Characterization of viroplasm-like structures by co-expression of NSP5 and NSP2 across rotavirus species A to J.

Rotaviruses (RVs) are classified into nine species, A-D and F-J, with species A being the most studied. In rotavirus of species A (RVA), replication occurs in viroplasms, which are cytosolic globular inclusions composed of main building block proteins NSP5, NSP2, and VP2. The co-expression of NSP5 with either NSP2 or VP2 in uninfected cells leads to the formation of viroplasm-like structures (VLSs). Although morphologically identical to viroplasms, VLSs do not produce viral progeny but serve as excellent tools for studying complex viroplasms. A knowledge gap exists regarding non-RVA viroplasms due to the lack of specific antibodies and suitable cell culture systems. In this study, we explored the ability of NSP5 and NSP2 from non-RVA species to form VLSs. The co-expression of these two proteins led to globular VLSs in RV species A, B, D, F, G, and I, while RVC formed filamentous VLSs. The co-expression of NSP5 and NSP2 of RV species H and J did not result in VLS formation. Interestingly, NSP5 of all RV species self-oligomerizes, with the ordered C-terminal region, termed the tail, being necessary for self-oligomerization of RV species A-C and G-J. Except for NSP5 from RVJ, all NSP5 interacted with their cognate NSP2. We also found that interspecies VLS are formed between closely related RV species B with G and D with F. Additionally, VLS from RVH and RVJ formed when the tail of NSP5 RVH and RVJ was replaced by the tail of NSP5 from RVA and co-expressed with their respective NSP2. IMPORTANCE: Rotaviruses (RVs) are classified into nine species, A-D and F-J, infecting mammals and birds. Due to the lack of research tools, all cumulative knowledge on RV replication is based on RV species A (RVA). The RV replication compartments are globular cytosolic structures named viroplasms, which have only been identified in RV species A. In this study, we examined the formation of viroplasm-like structures (VLSs) by the co-expression of NSP5 with NSP2 across RV species A to J. Globular VLSs formed for RV species A, B, D, F, G, and I, while RV species C formed filamentous structures. The RV species H and J did not form VLS with their cognates NSP5 and NSP2. Similar to RVA, NSP5 self-oligomerizes in all RV species, which is required for VLS formation. This study provides basic knowledge of the non-RVA replication mechanisms, which could help develop strategies to halt virus infection across RV species.

The diabetes management experiences questionnaire: Psychometric validation among adults with type 1 diabetes.

AIMS: To examine the psychometric properties of the Diabetes Management Experiences Questionnaire (DME-Q). Adapted from the validated Glucose Monitoring Experiences Questionnaire, the DME-Q captures satisfaction with diabetes management irrespective of treatment modalities. METHODS: The DME-Q was completed by adults with type 1 diabetes as part of a randomized controlled trial comparing hybrid closed loop (HCL) to standard therapy. Most psychometric properties were examined with pre-randomization data (n = 149); responsiveness was examined using baseline and 26-week follow-up data (n = 120). RESULTS: Pre-randomization, participants' mean age was 44 ± 12 years, 52% were women. HbA1c was 61 ± 11 mmol/mol (7.8 ± 1.0%), diabetes duration was 24 ± 12 years and 47% used an insulin pump prior to the trial. A forced three-factor analysis revealed three expected domains, that is, 'Convenience', 'Effectiveness' and 'Intrusiveness', and a forced one-factor solution was also satisfactory. Internal consistency reliability was strong for the three subscales ( α range = 0.74-0.84) and 'Total satisfaction' ( α = 0.85). Convergent validity was demonstrated with moderate correlations between DME-Q 'Total satisfaction' and diabetes distress (PAID: rs = -0.57) and treatment satisfaction (DTSQ; rs = 0.58). Divergent validity was demonstrated with a weak correlation with prospective/retrospective memory (PRMQ: rs = -0.16 and - 0.13 respectively). Responsiveness was demonstrated, as participants randomized to HCL had higher 'Effectiveness' and 'Total satisfaction' scores than those randomized to standard therapy. CONCLUSIONS: The 22-item DME-Q is a brief, acceptable, reliable measure with satisfactory structural and construct validity, which is responsive to intervention. The DME-Q is likely to be useful for evaluation of new pharmaceutical agents and technologies in research and clinical settings.

