Genetics of human neural tube defects

Neural tube defects (NTDs) are common, severe congenital malformations whose causation involves multiple genes and environmental factors. Although more than 200 genes are known to cause NTDs in mice, there has been rather limited progress in delineating the molecular basis underlying most human NTDs. Numerous genetic studies have been carried out to investigate candidate genes in cohorts of patients, with particular reference to those that participate in folate one-carbon metabolism. Although the homocysteine remethylation gene MTHFR has emerged as a risk factor in some human populations, few other consistent findings have resulted from this approach. Similarly, attention focused on the human homologues of mouse NTD genes has contributed only limited positive findings to date, although an emerging association between genes of the non-canonical Wnt (planar cell polarity) pathway and NTDs provides candidates for future studies. Priorities for the next phase of this research include: (i) larger studies that are sufficiently powered to detect significant associations with relatively minor risk factors; (ii) analysis of multiple candidate genes in groups of well-genotyped individuals to detect possible gene–gene interactions; (iii) use of high throughput genomic technology to evaluate the role of copy number variants and to detect ‘private’ and regulatory mutations, neither of which have been studied to date; (iv) detailed analysis of patient samples stratified by phenotype to enable, for example, hypothesis-driven testing of candidates genes in groups of NTDs with specific defects of folate metabolism, or in groups of fetuses with well-defined phenotypes such as craniorachischisis

Text-message reminders increase uptake of routine breast screening appointments : a randomised controlled trial in a hard-to-reach population

Background: There is a need for interventions to promote uptake of breast screening throughout Europe. Methods: We performed a single-blind randomised controlled trial to test whether text-message reminders were effective. Two thousand two hundred and forty women receiving their first breast screening invitation were included in the study and randomly assigned in a 1 : 1 ratio to receive either a normal invitation only (n=1118) or a normal invitation plus a text-message reminder 48 h before their appointment (n=1122). Findings: In the intention-to-treat analysis, uptake of breast screening was 59.1% among women in the normal invitation group and 64.4% in the text-message reminder group (χ2=6.47, odds ratio (OR): 1.26, 95% confidence intervals (CI): 1.05–1.48, P=0.01). Of the 1122 women assigned to the text-message reminder group, only 456 (41%) had a mobile number recorded by their GP and were thereby sent a text. In the per-protocol analysis, uptake by those in the control group who had a mobile number recorded on the GP system was 59.77% and by those in the intervention group who were sent a reminder 71.7% (χ2=14.12, OR=1.71, 95% CI=1.29–2.26, P<0.01). Interpretation: Sending women a text-message reminder before their first routine breast screening appointment significantly increased attendance. This information can be used to allocate resources efficiently to improve uptake without exacerbating social inequalities

Acquired immunologic tolerance: with particular reference to transplantation

The first unequivocally successful bone marrow cell transplantation in humans was recorded in 1968 by the University of Minnesota team of Robert A. Good (Gatti et al. Lancet 2: 1366–1369, 1968). This achievement was a direct extension of mouse models of acquired immunologic tolerance that were established 15 years earlier. In contrast, organ (i.e. kidney) transplantation was accomplished precociously in humans (in 1959) before demonstrating its feasibility in any experimental model and in the absence of a defensible immunologic rationale. Due to the striking differences between the outcomes with the two kinds of procedure, the mechanisms of organ engraftment were long thought to differ from the leukocyte chimerism-associated ones of bone marrow transplantation. This and other concepts of alloengraftment and acquired tolerance have changed over time. Current concepts and their clinical implications can be understood and discussed best from the perspective provided by the life and times of Bob Good

The pivotal role of clinical ethics consults in critical clinical decision making in the Neonatal Intensive Care Unit within an Arab culture

