The dynamics of SARS-CoV-2 infectivity with changes in aerosol microenvironment.

Understanding the factors that influence the airborne survival of viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in aerosols is important for identifying routes of transmission and the value of various mitigation strategies for preventing transmission. We present measurements of the stability of SARS-CoV-2 in aerosol droplets (∼5 to 10 µm equilibrated radius) over timescales spanning 5 s to 20 min using an instrument to probe survival in a small population of droplets (typically 5 to 10) containing ∼1 virus/droplet. Measurements of airborne infectivity change are coupled with a detailed physicochemical analysis of the airborne droplets containing the virus. A decrease in infectivity to ∼10% of the starting value was observable for SARS-CoV-2 over 20 min, with a large proportion of the loss occurring within the first 5 min after aerosolization. The initial rate of infectivity loss was found to correlate with physical transformation of the equilibrating droplet; salts within the droplets crystallize at relative humidities (RHs) below 50%, leading to a near-instant loss of infectivity in 50 to 60% of the virus. However, at 90% RH, the droplet remains homogenous and aqueous, and the viral stability is sustained for the first 2 min, beyond which it decays to only 10% remaining infectious after 10 min. The loss of infectivity at high RH is consistent with an elevation in the pH of the droplets, caused by volatilization of CO2 from bicarbonate buffer within the droplet. Four different variants of SARS-CoV-2 were compared and found to have a similar degree of airborne stability at both high and low RH.

Mechanisms controlling membrane recruitment and activation of the autoinhibited SHIP1 inositol 5-phosphatase.

Signal transduction downstream of growth factor and immune receptor activation relies on the production of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P3) lipids by PI3K. Regulating the strength and duration of PI3K signaling in immune cells, Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) controls the dephosphorylation of PI(3,4,5)P3 to generate phosphatidylinositol-(3,4)-bisphosphate. Although SHIP1 has been shown to regulate neutrophil chemotaxis, B-cell signaling, and cortical oscillations in mast cells, the role that lipid and protein interactions serve in controlling SHIP1 membrane recruitment and activity remains unclear. Using single-molecule total internal reflection fluorescence microscopy, we directly visualized membrane recruitment and activation of SHIP1 on supported lipid bilayers and the cellular plasma membrane. We find that localization of the central catalytic domain of SHIP1 is insensitive to dynamic changes in PI(3,4,5)P3 and phosphatidylinositol-(3,4)-bisphosphate both in vitro and in vivo. Very transient SHIP1 membrane interactions were detected only when membranes contained a combination of phosphatidylserine and PI(3,4,5)P3 lipids. Molecular dissection reveals that SHIP1 is autoinhibited with the N-terminal Src homology 2 domain playing a critical role in suppressing phosphatase activity. Robust SHIP1 membrane localization and relief of autoinhibition can be achieved through interactions with immunoreceptor-derived phosphopeptides presented either in solution or conjugated to a membrane. Overall, this work provides new mechanistic details concerning the dynamic interplay between lipid-binding specificity, protein-protein interactions, and the activation of autoinhibited SHIP1.

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.).

An assessment of the airborne longevity of group A Streptococcus.

Group A streptococcus (GAS) infections result in more than 500 000 deaths annually. Despite mounting evidence for airborne transmission of GAS, little is known about its stability in aerosol. Measurements of GAS airborne stability were carried out using the Controlled Electrodynamic Levitation and Extraction of Bioaerosols onto a Substrate (CELEBS) instrument. CELEBS measurements with two different isolates of GAS suggest that it is aerostable, with approximately 70 % of bacteria remaining viable after 20 min of levitation at 50 % relative humidity (RH), with lower survival as RH was reduced. GAS airborne viability loss was driven primarily by desiccation and efflorescence (i.e. salt crystallization), with high pH also potentially playing a role, given reduced survival in bicarbonate containing droplet compositions. At low enough RH for efflorescence to occur, a greater proportion of organic components in the droplet appeared to protect the bacteria from efflorescence. These first insights into the aerosol stability of GAS indicate that airborne transmission of these respiratory tract bacteria may occur, and that both the composition of the droplet containing the bacteria, and the RH of the air affect the duration of bacterial survival in this environment. Future studies will explore a broader range of droplet and air compositions and include a larger selection of GAS strains.

Gastric Alimetry Expands Patient Phenotyping in Gastroduodenal Disorders Compared with Gastric Emptying Scintigraphy.