Continuous ketone monitoring: Exciting implications for clinical practice.

Diabetic ketoacidosis (DKA) is a life-threatening complication usually affecting people with type 1 diabetes (T1D) and, less commonly, people with type 2 diabetes. Early identification of ketosis is a cornerstone in DKA prevention and management. Current methods for ketone measurement by people with diabetes include capillary blood or urine testing. These approaches have limitations, including the need to carry testing strips that have a limited shelf life and a requirement for the user to initiate a test. Recent studies have shown the feasibility of continuous ketone monitoring (CKM) via interstitial fluid with a sensor inserted subcutaneously employing an enzymatic electrochemical reaction. Ketone readings can be updated every 5 minutes. In the future, one would expect that commercialized devices will incorporate alarms linked with standardized thresholds and trend arrows. Ideally, to minimize the burden on users, CKM functionality should be integrated with other devices used to implement glucose management, including continuous glucose monitors and insulin pumps. We suggest CKM provision to all at risk of DKA and recommend that the devices should be worn continuously. Those who may particularly benefit are individuals who have T1D, are pregnant, on medications such as sodium-glucose linked transporter (SGLT) inhibitors that increase DKA, people with recurrent DKA, those with T1D undertaking high intensity exercise, are socially or geographically isolated, or those on low carbohydrate diets. The provision of ketone profiles will provide important clinical insights that have previously been unavailable to people living with diabetes and their healthcare professionals.

Differentiated Thyroid Cancer after Thyroidectomy.

The widespread use of neck US and other imaging modalities has contributed to a phenomenon of increased detection of differentiated thyroid cancer (DTC). Most of these cancers remain indolent, without requiring surgical intervention. Nonetheless, a subset of patients who require surgical treatment experience subsequent disease recurrence. This most commonly occurs in the cervical lymph nodes and thyroid bed, followed by distant metastasis to the lungs and bones. Because imaging is an integral part of postoperative surveillance, radiologists play a central role in the detection of recurrent tumors and in guiding treatment in these patients. US is the primary imaging modality used for postoperative evaluation. Other modalities such as CT, MRI, radioactive iodine imaging, and PET/CT aid in the accurate diagnosis and characterization of recurrent disease. Therefore, radiologists must have a thorough understanding of the utility of these imaging techniques and the imaging characteristics of recurrent DTC when interpreting these multimodality studies. The interpretation of imaging findings should also be correlated with the clinical status of patients and their biochemical markers to minimize interpretative errors. The authors present a broad overview of the postoperative evaluation of DTC, including its initial primary management, staging, and prognostication; clinical risk stratification for recurrent disease; postoperative surveillance with imaging and evaluation of biochemical markers; and management of recurrent DTC. Published under a CC BY 4.0 license. Supplemental material is available for this article.

Trends in diabetic ketoacidosis in Victoria, Australia 2002-2016.

