Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Ingesting yeast extract causes excitation of neurogenic and myogenic colonic motor patterns in the rat.

Fermented foods play a significant role in the human diet for their natural, highly nutritious and healthy attributes. Our aim was to study the effect of yeast extract, a fermented substance extracted from natural yeast, on colonic motility to better understand its potential therapeutic role. A yeast extract was given to rats by gavage for 3 days, and myogenic and neurogenic components of colonic motility were studied using spatiotemporal maps made from video recordings of the whole colon ex vivo. A control group received saline gavages. The yeast extract caused excitation of the musculature by increasing the propagation length and duration of long-distance contractions, the major propulsive activity of the rat colon. The yeast extract also evoked rhythmic propulsive motor complexes (RPMCs) which were antegrade in the proximal and mid-colon and retrograde in the distal colon. RPMC activity was evoked by distention-induced neural activity, but it was myogenic in nature since we showed it to be generated by bethanechol in the presence of tetrodotoxin. In conclusion, ingestion of yeast extract stimulates rat colon motility by exciting neurogenic and myogenic control mechanisms.

Novel insights into physiological mechanisms underlying fecal continence.

The machinery maintaining fecal continence prevents involuntary loss of stool and is based on the synchronized interplay of multiple voluntary and involuntary mechanisms, dependent on cooperation between motor responses of the musculature of the colon, pelvic floor, and anorectum, and sensory and motor neural pathways. Knowledge of the physiology of fecal continence is key toward understanding the pathophysiology of fecal incontinence. The idea that involuntary contraction of the internal anal sphincter is the primary mechanism of continence and that the external anal sphincter supports continence only by voluntary contraction is outdated. Other mechanisms have come to the forefront, and they have significantly changed viewpoints on the mechanisms of continence and incontinence. For instance, involuntary contractions of the external anal sphincter, the puborectal muscle, and the sphincter of O'Beirne have been proven to play a role in fecal continence. Also, retrograde propagating cyclic motor patterns in the sigmoid and rectum promote retrograde transit to prevent the continuous flow of content into the anal canal. With this review, we aim to give an overview of primary and secondary mechanisms controlling fecal continence and evaluate the strength of evidence.

Haustral rhythmic motor patterns of the human large bowel revealed by ultrasound.

Effective and widely available strategies are needed to diagnose colonic motility dysfunction. We investigated whether ultrasonography could generate spatiotemporal maps combined with motor pattern frequency analysis, to become a noninvasive method to characterize human colon motor patterns. Abdominal colonic ultrasonography was performed on healthy subjects (N = 7), focusing on the detailed recording of spontaneous haustral activities. We developed image segmentation and frequency analysis software to analyze the motor patterns captured. Ultrasonography recordings of the ascending, transverse, and descending colon identified three distinct rhythmic motor patterns: the 1 cycle/min and the 3 cycles/min cyclic motor pattern were seen throughout the whole colon, whereas the 12 cycles/min cyclic motor pattern was identified in the ascending colon. The rhythmic motor patterns of the human colon that are associated with interstitial cells of Cajal-associated pacemaking activity can be accurately identified and quantified using ultrasound.NEW & NOTEWORTHY Ultrasonography in the clinical field is an underutilized tool for assessing colonic motility; however, with the addition of frequency analysis techniques, it provides a method to identify human colonic motor patterns. Here we report on the 1, 3, and 12 cpm rhythmic motor patterns. Ultrasound has the potential to become a bedside assessment for colonic dysmotility and may reveal the health of interstitial cells of Cajal (ICC) pacemaker activities.

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. RESULTS: A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. CONCLUSIONS: Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

Root mean square of successive differences is not a valid measure of parasympathetic reactivity during slow deep breathing.