INTRODUCTION: Gastric emptying testing (GET) assesses gastric motility, however, is nonspecific and insensitive for neuromuscular disorders. Gastric Alimetry (GA) is a new medical device combining noninvasive gastric electrophysiological mapping and validated symptom profiling. This study assessed patient-specific phenotyping using GA compared with GET. METHODS: Patients with chronic gastroduodenal symptoms underwent simultaneous GET and GA, comprising a 30-minute baseline, 99m TC-labelled egg meal, and 4-hour postprandial recording. Results were referenced to normative ranges. Symptoms were profiled in the validated GA App and phenotyped using rule-based criteria based on their relationships to the meal and gastric activity: (i) sensorimotor, (ii) continuous, and (iii) other. RESULTS: Seventy-five patients were assessed, 77% female. Motility abnormality detection rates were as follows: GET 22.7% (14 delayed, 3 rapid), GA spectral analysis 33.3% (14 low rhythm stability/low amplitude, 5 high amplitude, and 6 abnormal frequency), and combined yield 42.7%. In patients with normal spectral analysis, GA symptom phenotypes included sensorimotor 17% (where symptoms strongly paired with gastric amplitude, median r = 0.61), continuous 30%, and other 53%. GA phenotypes showed superior correlations with Gastroparesis Cardinal Symptom Index, Patient Assessment of Upper Gastrointestinal Symptom Severity Index, and anxiety scales, whereas Rome IV Criteria did not correlate with psychometric scores ( P > 0.05). Delayed emptying was not predictive of specific GA phenotypes. DISCUSSION: GA improves patient phenotyping in chronic gastroduodenal disorders in the presence and absence of motility abnormalities with increased correlation with symptoms and psychometrics compared with gastric emptying status and Rome IV criteria. These findings have implications for the diagnostic profiling and personalized management of gastroduodenal disorders.

The evolution of femoral morphology in giant non-avian theropod dinosaurs.

Theropods are obligate bipedal dinosaurs that appeared 230 million years ago and are still extant as birds. Their history is characterized by extreme variations in body mass, with gigantism evolving convergently between many lineages. However, no quantification of hindlimb functional morphology has shown if these body mass increases led to similar specializations between distinct lineages. Here we studied femoral shape variation across 41 species of theropods (n= 68 specimens) using a high-density 3D geometric morphometric approach. We demonstrated that the heaviest theropods evolved wider epiphyses and a more distally located fourth trochanter, as previously demonstrated in early archosaurs, along with an upturned femoral head and a mediodistal crest that extended proximally along the shaft. Phylogenetically informed analyses highlighted that these traits evolved convergently within six major theropod lineages, regardless of their maximum body mass. Conversely, the most gracile femora were distinct from the rest of the dataset, which we interpret as a femoral specialization to "miniaturization" evolving close to Avialae (bird lineage). Our results support a gradual evolution of known "avian" features, such as the fusion between lesser and greater trochanters and a reduction of the epiphyses' offset, independently from body mass variations, which may relate to a more "avian" type of locomotion (more knee-than hip-driven). The distinction between body mass variations and a more "avian" locomotion is represented by a decoupling in the mediodistal crest morphology, whose biomechanical nature should be studied to better understand the importance of its functional role in gigantism, miniaturization and higher parasagittal abilities.

Safety and Efficacy of a Novel Miniaturized Robotic-Assisted Surgery System in Colectomy: A Prospective, Investigational Device Exemption Clinical Study Using the IDEAL Framework.