BACKGROUND: International longitudinal studies have indicated an increasing incidence of diabetic ketoacidosis (DKA). We aim to examine the incident trends, demographic differences, length of stay and mortality for DKA in adults with type 1 diabetes (T1D) and type 2 diabetes (T2D) in Victoria, Australia from 2002 to 2016. METHODS: Age and sex adjusted incident trends, length of stay and mortality for DKA was retrospectively obtained using the Victorian Admitted Episode Dataset between 2002 and 2016. Data for adults with T1D and T2D was obtained from the National Diabetes Services Scheme (NDSS). Joinpoint regression analysis was used to identify changes in linear trends that were described as average annual percentage change (AAPC). RESULTS: There were 23,628 DKA presentations in Victoria between 2002 and 2016. For T1D there was an increase in DKA presentations (AAPC + 6.8%) from 2003 to 2016 and for T2D there was a decline from 2003 to 2011 (APC - 3.5%), increase from 2011 to 2014 (APC + 38.5%), and a decrease from 2014 to 2016 (APC - 20.9%). Length of stay was longer for people with T2D than T1D (P < 0.001) and the mortality rate was 0.51% for the study period. CONCLUSIONS: DKA rates increased for T2D from 2011 to 2014 which correlates with the introduction of sodium glucose-linked transport protein 2 inhibitors. However, the aetiology for the observed increase in T1D from 2002 to 2016 remains unknown.

Descriptive Epidemiology of New York City Older Adult Patients With Multiple Chronic Conditions.

We characterized comorbidity profiles and cardiometabolic risk factors among older adults with multiple chronic conditions (MCCs) in New York City using an intersectionality approach. Electronic health record data were obtained from the INSIGHT Clinical Research Network on 367,901 New York City residents aged 50 years or older with MCCs. Comorbidity profiles were heterogeneous. The most common profile across sex and racial and ethnic groups was co-occurring hypertension and hyperlipidemia; prevalence of these 2 conditions differed across groups (4.7%-7.3% co-occurrence alone, 65.1%-88.0% with other conditions). Significant sex and racial and ethnic differences were observed, which may reflect accumulated disparities in risk factors and health care access across the life course.

Transcatheter occlusion of venovenous collaterals in the total cavopulmonary Fontan circulation.

BACKGROUND: Venovenous collaterals are abnormal connections between the systemic and pulmonary venous systems. They are commonly seen in the Fontan circulation and may lead to significant hypoxaemia. Transcatheter closure of venovenous collaterals is a potential but controversial treatment as the long-term benefits and outcomes are not well understood. METHODS: This retrospective cohort study utilised data from the Australian and New Zealand Fontan Registry. Patients who underwent transcatheter venovenous collateral occlusion for hypoxemia from the year 2000 onwards were included. Atriopulmonary and Kawashima-type Fontan circulations were excluded to reflect a more contemporary Fontan cohort. RESULTS: Nineteen patients (age 19.3 ± 7.8 years, 53% female) underwent transcatheter venovenous collateral occlusion. Compared to baseline, mean oxygen saturation was improved at latest follow-up (90.5% vs 87.0%; p = 0.003). Nine patients achieved a clinically significant response (defined as an increase of at least 5% to 90% or greater), and this was associated with lower baseline Fontan pressures (12.9 v 15.6 mmHg; p = 0.02). No heart failure hospitalisations, arrhythmia, transplant referrals, or mortality were observed during the median follow-up period of 4 years. Two patients experienced thromboembolic events and five patients underwent re-intervention. CONCLUSION: Transcatheter occlusion of venovenous collaterals in Fontan patients with chronic hypoxaemia resulted in a modest increase in oxygenation over a median follow-up of 4 years and longer-term prognosis did not appear to be adversely affected. Lower Fontan pressures at baseline were associated with a greater improvement in oxygenation.

Sensor-Integrated Chairs for Lower Body Strength and Endurance Assessment.

This paper describes an automated method and device to conduct the Chair Stand Tests of the Fullerton Functional Test Battery. The Fullerton Functional Test is a suite of physical tests designed to assess the physical fitness of older adults. The Chair Stand Tests, which include the Five Times Sit-to-Stand Test (5xSST) and the 30 Second Sit-to-Stand Test (30CST), are the standard for measuring lower-body strength in older adults. However, these tests are performed manually, which can be labor-intensive and prone to error. We developed a sensor-integrated chair that automatically captures the dynamic weight and distribution on the chair. The collected time series weight-sensor data is automatically uploaded for immediate determination of the sit-to-stand timing and counts, as well as providing a record for future comparison of lower-body strength progression. The automatic test administration can provide significant labor savings for medical personnel and deliver much more accurate data. Data from 10 patients showed good agreement between the manually collected and sensor-collected 30CST data (M = 0.5, SD = 1.58, 95% CI = 1.13). Additional data processing will be able to yield measurements of fatigue and balance and evaluate the mechanisms of failed standing attempts.

