Initiating prokinetics as solo new therapy had little benefit for patients with symptoms of gastroparesis. Neuromodulators as the only new therapy decreased symptoms other than nausea and vomiting, especially with nondelayed gastric emptying. Adding gastroparesis diets or neuromodulators to prokinetics offered relief, suggesting that combination therapies may be more useful in managing these patients. (ClinicalTrials.gov NCT02022826.).

Pantothenate Kinase Activation Restores Brain Coenzyme A in a Mouse Model of Pantothenate Kinase-Associated Neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is characterized by a motor disorder with combinations of dystonia, parkinsonism, and spasticity, leading to premature death. PKAN is caused by mutations in the PANK2 gene that result in loss or reduction of PANK2 protein function. PANK2 is one of three kinases that initiate and regulate coenzyme A biosynthesis from vitamin B5, and the ability of BBP-671, an allosteric activator of pantothenate kinases, to enter the brain and elevate coenzyme A was investigated. The metabolic stability, protein binding, and membrane permeability of BBP-671 all suggest that it has the physical properties required to cross the blood-brain barrier. BBP-671 was detected in plasma, liver, cerebrospinal fluid, and brain following oral administration in rodents, demonstrating the ability of BBP-671 to penetrate the brain. The pharmacokinetic and pharmacodynamic properties of orally administered BBP-671 evaluated in cannulated rats showed that coenzyme A (CoA) concentrations were elevated in blood, liver, and brain. BBP-671 elevation of whole-blood acetyl-CoA served as a peripheral pharmacodynamic marker and provided a suitable method to assess target engagement. BBP-671 treatment elevated brain coenzyme A concentrations and improved movement and body weight in a PKAN mouse model. Thus, BBP-671 crosses the blood-brain barrier to correct the brain CoA deficiency in a PKAN mouse model, resulting in improved locomotion and survival and providing a preclinical foundation for the development of BBP-671 as a potential treatment of PKAN. SIGNIFICANCE STATEMENT: The blood-brain barrier represents a major hurdle for drugs targeting brain metabolism. This work describes the pharmacokinetic/pharmacodynamic properties of BBP-671, a pantothenate kinase activator. BBP-671 crosses the blood-brain barrier to correct the neuron-specific coenzyme A (CoA) deficiency and improve motor function in a mouse model of pantothenate kinase-associated neurodegeneration. The central role of CoA and acetyl-CoA in intermediary metabolism suggests that pantothenate kinase activators may be useful in modifying neurological metabolic disorders.

Accuracy of patient-reported bowel symptoms for fecal incontinence: Historical recall versus prospective evaluation.

INTRODUCTION: Fecal incontinence (FI) is characterized by both irregular and unpredictable bowel symptoms. An accurate history of symptoms is important for diagnosis and guiding management. Whether a patient's history of bowel symptoms is reliable or if there is recall bias is unknown. AIM: To evaluate the accuracy of FI symptoms based on patient's recall compared with a prospective stool diary. METHODS: FI (Rome IV) patients completed a bowel questionnaire that included leakage episodes and stool consistency. Subsequently they completed a one-week FI stool diary. Agreement and correlation between historical recall and stool diary were compared. RESULTS: One hundred patients participated. On average they reported 12 bowel movements (BMs) and five FI episodes per week. Fifty-two percent had completed under-graduation, 33% high school and 15% postgraduation. Using recall, 23% of patients accurately reported the number of FI episodes, whereas 41% underestimated and 36% overestimated its prevalence compared to the FI diary. Similarly, the concordance for the number of BMs was 30%, urgency was 54%, amount of stool leakage was 16%, and stool consistency was 12.5%. The concordance for nocturnal FI events, use of pads and lack of stool awareness were 63%, 75%, and 66.6% respectively. CONCLUSION: There is poor concordance for key bowel symptoms including the number of FI episodes as reported by FI patients, suggesting significant recall bias. Thus, historical recall of chronic FI symptoms may be less accurate. A prospective stool diary could provide more accurate information for the evaluation of FI patients.