BACKGROUND: Robotics has increased rates of minimally invasive surgery, with distinct advantages over open surgery. However, current commercially available robotic platforms have device and system issues that limit robotic-assisted surgery expansion. OBJECTIVE: To demonstrate the safety and efficacy of a novel miniaturized robotic-assisted surgery device in colectomy. DESIGN: Prospective, Investigational Device Exemption clinical study following the idea, development, exploration, assessment, and long-term follow-up framework (stage 2b, exploration). SETTINGS: Three centers with high-volume robotic colorectal cases and surgeons. PATIENTS: Patients scheduled for a right or left colectomy for benign or malignant disease. INTERVENTION: Colectomy with the novel miniaturized robotic-assisted surgery device. MAIN OUTCOME MEASURES: For safety, intraoperative and device-related adverse events and 30-day morbidity. For efficacy, successful completion of predefined procedural steps without conversion. RESULTS: Thirty patients (13 women, 17 men) were analyzed. The mean age was 59.4 (SD 13.4) years. Seventy percent of patients (n = 21) were overweight/obese and 53.3% of patients (n = 16) had prior abdominal surgery. Forty percent of patients had malignant and 60% had benign disease. Cases were 15 right and 15 left colectomies. Overall operative time was a median of 146 (range, 80-309) minutes; console time was 70 (range, 34-174) minutes. There were no conversions to open surgery and no intraoperative or device-related adverse events. In 100% of patients (n = 30), the primary dissection was completed, and hemostasis was maintained with the novel miniaturized robotic-assisted surgery device. The morbidity rate was 26.7% minor and 3.3% major. The median length of stay was 2 days. There were no mortalities. LIMITATIONS: Single-arm study, short-term follow-up. CONCLUSIONS: This first clinical study of a novel miniaturized robotic-assisted surgery device along the IDEAL framework demonstrated that it was safe and effective. Given this success, further assessment and long-term follow-up of the miniaturized robotic-assisted surgery device are planned for comparative clinical and economic effectiveness in colorectal surgery. See Video Abstract . SEGURIDAD Y EFICACIA DE UN NOVEDOSO SISTEMA DE CIRUGA ASISTIDA POR ROBOT MINIATURIZADO EN COLECTOMA UN ESTUDIO CLNICO PROSPECTIVO DE INVESTIGACIN DE EXENCIN DE DISPOSITIVO QUE UTILIZA EL MARCO IDEAL: ANTECEDENTES:La robótica ha aumentado las tasas de cirugía mínimamente invasiva, con claras ventajas sobre la cirugía abierta. Sin embargo, las plataformas robóticas actualmente disponibles comercialmente tienen problemas con los dispositivos y sistemas que limitan la expansión de la cirugía asistida por robot.OBJETIVO:Demostrar la seguridad y eficacia de un novedoso dispositivo de cirugía asistida por robot miniaturizado en colectomía.DISEÑO:Estudio clínico prospectivo de investigación de exención de dispositivo siguiendo el marco IDEAL (Etapa 2b, exploración).ESCENARIO:Tres centros con cirujanos y casos colorrectales robóticos de gran volumen.PACIENTES:Pacientes programados para colectomía derecha o izquierda por enfermedad benigna o maligna.INTERVENCIÓN:Colectomía con el nuevo dispositivo de cirugía asistida por robot miniaturizado.PRINCIPALES MEDIDAS DE RESULTADO:Para la seguridad, eventos adversos intraoperatorios y relacionados con el dispositivo y morbilidad a 30 días. Para la evaluación de la eficacia, la finalización exitosa de los pasos predefinidos sin conversión.RESULTADOS:Se analizaron treinta pacientes (13 mujeres, 17 hombres). La edad media fue 59,4 (DE 13,4) años. El 70% (n=21) tenía sobrepeso/obesidad y el 53,3% (n=16) había tenido cirugía abdominal previa. El 40% tenía enfermedad maligna y el 60% benigna. Los casos fueron 15 colectomías derechas y 15 izquierdas. La mediana del tiempo operatorio general fue de 146 (rango, 80-309) minutos; 70 (rango, 34-174) minutos fue el tiempo de consola. No hubo conversiones a cirugía abierta ni eventos adversos intraoperatorios o relacionados con el dispositivo. En el 100% (n=30), se completó la disección primaria y se mantuvo la hemostasia con el novedoso dispositivo de cirugía asistida por robot miniaturizado. La tasa de morbilidad menor fue de un 26,7% y mayor un 3,3%. La mediana de estadía fue de 2 días. No hubo mortalidad.LIMITACIONES:Estudio de un solo brazo, corto plazo de seguimiento.CONCLUSIONES:Este primer estudio clínico de un novedoso dispositivo de cirugía asistida por robot miniaturizado según el marco IDEAL demostró que era seguro y eficaz. Dado este éxito, se planean evaluaciones adicionales y seguimiento a largo plazo del dispositivo de cirugía asistida por robot miniaturizado para comparar la efectividad clínica y económica en la cirugía colorrectal. (Traducción-Dr. Felipe Bellolio ).

Toward Standardized Aerovirology: A Critical Review of Existing Results and Methodologies.