Validity and Reliability of the Power Slap Board as an Application to Measure Upper Body Vertical Pulling Power for Female Water Polo Players.

ABSTRACT: Lim, C, Wee, J, Lee, M, Lim, S, and Leow, S. Validity and reliability of the power slap board as an application to measure upper body vertical pulling power for female water polo players. J Strength Cond Res 38(11): e670-e677, 2024-This study examined the validity and reliability of the power slap test (PS) as an assessment for upper body pulling power to predict water polo functional performance and competitive experience of female water polo players. Seventeen female water polo players from the national and development squads were recruited. Subjects completed test-retest sessions of PS testing and 1 session of functional performance tests for the 15-m arms-only sprint (15 mAOS) and the 5-m maximum shooting velocity (5 mMSV). All PS, 15 mAOS and 5 mMSV results were compared for predictability. Power slap scores demonstrated high reliability for left PS (intraclass correlations [ICC]: 0.96, 90% confidence interval [CI]: 0.91-0.98), right PS (ICC: 0.96, 90% CI: 0.90-0.98), left and right center of mass (COM) displacement (ICC: 0.98, 90% CI: 0.96-0.99; ICC: 0.95, 90% CI: 0.88-0.98), and summed PS (ICC: 0.96, 90% CI: 0.92-0.99). All absolute PS scores and left COM displacement (COM disp L) demonstrated large correlations with the 15 mAOS times ( r = -0.542 to -0.52, r2 = 0.27-0.29, p < 0.05). No performance parameters of the PS were correlated with the 5 mMSV performance ( p > 0.05). This study validates the reliability of the PS as a dryland assessment tool for upper body pulling power. Only absolute PS scores and COM disp were validated as weak predictors of the arms-only sprint times over 15 m. Its predictive power significantly improved when considered in combination with shooting performance. All absolute and normalized kinetic and kinematic PS parameters did not predict functional performance and competitive experience.

Lived experience of older adults with type 1 diabetes using closed-loop automated insulin delivery in a randomised trial.

AIM: To explore the lived experience of older adults with type 1 diabetes using closed-loop automated insulin delivery, an area previously receiving minimal attention. METHODS: Semi-structured interviews were conducted with adults aged 60 years or older with long-duration type 1 diabetes who participated in a randomised, open-label, two-stage crossover trial comparing first-generation closed-loop therapy (MiniMed 670G) versus sensor-augmented pump therapy. Interview recordings were transcribed, thematically analysed and assessed. RESULTS: Twenty-one older adults participated in interviews after using closed-loop therapy. Twenty were functionally independent, without frailty or major cognitive impairment; one was dependent on caregiver assistance, including for diabetes management. Quality of life benefits were identified, including improved sleep and reduced diabetes-related psychological burden, in the context of experiencing improved glucose levels. Gaps between expectations and reality of closed-loop therapy were also experienced, encountering disappointment amongst some participants. The cost was perceived as a barrier to continued closed-loop access post-trial. Usability issues were identified, such as disruptive overnight alarms and sensor inaccuracy. CONCLUSIONS: The lived experience of older adults without frailty or major cognitive impairment using first-generation closed-loop therapy was mainly positive and concordant with glycaemic benefits found in the trial. Older adults' lived experience using automated insulin delivery beyond trial environments requires exploration; moreover, the usability needs of older adults should be considered during future device development.

What difference does sleep make? Continuous glucose monitoring metrics during fixed-overnight time versus sleep periods among older adults with type 1 diabetes.