Medical Ethics is a relatively new field in developing countries and, to date, Lebanon is the only Arab country that offers bedside ethics consults; however, this is limited to a single medical center, the American University of Beirut Medical Center (AUBMC). The clinical ethicist running the bedside clinical ethics service was trained in the United States and the United Kingdom. However, once she began practicing in Lebanon, she realized that much of what she learned in terms of theory and practice as well as navigating ethical issues did not apply to the local context. Rather, much needed to be sifted and adapted to a different culture, social decorum, and mentality. This is more evident when working with patients in the Neonatal Intensive Care Unit (NICU), where parents coming from various areas in the region bring in their unique values and beliefs. The admission of a premature newborn to the NICU is often a strenuous experience for parents and a challenge for healthcare providers. Ethical conundrums often arise when there is a potential partial success with a plan of treatment(s). For example, from an ethical point of view resuscitation is less problematic than surviving severe illness with brain damage, and thus controversial issues linked to quality of life surface as living in a vegetative or incapacitated state can be deemed worse than death. In this article, we present our own experience as neonatologists and clinical ethics consultant (CEC) teaming up at the AUBMC’s NICU in an attempt at navigating the muddy waters of decision-making and ethical controversies within an Arab culture characterized with specificities that are often neglected and thus might negatively impact the decision regarding the right plan of treatment. The aim is trying to come up with a recommendation that is in the best interest of the infant and his/her parents and in an attempt to ensure that parents understand the importance of them being part of the decision-making process

Turnpike Catheter failure, causes and mechanisms: Insights from the MAUDE database.

Background: The Turnpike catheters (Teleflex, Wayne, PA, USA) is a microcatheter that was approved by the Food and Drug Administration in November 2014 to be used to access discrete regions of the coronary and peripheral vasculature. Methods: The Manufacturer and User Facility Device Experience (MAUDE) database was queried for reports of the Turnpike catheters from March 2015 through August 2021. Results: A total of 216 reports were found during the study period. After excluding duplicate reports (n = 21), our final cohort included 195 reports. The most common failure mode was catheter tip break or detachment (83%, n = 165) which was significantly associated with over-torquing (p-value = 0.025). The most common clinical consequence was the entrapment of the catheter (33%, n = 65), followed by vessel injury (7.8% n = 15) and vessel occlusion (3.6%, n = 7). Most patients had no consequences (47.0%, n = 93) or recovered (11%, n = 22). A total of 4 deaths were reported. 35.8% of reports (n = 69) specified the presence of severe calcification in the target vessel. Over torquing by interventionists was reported in 33.2% of events (n = 64). Conclusion: Despite clinical trials demonstrating the safety of the Turnpike catheters, complications can still occur. These data serve to inform operators about potentional risks and complications associated with the use of the device. Physicians should avoid over-torqueing which seems to be the most common mechanism for device complications

Effect of a “handshake” stewardship program versus a formulary restriction policy on High-End antibiotic use, expenditure, antibiotic resistance, and patient outcome

This study reports the effect of implementing an antibiotic stewardship program (ASP) based on the “handshake” strategy for 2 years on multiple endpoints compared with that in a preceding period when an antimicrobial restriction policy was only applied in the absence of a complete program in a tertiary-care Lebanese hospital. The studied endpoints were broad-spectrum antibiotic consumption, antibiotic expenditure, nosocomial bacteremia incidence rate, and patient outcome. An interrupted time series analysis was undertaken to assess the changes in the trend (ΔT) and level (ΔL) of the aforementioned endpoints among adult inpatients before (October 2013 to September 2015) and after the introduction of the ASP (October 2016 to September 2018). After the implementation of the “handshake” ASP, marked changes were observed in the consumption of broad-spectrum antibiotics. The mean use density levels for imipenem and meropenem decreased by 13.72% (P = 0.017), coupled with a decreasing rate of prescription (ΔT = −24.83 defined daily dose [DDD]/1,000 patient days [PD]/month; P = 0.02). Tigecycline use significantly decreased in level by 69.19% (P < 0.0001) and in trend (ΔT = −25.63 DDD/1,000 PD/month; P < 0.0001). A reduction in the use of colistin was also documented but did not reach statistical significance (ΔL = −8.71%, P = 0.56; ΔT = −5.51 DDD/1,000 PD/month = −5.5; P = 0.67). Antibiotic costs decreased by 24.6% after ASP implementation (P < 0.0001), and there was a distinct change from an increasing rate to a decreasing rate of expenditure (ΔT = −12.19 US dollars/PD/month; P = 0.002). The incidence rate of nosocomial bacteremia caused by carbapenem-resistant gram-negative bacteria (CRGNB) decreased by 34.84% (P = 0.13) coupled with a decreasing trend (ΔT = −0.23 cases/1,000 PD/month, P = 0.08). Specifically, a noticeable reduction in the incidence rate of bacteremia due to carbapenem-resistant Acinetobacter baumannii was documented (ΔL = −54.34%, P = 0.01; ΔT = −0.24 cases/1000 PD/month, P = 0.01). Regarding patient outcome, all-cause mortality rates did not increase in level or in rate (ΔL = −3.55%, P = 0.59; ΔT = −0.29 deaths/1000 PD/month, P = 0.6). The length of stay and 7-day readmission rate remained stable between the two periods. In conclusion, the “handshake” ASP succeeded in controlling the prescription rates of antibiotics and in decreasing the nosocomial bacteremia rates caused by CRGNB without compromising patient outcome in our facility. It also had an economic effect in reducing antibiotic costs compared with the previous restriction policy on antimicrobial dispensing. © 2020 Edizioni Scientifi che per l'Informazione su Farmaci e Terapia