Understanding the airborne survival of viruses is important for public health and epidemiological modeling and potentially to develop mitigation strategies to minimize the transmission of airborne pathogens. Laboratory experiments typically involve investigating the effects of environmental parameters on the viability or infectivity of a target airborne virus. However, conflicting results among studies are common. Herein, the results of 34 aerovirology studies were compared to identify links between environmental and compositional effects on the viability of airborne viruses. While the specific experimental apparatus was not a factor in variability between reported results, it was determined that the experimental procedure was a major factor that contributed to discrepancies in results. The most significant contributor to variability between studies was poorly defined initial viable virus concentration in the aerosol phase, causing many studies to not measure the rapid inactivation, which occurs quickly after particle generation, leading to conflicting results. Consistently, studies that measured their reference airborne viability minutes after aerosolization reported higher viability at subsequent times, which indicates that there is an initial loss of viability which is not captured in these studies. The composition of the particles which carry the viruses was also found to be important in the viability of airborne viruses; however, the mechanisms for this effect are unknown. Temperature was found to be important for aerosol-phase viability, but there is a lack of experiments that directly compare the effects of temperature in the aerosol phase and the bulk phase. There is a need for repeated measurements between different research groups under identical conditions both to assess the degree of variability between studies and also to attempt to better understand already published data. Lack of experimental standardization has hindered the ability to quantify the differences between studies, for which we provide recommendations for future studies. These recommendations are as follows: measuring the reference airborne viability using the "direct method"; use equipment which maximizes time resolution; quantify all losses appropriately; perform, at least, a 5- and 10-min sample, if possible; report clearly the composition of the virus suspension; measure the composition of the gas throughout the experiment. Implementing these recommendations will address the most significant oversights in the existing literature and produce data which can more easily be quantitatively compared.

Whole Gut Transit Scintigraphy for the Assessment of Patients with Symptoms of Chronic Constipation.

INTRODUCTION: Whole gut transit scintigraphy (WGTS) can detect delayed colonic transit (CT), different types of CT delays, and assess upper GI tract transit. AIM: To delineate the frequency of different types of CT patterns in patients with chronic constipation (CC), determine the relationship between these CT patterns and upper GI tract transit abnormalities, and assess how symptoms relate to different colonic transit patterns. METHODS: Retrospective review of patients who had WGTS for CC. Patients completed a modified PAGI-SYM questionnaire to assess symptoms. Patients ingested a standard solid (Tc-99m egg sandwich)-liquid (In-111 water) meal to assess solid meal gastric emptying (GE), liquid GE, small bowel transit (SBT), and geometric center of colonic activity at 24, 48, and 72h. RESULTS: One hundred and eighty six patients underwent WGTS. Main symptoms were constipation (41%), nausea (24%), and bloating (22%). CT assessment showed 32% of patients had normal transit, 31% colonic inertia (CI), 28% functional rectosigmoid obstruction (FRS0), and 9% generalized slow colonic transit (GSCT). GE was delayed in 36%; more commonly in CI and FRSO. SBT was delayed in 19%; more commonly in GSCT and CI. Patients with CI had less bowel movements per week whereas patients with normal CT had more bm/week. CONCLUSIONS: In this series of patients with symptomatic constipation, WGTS assessment showed delayed colonic transit in 68% of patients, with 31% having colonic inertia, 28% a functional rectosigmoid obstruction pattern, and 9% generalized delay in colonic transit. Abnormalities in GE and SBT were present in 36 and 19%. WGTS is helpful to document delayed colonic transit (CT), assess the pattern of the delay in CT, and determine if there are upper GI transit abnormalities.

Low Vitamin D Levels in Patients with Symptoms of Gastroparesis: Relationships with Nausea and Vomiting, Gastric Emptying and Gastric Myoelectrical Activity.

Patients with gastroparesis (Gp) often have diets deficient in calories, electrolytes, and vitamins. Vitamin D levels have been reported to be low in some patients with Gp but has not been systematically studied. AIMS: To determine vitamin D levels and relationships among symptoms, gastric emptying and gastric myoelectrical activity (GMA) in patients with symptoms of Gp. METHODS: 25-hydroxy-vitamin D was measured in patients at enrollment in the Gastroparesis Clinical Consortium Registry. Gastroparesis Cardinal Symptoms Index (GCSI), gastric emptying, and GMA before and after water load satiety test (WLST) were measured. GMA, expressed as percentage distribution of activity in normal and dysrhythmic ranges, was recorded using electrogastrography. RESULTS: Overall, vitamin D levels were low (< 30 ng/ml) in 288 of 513 (56.1%) patients with symptoms of Gp (206 of 376 (54.8%) patients with delayed gastric emptying (Gp) and 82 of 137 (59.9%) patients with symptoms of Gp and normal gastric emptying). Low vitamin D levels were associated with increased nausea and vomiting (P < 0.0001), but not with fullness or bloating subscores. Low vitamin D levels in patients with Gp were associated with greater meal retention at four hours (36% retention) compared with Gp patients with normal vitamin D levels (31% retention; P = 0.05). Low vitamin D in patients with normal gastric emptying was associated with decreased normal 3 cpm GMA before (P = 0.001) and increased tachygastria after WLST (P = 0.01). CONCLUSIONS: Low vitamin D levels are present in half the patients with symptoms of gastroparesis and are associated with nausea and vomiting and gastric neuromuscular dysfunction.