Hypoglycaemia during sleep is a common and clinically important issue for people living with insulin-treated diabetes. Continuous glucose monitoring devices can help to identify nocturnal hypoglycaemia and inform treatment strategies. However, sleep is generally inferred, with diabetes researchers and physicians using a fixed-overnight period as a proxy for sleep-wake status when analysing and interpretating continuous glucose monitoring data. No study to date has validated such an approach with established sleep measures. Continuous glucose monitoring and research-grade actigraphy devices were worn and sleep diaries completed for 2 weeks by 28 older adults (mean age 67 years [SD 5]; 17 (59%) women) with type 1 diabetes. Using continuous glucose monitoring data from a total of 356 nights, fixed-overnight (using the recommended period of 00:00 hours-06:00 hours) and objectively-measured sleep periods were compared. The fixed-overnight period approach missed a median 57 min per night (interquartile range: 49-64) of sleep for each participant, including five continuous glucose monitoring-detected hypoglycaemia episodes during objectively-measured sleep. Twenty-seven participants (96%) had at least 1 night with continuous glucose monitoring time-in-range and time-above-range discrepancies both ≥ 10 percentage points, a clinically significant discrepancy. The utility of fixed-overnight time continuous glucose monitoring as a proxy for sleep-awake continuous glucose monitoring is inadequate as it consistently excludes actual sleep time, obscures glycaemic patterns, and misses sensor hypoglycaemia episodes during sleep. The use of validated measures of sleep to aid interpretation of continuous glucose monitoring data is encouraged.

3D Airway Epithelial-Fibroblast Biomimetic Microfluidic Platform to Unravel Engineered Nanoparticle-Induced Acute Stress Responses as Exposome Determinants.

Insights into how biological systems respond to high- and low-dose acute environmental stressors are a fundamental aspect of exposome research. However, studying the impact of low-level environmental exposure in conventional in vitro settings is challenging. This study employed a three-dimensional (3D) biomimetic microfluidic lung-on-chip (µLOC) platform and RNA-sequencing to examine the effects of two model anthropogenic engineered nanoparticles (NPs): zinc oxide nanoparticles (Nano-ZnO) and copier center nanoparticles (Nano-CCP). The airway epithelium exposed to these NPs exhibited dose-dependent increases in cytotoxicity and barrier dysregulation (dominance of the external exposome). Interestingly, even nontoxic and low-level exposure (10 µg/mL) of the epithelium compartment to Nano-ZnO triggered chemotaxis of lung fibroblasts toward the epithelium. An increase in α smooth muscle actin (α-SMA) expression and contractile activity was also observed in these cells, indicating a bystander-like adaptive response (dominance of internal exposome). Further bioinformatics and network analysis showed that a low-dose Nano-ZnO significantly induced a robust transcriptomic response and upregulated several hub genes associated with the development of lung fibrosis. We propose that Nano-ZnO, even at a no observable effect level (NOEL) dose according to conventional standards, can function as a potent nanostressor to disrupt airway epithelium homeostasis. This leads to a cascade of profibrotic events in a cross-tissue compartment fashion. Our findings offer new insights into the early acute events of respiratory harm associated with environmental NPs exposure, paving the way for better exposomic understanding of this emerging class of anthropogenic nanopollutants.