Deep breathing exercises are the second most used complementary health approach in the United States. Two heart rate variability (HRV) parameters, the root mean square of successive differences (RMSSD) and the respiratory sinus arrhythmia (RSA), are used to assess parasympathetic reactivity to deep breathing, but they are often not in agreement. Our purpose was to determine the cause of the disagreement. We investigated HRV parameters in 38 subjects during baseline, deep breathing, and recovery. Here we show that RMSSD as a measure of parasympathetic reactivity is unreliable; it does not reflect the increase in HRV during deep breathing as determined by RSA. We observed a decrease in RMSSD values despite a marked increase in HRV as determined by RSA and the standard deviation of normal heartbeat interval (SDNN) in healthy subjects and patients with functional bowel disorders. We show that RSA captures all aspects of HRV, whereas successive differences in heart rate intervals are only a small part of HRV, with decreasing variability during deep breathing in most subjects. We present a new measure of calculating RSA during deep breathing that may become an essential tool for researchers and clinicians. We also provide a unique visualization of the increased heart rate variability during deep breathing. Hence, RMSSD cannot be used to assess parasympathetic reactivity during deep breathing; using RSA is recommended. The use of RMSSD in previous influential studies may have led to erroneous conclusions about parasympathetic reactivity during deep breathing. Its continued use may undervalue the effects of the autonomic nervous system in slow deep breathing.

From Black Boxes to Actionable Insights: A Perspective on Explainable Artificial Intelligence for Scientific Discovery.

The application of Explainable Artificial Intelligence (XAI) in the field of chemistry has garnered growing interest for its potential to justify the prediction of black-box machine learning models and provide actionable insights. We first survey a range of XAI techniques adapted for chemical applications and categorize them based on the technical details of each methodology. We then present a few case studies to illustrate the practical utility of XAI, such as identifying carcinogenic molecules and guiding molecular optimizations, in order to provide chemists with concrete examples of ways to take full advantage of XAI-augmented machine learning for chemistry. Despite the initial success of XAI in chemistry, we still face the challenges of developing more reliable explanations, assuring robustness against adversarial actions, and customizing the explanation for different applications and needs of the diverse scientific community. Finally, we discuss the emerging role of large language models like GPT in generating natural language explanations and discusses the specific challenges associated with them. We advocate that addressing the aforementioned challenges and actively embracing new techniques may contribute to establishing machine learning as an indispensable technique for chemistry in this digital era.

Protease-Activated Receptor-2 and Phospholipid Metabolism Analysis in Hyperuricemia-Induced Renal Injury.

Interstitial inflammation is an important mechanism of pathological damage in renal injury caused by hyperuricemia. Protease-activated receptor-2 (PAR2) is a class of targets that act upstream of the PI3K/AKT/NF-κB pathway and is involved in various inflammatory diseases. We induced a hyperuricemia model in rats by adenine and ethambutol gavage in an in vivo experiment. We demonstrated that PAR2 and PI3K/AKT/NF-κB pathway expression were significantly upregulated in renal tissues, with massive inflammatory cell infiltration in the renal interstitium and renal tissue injury. Treating hyperuricemic rats with AZ3451, a selective metabotropic antagonist of PAR2, we demonstrated that PAR2 antagonism inhibited the PI3K/AKT/NF-κB pathway and attenuated tubular dilation and tubulointerstitial inflammatory cell infiltration. The phospholipid metabolism profiles provided a perfect separation between the normal and hyperuricemic rats. In addition, we also found that AZ3451 can affect phospholipid metabolism. Our work suggests that PAR2 may mediate hyperuricemia-mediated renal injury by activating the PI3K/AKT/NF-κB pathway. The PAR2 antagonist AZ3451 may be a promising therapeutic strategy for hyperuricemia-induced inflammatory responses.

Ultra-sensitive electrochemiluminescent biosensor for miRNA based on CRISPR/Cas13a trans-cleavage-triggered hybridization chain reaction and magnetic-assisted enrichment.