Prorelaxant E-type Prostanoid Receptors Functionally Partition to Different Procontractile Receptors in Airway Smooth Muscle.

Prostaglandin E2 imparts diverse physiological effects on multiple airway cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4). Gs-coupled EP2 and EP4 receptors are expressed on airway smooth muscle (ASM), yet their capacity to regulate the ASM contractile state remains subject to debate. We used EP2 and EP4 subtype-specific agonists (ONO-259 and ONO-329, respectively) in cell- and tissue-based models of human ASM contraction-magnetic twisting cytometry (MTC), and precision-cut lung slices (PCLSs), respectively-to study the EP2 and EP4 regulation of ASM contraction and signaling under conditions of histamine or methacholine (MCh) stimulation. ONO-329 was superior (<0.05) to ONO-259 in relaxing MCh-contracted PCLSs (log half maximal effective concentration [logEC50]: 4.9 × 10-7 vs. 2.2 × 10-6; maximal bronchodilation ± SE, 35 ± 2% vs. 15 ± 2%). However, ONO-259 and ONO-329 were similarly efficacious in relaxing histamine-contracted PCLSs. Similar differential effects were observed in MTC studies. Signaling analyses revealed only modest differences in ONO-329- and ONO-259-induced phosphorylation of the protein kinase A substrates VASP and HSP20, with concomitant stimulation with MCh or histamine. Conversely, ONO-259 failed to inhibit MCh-induced phosphorylation of the regulatory myosin light chain (pMLC20) and the F-actin/G-actin ratio (F/G-actin ratio) while effectively inhibiting their induction by histamine. ONO-329 was effective in reversing induced pMLC20 and the F/G-actin ratio with both MCh and histamine. Thus, the contractile-agonist-dependent differential effects are not explained by changes in the global levels of phosphorylated protein kinase A substrates but are reflected in the regulation of pMLC20 (cross-bridge cycling) and F/G-actin ratio (actin cytoskeleton integrity, force transmission), implicating a role for compartmentalized signaling involving muscarinic, histamine, and EP receptor subtypes.

Microbiology, Public Health and the Murals of Diego Rivera.

Diego Rivera, an acclaimed Mexican painter active during the first half of the twentieth century, painted multiple frescoes in Mexico and the United States. Some include depictions of bacteria, their interactions with human hosts, and processes related to microbiology and public health including the microbial origin of life, diagnosis of infection, vaccine production and immunization. Microbiological subjects in Rivera's murals at the Mexican Ministry of Health in Mexico City; the Detroit Institute of Art, Detroit; Rockefeller Center, New York/Palacio de Bellas Artes, Mexico City; Chapultepec Park, Mexico City; and the Institute of Social Security, Mexico City, span almost 25 years, from 1929 to 1953. Illustrating the successes of the application of microbiological discoveries and methods to public health and the prevention and treatment of infectious diseases, they benefited from Rivera's creativity in melding microbiology's unique technological and scientific aspects and public health elements with industrial and political components.

Relationships among intragastric meal distribution during gastric emptying scintigraphy, water consumption during water load satiety testing, and symptoms of gastroparesis.