Impact of Telehealth on Failure to Attend Rates and Patient Re-Engagement in Adult Congenital Heart Disease Clinic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic paved the way for telehealth consultations. We aimed to determine the impact of telehealth on rates of failure to attend (FTA) in adult congenital heart disease (ACHD) clinics and whether telehealth could re-engage patients with previous FTA face-to-face appointments. METHODS: This was a retrospective audit of a tertiary ACHD clinic over a 12-month pre-telehealth (26 March 2019-17 March 2020) and 12-month post-telehealth implementation period (24 March 2020-16 March 2021). Patients with one or more FTAs during the 24-month study period were included. Our ACHD clinic is run three times per month. Patients with ACHD are offered lifelong follow-up and reviewed annually on average. Re-engagement was defined as two or more consecutive face-to-face FTAs immediately before the telehealth period with subsequent attendance of their telehealth appointment. RESULTS: A total of 359 patients with a total of 623 FTAs were included. Complexity of congenital heart disease was moderate in 56% (202/359) and severe in 19% (69/359) of patients. Overall FTA rate was 18% (623/3,452). FTA rate was significantly lower in the post-telehealth period (15%, 257/1,664) compared with the pre-telehealth period (20%, 366/1,788) (p<0.00001). At study conclusion, 1% of patients had died (5/359). Of the 354 remaining patients, 42% (150/354) were considered lost to follow-up (two or more FTAs including telehealth), 37% (132/354) missed only one clinic appointment, and 20% (72/354) previously considered lost to follow-up had re-engaged in the telehealth period. CONCLUSIONS: Rates of FTA in a tertiary ACHD clinic significantly reduced after the introduction of telehealth consultation. A fifth of patients considered lost to follow-up were re-engaged with telehealth. Additional strategies to further reduce FTA should be explored.

Insulin antibodies are prevalent in adults with type 1 diabetes referred for islet cell transplantation and are modified by islet transplantation and immunosuppression: an Australian experience.

We have analysed insulin antibodies in 149 adults with type 1 diabetes and 2859 people without diabetes. We have determined that insulin antibody levels are higher in adults with, versus without, diabetes and that the levels are falling, and more patients are becoming antibody-negative post islet cell transplantation.

Poorer Self-Reported Physical Health and Higher Anxiety Trait in Young Adults With Previous Coarctation Repair.

BACKGROUND: Little is known about the impact of a coarctation repair on the functional outcomes of young adults. This study aimed to determine (1) the functional and mental health status in young adults with previous coarctation repair, and (2) the impact of late hypertension on their quality of life. METHODS: A cross-sectional study using validated self-reported questionnaires (Short Form 36 version 2 [SF-36v2], Beck Depression Inventory [BDI], and State-Trait Anxiety Inventory [STAI]) was performed in 54 patients aged 15-47 years with previous paediatric coarctation repair. Questionnaire scores were compared to healthy age- and gender-matched controls. Patients' previously published 24-hour blood pressure monitoring results were included. RESULTS: Late hypertension was present in 64% (34/54) at a mean of 29±8 years after coarctation repair. SF-36v2 mean physical component summary score was significantly lower in coarctation patients compared with controls (53.1±6.8 vs 56.0±4.7, p=0.02), but there was no significant difference in mean mental component summary score (p=0.2). SF-36v2 mean role emotional score tended to be associated with 10 mmHg increases in mean 24-hour systolic blood pressure (regression coefficient 4.3 p=0.06). STAI mean trait anxiety score tended to be higher in coarctation patients compared with controls (36.6±9.0 vs 33.5±7.8, p=0.06). There was no significant difference in BDI scores between patients and controls. CONCLUSIONS: Young adults with previous coarctation repair report poorer physical health and tended towards higher anxiety trait compared to healthy controls. Strategies to improve self-reported physical health and anxiety should be explored. Long-term assessment of quality of life outcomes in coarctation patients is warranted.

Berlin Heart EXCOR Support in the First Year of Life: A Single Centre Experience.