The great selectivity and trans-cleavage activity of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas13a had been coupled with high amplification efficiency of hybridization chain reaction (HCR) and magnetic-assisted enrichment, high sensitivity of electrochemiluminescence (ECL) detection to develop an ultra-sensitive biosensor for microRNA-21 (miRNA-21). The CRISPR/Cas13a was used to recognize target RNA with high specificity and performed the trans-cleavage activity. An initiation strand was generated to bind to the probe on the surface of nanomagnetic beads and then trigged HCR to produce long double-strand DNAs (dsDNAs) to realize signal amplification. Ru(phen)32+ can be inserted in the groove of the dsDNAs and acts as the ECL indicator, which can be separated through magnetic enrichment and allowed the platform to reduce the signal background. Under the optimized conditions, there is a good linear correlation between the ECL intensity and the logarithm of miRNA-21 concentration in the range 1 fM-10 nM; the limit of detection (LOD) was 0.53 fM. The proposed system was applied to detect miRNA-21 from the urine of acute kidney injury (AKI) patients with good results.

Spatiotemporal heterogeneity of the relationships between PM2.5 concentrations and their drivers in China's coastal ports.

PM2.5 is one of the primary air pollutants that affect air quality and threat human health in the port areas. To prevent and control air pollution, it is essential to understand the spatiotemporal distributions of PM2.5 concentrations and their key drivers in ports. 19 coastal ports of China are selected to examine the spatiotemporal distributions of PM2.5 concentrations during 2013-2020. The annual average PM2.5 concentration decreases from 61.03 µg/m3 to 30.17 µg/m3, with an average decrease rate of 51.57%. Significant spatial autocorrelation exists among PM2.5 concentrations of ports. The result of the geographically and temporally weighted regression (GTWR) model shows significant spatiotemporal heterogeneity in the effects of meteorological and socioeconomic factors on PM2.5 concentrations. The effects of boundary layer height on PM2.5 concentrations are found to be negative in most ports, with a stronger effect found in the Pearl River Delta, Yangtze River Delta and some ports of the Bohai Rim Area. The total precipitation shows negative effects on PM2.5 concentrations, with the strongest effect found in ports of the Southeast Coast. The effects of surface pressure on PM2.5 concentrations are positive, with stronger effects found in Beibu Gulf Port and Zhanjiang Port. The effects of wind speed on PM2.5 concentrations generally increase from south to north. Cargo throughput shows strong and positive effects on PM2.5 concentrations in ports of Bohai Rim Area; the positive effects found in Beibu Gulf Port increased from 2013 to 2018 and decreased since 2019. The positive effects of GDP and nighttime light on PM2.5 concentrations gradually decrease and turn negative from south to north. Understandings obtained from this study can potentially support the prevention and control of air pollution in China's coastal ports.

International crew changes amid global pandemic outbreaks: Key issues and system innovations.

The outbreak of COVID-19 pandemic all over the world has seriously affected seafarers' work and life. In this paper, we focus on the countermeasures of major countries and organizations on the seafarer shift matter during the pandemic period. And the target of this paper is to become useful in promoting the shift change of seafarers more smoothly. Policies are identified on the basis of a systematic review of importance in combination with a detailed analysis of the primary global and national policy initiatives. Findings suggest that the root cause of the international crew change crisis lies in the issues and deficiencies in the crew change system, economic security, seafarers' welfare, and seafarers' social security among other aspects. On this basis, this paper gives feasible suggestions in the respects of system innovation, economic security and welfare, social security system innovation and technical innovation.

Generation of Gut Motor Patterns Through Interactions Between Interstitial Cells of Cajal and the Intrinsic and Extrinsic Autonomic Nervous Systems.

The musculature of the gastrointestinal tract is a vast network of collaborating excitable cell types. Embedded throughout are the interstitial cells of Cajal (ICC) intertwined with enteric nerves. ICC sense external stimuli such as distention, mediate nerve impulses to smooth muscle cells, and provide rhythmic excitation of the musculature. Neural circuitry involving both the intrinsic and extrinsic autonomic nervous systems, in collaboration with the ICC, orchestrate an array of motor patterns that serve to provide mixing of content to optimize digestion and absorption, microbiome homeostasis, storage, transit, and expulsion. ICC are specialized smooth muscle cells that generate rhythmic depolarization to the musculature and so provide the means for peristaltic and segmenting contractions. Some motor patterns are purely myogenic, but a neural stimulus initiates most, further depolarizing the primary pacemaker cells and the musculature and/or initiating transient pacemaker activity in stimulus-dependent secondary ICC pacemaker cells. From stomach to rectum, ICC networks rhythmically provide tracks along which contractions advance.