Gastric emptying scintigraphy (GES) measures total gastric retention after a solid meal and can assess intragastric meal distribution (IMD). Water load satiety test (WLST) measures gastric capacity. Both IMD immediately after meal ingestion [ratio of proximal gastric counts after meal ingestion to total gastric counts at time 0 (IMD0)] and WLST (volume of water ingested over 5 min) are indirect measures of gastric accommodation. In this study, IMD0 and WLST were compared with each other and to symptoms of gastroparesis to gauge their clinical utility for assessing patients with symptoms of gastroparesis. Patients with symptoms of gastroparesis underwent GES to obtain gastric retention and IMD0, WLST, and filled out patient assessment of upper GI symptoms. A total of 234 patients with symptoms of gastroparesis were assessed (86 patients with diabetes, 130 idiopathic, 18 postfundoplication) and 175 (75%) delayed gastric emptying. Low IMD0 <0.568 suggesting initial rapid transit to the distal stomach was present in 8% and correlated with lower gastric retention, less heartburn, and lower volumes consumed during WLST. Low WLST volume (<238 mL) was present in 20% and associated with increased severity of early satiety, postprandial fullness, loss of appetite, and nausea. Low IMD0 is associated with less gastric retention and less heartburn. Volume of water consumed during WLST, while associated with IMD0, has associations with early satiety, postprandial fullness, loss of appetite, and nausea. Thus, IMD0 and WLST appear to overlap somewhat in their assessment of gastric physiology in adults with symptoms of gastroparesis but relate to different dyspeptic symptoms.NEW & NOTEWORTHY IMD0 and WLST were assessed for their clinical utility in assessing patients with symptoms of gastroparesis. Low IMD0 is associated with less gastric retention and less heartburn. Volume of water consumed during WLST, while associated with IMD0, has associations with early satiety, postprandial fullness, loss of appetite, and nausea. IMD0 and WLST appear to overlap somewhat in their assessment of gastric physiology in adults with symptoms of gastroparesis but relate to different dyspeptic symptoms.

Metoclopramide Nasal Spray in Women with Symptomatic Diabetic Gastroparesis: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

BACKGROUND & AIMS: Metoclopramide nasal spray (MNS) was developed as an alternative to oral metoclopramide. Prior phase 2 studies demonstrated efficacy in reducing symptoms in women, but not men with diabetic gastroparesis. The aim of this phase 3 study was to further determine the safety and efficacy of MNS compared with placebo in reducing symptoms of diabetic gastroparesis in women. METHODS: This US multicenter, randomized, double-blind, parallel group study enrolled women aged 18-75 years with diabetic gastroparesis and delayed gastric emptying. Subjects were randomized 1:1 to receive placebo or MNS 10 mg. The primary efficacy end point was change in mean daily Gastroparesis Symptom Assessment total score from baseline to Week 4. The Gastroparesis Symptom Assessment daily diary is a validated patient-reported outcome instrument that averages scores of nausea, early satiety, prolonged fullness, bloating, and upper abdominal pain on a 5-point ordinal scale. RESULTS: Two hundred and five subjects were randomized to receive placebo (n = 103) or MNS (n = 102). Overall, the MNS group did not experience a significant reduction in symptoms compared with the placebo group from baseline to Week 4 (P = .881). However, subjects with moderate-to-severe symptoms at baseline had a significant treatment effect from Weeks 1 to 3 (P < .05) and experienced a significant reduction in nausea and upper abdominal pain for all 4 weeks versus placebo (P < .05). Treatment-emergent adverse events were primarily mild to moderate with headache and abdominal pain reported most frequently. CONCLUSIONS: Although the primary end point was not met using all enrolled patients, treatment with MNS provided significant relief for women with moderate-to-severe diabetic gastroparesis symptoms. MNS was well tolerated and demonstrated a similar safety profile to placebo. (ClinicalTrials.gov identifier: NCT02025725.).

Normative Values for Body Surface Gastric Mapping Evaluations of Gastric Motility Using Gastric Alimetry: Spectral Analysis.

INTRODUCTION: Body surface gastric mapping (BSGM) is a new noninvasive test of gastric function. BSGM offers several novel and improved biomarkers of gastric function capable of differentiating patients with overlapping symptom profiles. The aim of this study was to define normative reference intervals for BSGM spectral metrics in a population of healthy controls. METHODS: BSGM was performed in healthy controls using Gastric Alimetry (Alimetry, New Zealand) comprising a stretchable high-resolution array (8 × 8 electrodes; 196 cm 2 ), wearable Reader, and validated symptom-logging App. The evaluation encompassed a fasting baseline (30 minutes), 482 kCal meal, and 4-hour postprandial recording. Normative reference intervals were calculated for BSGM metrics including the Principal Gastric Frequency, Gastric Alimetry Rhythm Index (a measure of the concentration of power in the gastric frequency band over time), body mass index (BMI)-adjusted amplitude (µV), and fed:fasted amplitude ratio. Data were reported as median and reference interval (5th and/or 95th percentiles). RESULTS: A total of 110 subjects (55% female, median age 32 years [interquartile range 24-50], median BMI 23.8 kg/m 2 [interquartile range 21.4-26.9]) were included. The median Principal Gastric Frequency was 3.04 cycles per minute; reference interval: 2.65-3.35 cycles per minute. The median Gastric Alimetry Rhythm Index was 0.50; reference interval: ≥0.25. The median BMI-adjusted amplitude was 37.6 µV; reference interval: 20-70 µV. The median fed:fasted amplitude ratio was 1.85; reference interval ≥1.08. A higher BMI was associated with a shorter meal-response duration ( P = 0.014). DISCUSSION: This study provides normative reference intervals for BSGM spectral data to inform diagnostic interpretations of abnormal gastric function.