BACKGROUND: Berlin Heart EXCOR Pediatric Ventricular Assist Device (BHE) (Berlin Heart AG, Berlin, Germany, BHE) is used worldwide for mechanical circulatory support as a bridge to transplantation or recovery for children with end-stage heart failure. The study aim was to evaluate morbidity and mortality of children less than one year old supported with BHE to identify predictors of adverse outcomes. METHODS: Data of all children aged less than one year supported with BHE between 2005 and 2018 at the Royal Children's Hospital, Melbourne were reviewed. Adverse events were defined using PediMACS criteria. RESULTS: Fourteen (14) children under 1 year of age were implanted with BHE at a median age and weight of 0.37 years (IQR 0.09-0.7) and 5.7 kg (IQR 3.5-7.95) respectively. Four (4) patients were neonates, and 10 were older infants. Twelve (12) patients had cardiomyopathy and two, myocarditis. Preoperative extracorporeal membrane oxygenation (ECMO) support was required in six patients for a mean of 9 days (IQR 6-13). Sepsis occurred in five patients (36%) and thromboembolic stroke in two patients (14%). Survival to bridge to transplantation (11) and recovery (1) was achieved in 12 patients (86%). Mortality was 14%. The median duration of BHE support was 110 days (IQR 40-161). Both patients who died were neonates with myocarditis and required surgical re-intervention during BHE support. CONCLUSIONS: BHE provides excellent support as a bridge to transplantation or recovery in infants, with a low incidence of neurological dysfunction. Neonates with myocarditis may be at greater risk for death after BHE implantation.

Relationship between distension-contraction waveforms during esophageal peristalsis: effect of bolus volume, viscosity, and posture.

High-resolution esophageal manometry (HRM) in its current form assesses only the contraction phase of peristalsis. Degree of esophageal distension ahead of contraction is a surrogate of relaxation and can be measured from intraluminal esophageal impedance measurements. The characteristics of esophageal contractions, i.e., their amplitude, duration, velocity, and modulating factors, have been well studied. We studied the effect of bolus volume and viscosity and posture on swallow-induced distension and contraction and the temporal relationship between the two. HRM impedance recordings of 50 healthy subjects with no esophageal symptoms were analyzed. Eight to ten swallows of 5 and 10 mL of 0.5 N saline and a viscous bolus were recorded in the supine and Trendelenburg positions. Custom-built computer software generated the distension-contraction plots and numerical data of the amplitudes of distension (cross-sectional area) and contraction, and the temporal relationship between distension and peak contraction. The hallmarks of distension waveforms are that 1) distension peak, similarly to contraction, travels the esophagus in a peristaltic fashion, and the amplitude of distension increases from the proximal-to-distal direction; 2) the amplitude of distension is greater with 10 mL than with 5 mL and greater in Trendelenburg than in supine posture; and 3) bolus viscosity increases the amplitude of distension and alters the temporal relationship between distension and contraction waveforms. We describe the characteristics of esophageal distension during peristalsis and the relationship between distension and contraction in a relatively large cohort of normal subjects. These data can be used to compare differences between normal subjects and patients with various esophageal motility disorders in future studies.NEW & NOTEWORTHY We studied esophageal distension (surrogate of inhibition) ahead of contraction during peristalsis from intraluminal esophageal impedance measurements. Esophageal distension, similarly to contraction, travels the esophagus in a sequential manner, and the amplitude of esophageal distension increases from proximal to distal direction in the esophagus. Bolus volume, viscosity and posture have significant effects on the amplitude of distension and its temporal relationship with contraction.

Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites.

We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cystic fibrosis (CF). Among 1,423 unannotated CFTR disease-associated variants, the method identified 32 potential exonic cryptic splice variants, two of which were experimentally evaluated and confirmed. After complete CFTR sequencing, the method found three cryptic intronic splice variants (one known and two experimentally verified) that completed the molecular diagnosis of CF in 6 of 14 individuals. CryptSplice interrogation of sequence data from six individuals with X-linked dyskeratosis congenita caused by an unknown disease-causing variant in DKC1 identified two splice-altering variants that were experimentally verified. To assess the extent to which disease-associated variants might activate cryptic splicing, we selected 458 pathogenic variants and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar. Splice-site activation was predicted for 129 (28%) of the pathogenic variants and 75 (22%) of the VUSs. Our findings suggest that cryptic splice-site activation is more common than previously thought and should be routinely considered for all variants within the transcribed regions of genes.