Evaluation of bidirectional gut-brain axis and anorectal function in Parkinson's disease with constipation.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative movement disorder with prodromal and highly prevalent gastrointestinal (GI) symptoms, especially constipation. Although PD models suggest gut-brain axis dysfunction, the mechanistic underpinnings and their correlation with GI symptoms are poorly understood. AIM: To examine the bidirectional gut-brain axis function in PD and correlate it with constipation severity, PD duration, and severity. METHODS: Rectal sensory thresholds and afferent cortical evoked potentials (CEP) were assessed using a 4-ring EMG electrode probe. Efferent anal and rectal motor evoked potentials (MEPs) were obtained following transcranial and lumbosacral magnetic stimulation. Bowel symptoms were assessed by prospective stool diary. The CEP and MEP latencies, rectal sensory thresholds, and anorectal sensorimotor data were compared between PD subjects and age-adjusted healthy subjects. KEY RESULTS: Twenty-five PD subjects with constipation (F/M = 6/19) and 20 healthy subjects (F/M = 14/6) were enrolled. The first and pain sensation thresholds were higher in PD subjects than healthy subjects (p < 0.002) but lost significance after adjustment for age. Age-adjusted rectal CEP and right-sided cortico-anal MEP latencies were prolonged in PD subjects compared to healthy subjects (p < 0.04). Also, half (4 of 8) age-adjusted spino-anal and rectal MEP latencies in PD subjects were significantly longer. In multivariate linear analysis, first rectal sensation and right-sided MEP latencies showed moderate correlation with constipation severity. CONCLUSIONS & INFERENCES: Parkinson's disease is associated with significant bidirectional gut-brain axis dysfunction as evidenced by prolonged afferent and efferent neuronal signaling. Constipation severity in PD is correlated to abnormal rectal sensation and lateralized disturbance of efferent brain-gut signaling.

Radioprotective potential of probiotics against gastrointestinal and neuronal toxicity: a preclinical study

Purpose Radiotherapy is a critical component of cancer treatment, along with surgery and chemotherapy. Approximately, 90% of cancer patients undergoing pelvic radiotherapy show gastrointestinal (GI) toxicity, including bloody diarrhea, and gastritis, most of which are associated with gut dysbiosis. In addition to the direct effect of radiation on the brain, pelvic irradiation can alter the gut microbiome, leading to inflammation and breakdown of the gut–blood barrier. This allows toxins and bacteria to enter the bloodstream and reach the brain. Probiotics have been proven to prevent GI toxicity by producing short-chain fatty acids and exopolysaccharides beneficial for protecting mucosal integrity and oxidative stress reduction in the intestine and also shown to be beneficial in brain health. Microbiota plays a significant role in maintaining gut and brain health, so it is important to study whether bacterial supplementation will help in maintaining the gut and brain structure after radiation exposure. Methods In the present study, male C57BL/6 mice were divided into control, radiation, probiotics, and probiotics + radiation groups. On the 7th day, animals in the radiation and probiotics + radiation groups received a single dose of 4 Gy to whole-body. Posttreatment, mice were sacrificed, and the intestine and brain tissues were excised for histological analysis to assess GI and neuronal damage. Results Radiation-induced damage to the villi height and mucosal thickness was mitigated by the probiotic treatment significantly (p < 0.01). Further, radiation-induced pyknotic cell numbers in the DG, CA2, and CA3 areas were substantially reduced with bacterial supplementation (p < 0.001). Similarly, probiotics reduced neuronal inflammation induced by radiation in the cortex, CA2, and DG region (p < 0.01) (AU)

Pathoetiology of Levator Ani Syndrome and Its Treatment With Translumbosacral Neuromodulation Therapy.

INTRODUCTION: The pathoetiology and treatment of levator ani syndrome (LAS) remain unclear. METHODS: We evaluated pathophysiology using translumbosacral motor-evoked potentials and anorectal manometry in patients with LAS and compared with healthy controls. A cohort underwent translumbosacral neuromodulation therapy (TNT). RESULTS: Lumbar and sacral motor-evoked potential latencies were prolonged in 32 patients with LAS compared with 31 controls ( P < 0.013), with higher prevalence of anal neuropathy ( P = 0.026). TNT improved anorectal pain ( P = 0.003) and neuropathy ( P < 0.02) in 13 patients with LAS. DISCUSSION: Patients with LAS demonstrate significant lumbosacral neuropathy that may cause anorectal pain. TNT improved anorectal pain and neuropathy, providing a novel therapeutic option.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.