Center-level factors associated with shorter length of stay following stage 1 palliation: An analysis of the national pediatric cardiology quality improvement collaborative registry.

BACKGROUND: Stage 1 single ventricle palliation (S1P) has the longest length of stay (LOS) of all benchmark congenital heart operations. Center-level factors contributing to prolonged hospitalization are poorly defined. METHODS: We analyzed data from infants status post S1P included in the National Pediatric Cardiology Quality Improvement Collaborative Phase II registry. Our primary outcome was patient-level LOS with days alive and out of hospital before stage 2 palliation (S2P) used as a balancing measure. We compared patient and center-level characteristics across quartiles for median center LOS, and used multivariable regression to calculate center-level factors associated with LOS after adjusting for case mix. RESULTS: Of 2,510 infants (65 sites), 2037 (47 sites) met study criteria (61% male, 61% white, 72% hypoplastic left heart syndrome). There was wide intercenter variation in LOS (first quartile centers: median 28 days [IQR 19, 46]; fourth quartile: 62 days [35, 95], P < .001). Mortality prior to S2P did not differ across quartiles. Shorter LOS correlated with more pre-S2P days alive and out of hospital, after accounting for readmissions (correlation coefficient -0.48, P < .001). In multivariable analysis, increased use of Norwood with a right ventricle to pulmonary artery conduit (aOR 2.65 [1.1, 6.37]), shorter bypass time (aOR 0.99 per minute [0.98,1.0]), fewer additional cardiac operations (aOR 0.46 [0.22, 0.93]), and increased use of NG tubes rather than G tubes (aOR 7.03 [1.95, 25.42]) were all associated with shorter LOS centers. CONCLUSIONS: Modifiable center-level practices may be targets to standardize practice and reduce overall LOS across centers.

Regional Measures of Sexual-Orientation Bias Predict Where Same-Gender Couples Live.

Regional explicit and implicit bias are associated with real-world discrimination and marginalization. We extended this research area by focusing on sexual minorities and where same-gender couples live. Using data on 2,939 U.S. counties from Project Implicit and other publicly available sources, we found that measures with known associations with systemic anti-lesbian, gay, and bisexual (anti-LGB) bias are similarly associated with regional implicit and explicit anti-LGB bias. Furthermore, we found that fewer same-gender couples reside in counties with more explicit and implicit anti-LGB bias, above and beyond other factors that likely influence same-gender-couple residency. These findings further suggest that explicit and implicit measures of regional bias are capturing similar, if not the same, construct of a region's culture of bias toward particular groups. Couched specifically within the ongoing systemic political antagonization of the lesbian, gay, bisexual, transgender, queer, plus (LGBTQ+) community, these findings also highlight the importance of considering contextual (in addition to individual) factors that reinforce systemic inequality.

Protein familiarity is a fundamental but rarely operationalized concept in the safety assessment of genetically modified crops: example of phosphomannose isomerase (PMI).

Fundamental to the safety assessment of genetically modified (GM) crops is the concept of negligible risk for newly expressed proteins for which there is a history of safe use. Although this simple concept has been stated in international and regional guidance for assessing the risk of newly expressed proteins in GM crops, its full implementation by regulatory authorities has been lacking. As a result, safety studies are often repeated at a significant expenditure of resources by developers, study results are repeatedly reviewed by regulators, and animals are sacrificed needlessly to complete redundant animal toxicity studies. This situation is illustrated using the example of the selectable marker phosphomannose isomerase (PMI) for which familiarity has been established. Reviewed is the history of safe use for PMI and predictable results of newly conducted safety studies including bioinformatic comparisons, resistance to digestion, and acute toxicity that were repeated to gain regulatory reapproval of PMI expressed from constructs in recently developed GM maize. As expected, the results of these newly repeated hazard-identification and characterization studies for PMI indicate negligible risk. PMI expressed in recently developed GM crops provides an opportunity to use the concept of familiarity by regulatory authorities to reduce risk-disproportionate regulation of these new events and lessen the resulting waste of both developer and regulator resources, as well as eliminate unnecessary animal testing. This would also correctly imply that familiar proteins like PMI have negligible risk. Together, such modernization of regulations would benefit society through enabling broader and faster access to needed technologies.