Cruise tourism in the context of COVID-19: Dilemmas and solutions.

COVID-19 cases on international cruise ships have attracted extensive attention from the international community as well as the world's tourism and shipping industry. This virus highlighted the plight that must be faced by cruise ships in complicated times and situations such as pandemics. The comparative method is adopted to analyze the management measures taken by the "Diamond Princess", "Costa Serena", "Westerdam" and "Grand Princess" cruises in response to the COVID-19 pandemic and then to summarize the common dilemmas faced by these cruise ships, including defects of their internal environment, unclear health-care obligations during an epidemic, weak collaboration between the parties involved and their limited performance, and widespread infodemic and unfavorable public opinion. Given these dilemmas, measures are suggested to deal with the "cruise dilemma", including establishing and defining isolation standards on boards, enhancing the capacity of international organizations, the international community's joint response to the pandemic, promoting cooperation between countries, building an effective mechanism for the broad participation of the whole society, and standardizing the release of information and reasonably guiding public social opinion.

Appeal of word of mouth: Influences of public opinions and sentiment on ports in corporate choice of import and export trade in the post-COVID-19 era.

With the advent of the post-COVID-19 era, corporate managers of import and export trade are now more sensitive in their daily work, and their decisions are more likely to be influenced by the emotional bias of public opinions, especially regarding cooperation with trade ports of frequent circulation. Therefore, how to manage public opinion and sentiment in the post-COVID-19 era will be a new opportunity and challenge for the marketing management of ports. For the above considerations, through the same frequency verification between public opinions and sentiment on ports and corporate choice of import and export trade, and through analysis of the influence mechanism, the present study demonstrates the positive effects of public opinions and sentiment on ports in corporate choice of import and export trade in the post-COVID-19 era, verifies the significance of shaping word of mouth in port management, puts forward the great role of public opinions and sentiment in the cognitive and emotional empathy in the choice of import and export trade, and provides theoretical guidance for port managers' strategic choices in the post-COVID-19 era.

Interstitial cells of Cajal and human colon motility in health and disease.

Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.

Characterization of haustral activity in the human colon.

Contraction patterns of the human colon are rarely discussed from the perspective of its haustra. Colonic motility was analyzed in 21 healthy subjects using 84-sensor manometry catheters with 1-cm sensor spacing. Capsule endoscopy and manometry showed evidence of narrow rhythmic circular muscle contractions. X-ray images of haustra and sensor locations allowed us to identify manometry motor activity as intrahaustral activity. Two common motor patterns were observed that we infer to be associated with individual haustra: rhythmic pressure activity confined to a single sensor, and activity confined to a section of the colon of 3-6 cm length. Intrahaustral activity was observed by 3-4 sensors. Approximately 50% of the haustra were intermittently active for ∼30% of the time; 2,402 periods of haustral activity were analyzed. Intrahaustral activity showed rhythmic pressure waves, propagating in mixed direction, 5-30 mmHg in amplitude at a frequency of ∼3 cpm (range 2-6) or ∼12 cpm (range 7-15), or exhibiting a checkerboard segmentation pattern. Boundaries of the haustra showed rhythmic pressure activity with or without elevated baseline pressure. Active haustra often showed no boundary activity probably allowing transit to neighboring haustra. Haustral boundaries were seen at the same sensor for the 6- to 8-h study duration, indicating that they did not propagate, thereby likely contributing to continence. The present study elucidates the motility characteristics of haustral boundaries and the nature of intrahaustral motor patterns and paves the way for investigating their possible role in pathophysiology of defecation disorders.NEW & NOTEWORTHY Here, we present the first full characterization and quantification of motor patterns that we infer to be confined to single haustra, both intrahaustral activity and haustral boundary activity, in the human colon using high-resolution manometry. Haustral activity is intermittent but consistently present in about half of the haustra. Intrahaustral activity presents as a cyclic motor pattern of mixed propagation direction dominated by simultaneous pressure waves that can resolve into checkerboard segmentation, allowing for mixing, absorption, and stool formation.

Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.

BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

The Sphincter of O'Beirne - Part 1: Study of 18 Normal Subjects.

BACKGROUND: Gastroenterologists have ignored or emphasized the importance of the rectosigmoid junction in continence or constipation on and off for 200 years. Here, we revisit its significance using high-resolution colonic manometry. METHODS: Manometry, using an 84-channel water-perfused catheter, was performed in 18 healthy volunteers. RESULTS: The rectosigmoid junction registers as an intermittent pressure band of 26.2 ± 7.2 mmHg, or intermittent phasic transient pressure increases at a dominant frequency of 3 cpm and an amplitude of 28.6 ± 8.6 mmHg; or a combination of tone and transient pressures, at a single sensor, 10-17 cm above the anal verge. Features are its relaxation or contraction in concert with relaxation or contraction of the anal sphincters when a motor pattern such as a high-amplitude propagating pressure wave or a simultaneous pressure wave comes down, indicating that such pressure increases or decreases at the rectosigmoid junction are part of neurally driven programs. We show that the junction is a site where motor patterns end, or where they start; e.g. retrogradely propagating cyclic motor patterns emerge from the junction. CONCLUSIONS: The rectosigmoid junction is a functional sphincter that should be referred to as the sphincter of O'Beirne; it is part of the "braking mechanism," contributing to continence by keeping content away from the rectum. In an accompanying case report, we show that its excessive presence in a patient with severe constipation can be a primary pathophysiology.

The Sphincter of O'Beirne-Part 2: Report of a Case of Chronic Constipation with Autonomous Dyssynergia.

BACKGROUND: Chronic constipation can have one or more of many etiologies, and a diagnosis based on symptoms is not sufficient as a basis for treatment, in particular surgery. AIM: To investigate the cause of chronic constipation in a patient with complete absence of spontaneous bowel movements. METHODS: High-resolution colonic manometry was performed to assess motor functions of the colon, rectum, the sphincter of O'Beirne and the anal sphincters. RESULTS: Normal colonic motor patterns were observed, even at baseline, but a prominent high-pressure zone at the rectosigmoid junction, the sphincter of O'Beirne, was consistently present. In response to high-amplitude propagating pressure waves (HAPWs) that were not consciously perceived, the sphincter and the anal sphincters would not relax and paradoxically contract, identified as autonomous dyssynergia. Rectal bisacodyl evoked marked HAPW activity with complete relaxation of the sphincter of O'Beirne and the anal sphincters, indicating that all neural pathways to generate the coloanal reflex were intact but had low sensitivity to physiological stimuli. A retrograde propagating cyclic motor pattern initiated at the sphincter of O'Beirne, likely contributing to failure of content to move into the rectum. CONCLUSIONS: Chronic constipation without the presence of spontaneous bowel movements can be associated with normal colonic motor patterns but a highly exaggerated pressure at the rectosigmoid junction: the sphincter of O'Beirne, and failure of this sphincter and the anal sphincters to relax associated with propulsive motor patterns. The sphincter of O'Beirne can be an important part of the pathophysiology of chronic constipation.

The effect of COVID-19 pandemic on port performance: Evidence from China.

The COVID-19 outbreak has had a serious effect on the global economy, particularly the volume of port trade between imports and exports. We construct a panel regression model with month as time series where panel data from 14 major ports in China from January to October 2020 to analyze how the macro economy, the severity of the epidemic, and government control measures affect port operations. Based on the results, we have identified the key factors affecting port operations in the context of the pandemic and the managerial insights can help shipping company, port operator and government to change the strategy to copy with the effect of COVID-19 pandemic.