Maternal health services utilisation among primigravidas in Uganda: what did the MDGs deliver?

BACKGROUND: Achieving maternal health outcomes in the SDGs requires the implementation of more targeted policies and strategies. While the MDGs may have deepened our understanding in this regard, we know little about the trends in maternal health services utilisation among primigravidas, and how age and geographical regions could have influenced these trends. In this study, we examined utilisation of antenatal and skilled delivery services among primigravidas in Uganda, a country with one of the highest maternal mortality ratios, and where early childbearing and its attendant challenges are common. METHODS: Guided by Andersen's Behavioural Model, we fitted multivariate regression models to a pooled dataset of the 2006, 2011 and 2016 Ugandan Demographic and Health Survey (n = 3477) to understand the dynamics in Antenatal Care (ANC) and Skilled Birth Attendance (SBAs) utilisation among primigravidas. Post-estimation margins were employed to further highlight the effect of age and geographical regions. RESULTS: The analyses show an improvement in access to maternal health services among primigravidas from 2006 to 2016. Compared to 2006, primigravidas in 2016 were 48%, 24% and 2.98 times more likely to have early ANC, four or more ANC visits, and SBAs, respectively. Altogether, a primigravida in 2016 relative to 2006 was 42% more likely to meet all three maternal health service indicators. Post-estimation margins analyses on age and geographical disparities revealed that younger primigravidas have lower probability, while primigravidas in Eastern Region, one of the most deprived in the country, have the lowest probability of accessing maternal health services. Also, the study found education, wealth, women's household decision-making power, place of residence as important determinants of ANC visits and SBAs. CONCLUSIONS: Based on our findings, it is important to address the vulnerabilities of primigravidas, particularly younger individuals, in accessing early ANC. Uganda should scale-up decentralisation and integration of maternal health delivery in local communities as a strategy of addressing lingering geographical disparities, and ultimately improve maternal health outcomes in the SDGs period.

Topographical plots of esophageal distension and contraction: effects of posture on esophageal peristalsis and bolus transport.

Each swallow induces a wave of inhibition followed by contraction in the esophagus. Unlike contraction, which can easily be measured in humans using high-resolution manometry (HRM), inhibition is difficult to measure. Luminal distension is a surrogate of the esophageal inhibition. The aim of this study was to determine the effect of posture on the temporal and quantitative relationship between distension and contraction along the entire length of the esophagus in normal healthy subjects by using concurrent HRM, HRM impedance (HRMZ), and intraluminal ultrasound (US). Studies were conducted in 15 normal healthy subjects in the supine and Trendelenburg positions. Both manual and automated methods were used to extract quantitative pressure and impedance-derived features from the HRMZ recordings. Topographical plots of distension and contraction were visualized along the entire length of the esophagus. Distension was also measured from the US images during 10-ml swallows at 5 cm above the lower esophageal sphincter. Each swallow was associated with luminal distension followed by contraction, both of which traversed the esophagus in a sequential/peristaltic fashion. Luminal distension (US) and esophageal contraction amplitude were greater in the Trendelenburg compared with the supine position. Length of esophageal breaks (in the transition zone) were reduced in the Trendelenburg position. Change in posture altered the temporal relationship between distension and contraction, and bolus traveled closer to the esophageal contraction in the Trendelenburg position. Topographical contraction-distension plots derived from HRMZ recordings is a novel way to visualize esophageal peristalsis. Future studies should investigate if abnormalities of esophageal distension are the cause of functional dysphagia. NEW & NOTEWORTHY Ascending contraction and descending inhibition are two important components of peristalsis. High-resolution manometry only measures the contraction phase of peristalsis. We measured esophageal distension from intraluminal impedance recordings and developed novel contraction-distension topographical plots to prove that similar to contraction, distension also travels in a peristaltic fashion. Change in posture from the supine to the Trendelenburg position also increased the amplitude of esophageal distension and contraction and altered the temporal relationship between distension and contraction.