Incidence of group B streptococcus early-onset sepsis in term neonates with second-line prophylaxis maternal intrapartum antibiotics: a multicenter retrospective study.

BACKGROUND: The difference in the incidence of early-onset sepsis caused by group B streptococcus among term neonates whose mothers received first-line vs second-line intrapartum prophylaxis is poorly described. OBJECTIVE: This study aimed to compare the incidence of group B streptococcus early-onset sepsis among term neonates born to mothers who receive first-line, second-line, or no intrapartum antibiotics and to describe the short-term and survival outcomes of neonates who developed group B streptococcus early-onset sepsis stratified by maternal antepartum prophylaxis. STUDY DESIGN: This was a retrospective review of electronic medical records. We queried the Pediatrix Medical Group Clinical Data Warehouse to evaluate the outcomes of term neonates born to group B streptococcus positive mothers between 2003 and 2020 and compared the incidence and outcomes of neonates with group B streptococcus early-onset sepsis whose mothers received first-line vs second-line or no intrapartum prophylaxis. RESULTS: Among the 496,180 neonates, 104,196 (21%) were born to mothers who were group B streptococcus positive. Of 97,983 mothers who were group B streptococcus positive with adequate prenatal antibiotic documentation, 49,234 (50%), 12,679 (13%), and 36,070 (37%) received first-line, second-line, and no intrapartum prophylaxis, respectively. The incidence of group B streptococcus early-onset sepsis among all neonates with maternal group B streptococcus carriage was 0.22% (231/104,196). Neonates whose mothers received second-line intrapartum antibiotics and no antibiotics had a higher risk for group B streptococcus early-onset sepsis infection than those whose mothers received first-line intrapartum antibiotics (adjusted odds ratio, 4.12; 95% confidence interval, 2.66-6.38 and adjusted odds ratio, 3.80; 95% confidence interval, 2.66-5.44, respectively). There was no statistically significant difference in the risk for group B streptococcus early-onset sepsis among neonates born to mothers who received second-line vs no antibiotics (adjusted odds ratio, 0.92; 95% confidence interval, 0.64-1.33). CONCLUSION: Neonates exposed to second-line maternal group B streptococcus prophylaxis had an increased risk for group B streptococcus early-onset sepsis when compared with those exposed to first-line maternal group B streptococcus prophylaxis. There was no statistically significant difference in group B streptococcus early-onset sepsis incidence between second-line antibiotic prophylaxis and no antibiotics in mothers with group B streptococcus carriage.

Atypical Causes of Gastroparesis: Prevalence, Gastric Emptying, and Clinical Features.

BACKGROUND: Gastroparesis is commonly attributed to idiopathic or diabetic causes. GOALS: We aimed to describe atypical causes of gastroparesis and examine the clinical features and severity of delayed gastric emptying compared with idiopathic and diabetic causes. STUDY: Between 2018 and 2021, gastroparesis patients being evaluated at our tertiary care center completed a 4-hour gastric emptying scintigraphy and questionnaires assessing for gastrointestinal disorders, including patient assessment of upper gastrointestinal symptoms. Patients were divided into groups relating to gastroparesis cause: diabetic, postsurgical (PSGp), connective tissue (CTGp), neurological and idiopathic. RESULTS: Two hundred fifty-six patients with delayed emptying on gastric emptying scintigraphy completed the questionnaires. Gastroparesis causes included 149 (58.2%) idiopathic, 60 (23.4%) diabetic, 29 (11.3%) postsurgical, 13 (5.1%) connective tissue, and 5 (2.0%) neurological. In each group, most patients were female and White. Gastric retention at 4 hours was significantly greater in patients with diabetic (39.3±25.7% P <0.001), postsurgical (41.3±24.0% P =0.002), and connective tissue gastroparesis (37.8±20.0% P =0.049) compared with patients with idiopathic gastroparesis (25.5±17.6%). In PSGp, diabetic and idiopathic causes, the main symptoms were early satiety and postprandial fullness, whereas in CTGp, bloating and abdominal distension were the predominant symptoms. Vomiting severity was significantly greater in patients with diabetes compared with idiopathic gastroparesis (2.9±1.9 vs. 2.1±1.8 P =0.006). CONCLUSIONS: Atypical causes contributed to gastroparesis in 47 of 256 (18.4%) patients with delayed gastric emptying. Gastric emptying was significantly more delayed in PSGp and CTGp patients. PSGp patients mainly experienced stomach fullness and early satiety, whereas CTGp patients had predominantly bloating and distension.