Visualization of transcoronary ablation of septal hypertrophy in patients with hypertrophic obstructive cardiomyopathy: a comparison between cardiac MRI, invasive measurements and echocardiography

Hypertrophic obstructive cardiomyopathy (HOCM) is treated by surgical myectomy or transcoronary ablation of septal hypertrophy (TASH). The aim of this study was to visualize the feasibility, success and short-term results of TASH on the basis of cardiac MRI (CMR) in comparison with cardiac catheterization and echocardiography. In this in vivo study, nine patients with HOCM were treated with TASH. Patients were evaluated by transthoracic echocardiography, invasive cardiac angiography and CMR. Follow-up examinations were carried out after 1, 3 and 12 months. MR imaging was performed on a 1.5-T scanner. All images were processed using the semiautomatic Argus software and were evaluated by an attending thoracic radiologist and cardiologist. The echocardiographic pressure gradient (at rest) was 69.3 +/- A 15.3 mmHg before and 22.1 +/- A 5.7 mmHg after TASH (P < 0.01, n = 9). The flux acceleration over the aortic valve examined (V (max)) was 5.1 +/- A 0.6 m/s before and 3.4 +/- A 0.3 m/s after the TASH procedure (P < 0.05). Also, there was a decrease of septum thickness from 22.0 +/- A 1.2 to 20.2 +/- A 1.0 mm (P < 0.05) after 6 +/- A 3 weeks. The invasively assessed pressure gradient at rest was reduced from 63.7 +/- A 15.2 to 21.2 +/- A 11.1 mmHg (P < 0.01) and the post-extrasystolic gradient was reduced from 138.9 +/- A 12.7 to 45.6 +/- A 16.5 mmHg (P < 0.01). All differences as well as the quantity of injected ethanol were plotted against the size or amount of scar tissue as assessed in the MRI. There was a statistically significant correlation between the post-extrasystolic gradient decrease and the amount of scar tissue (P = 0.03, r (2) = 0.5). In addition, the correlation between the quantity of ethanol and scar tissue area was highly significant (P < 0.01, r (2) = 0.6), whereas the values for the gradient deviation (P = 0.10, r (2) = 0.34), Delta V (max) (P = 0.12, r (2) = 0.31), as well as the gradient at rest (P = 0.27, r (2) = 0.17) were not significant. TASH was consistently effective in reducing the gradient in all patients with HOCM. In contrast to the variables investigated by echocardiography, the invasively measured post-extrasystolic gradient correlated much better with the amount of scar tissue as assessed by CMR. We conclude that the optimal modality to visualize the TASH effect seems to be a combination of CMR and the invasive identification of the post-extrasystolic gradient.Deutsche Forschungsgemeinschaft (DFG) [MA 1982/2-2, MA 1982/4-1

Towards an end-to-end analysis and prediction system for weather, climate, and Marine applications in the Red Sea

AbstractThe Red Sea, home to the second-longest coral reef system in the world, is a vital resource for the Kingdom of Saudi Arabia. The Red Sea provides 90% of the Kingdom’s potable water by desalinization, supporting tourism, shipping, aquaculture, and fishing industries, which together contribute about 10%–20% of the country’s GDP. All these activities, and those elsewhere in the Red Sea region, critically depend on oceanic and atmospheric conditions. At a time of mega-development projects along the Red Sea coast, and global warming, authorities are working on optimizing the harnessing of environmental resources, including renewable energy and rainwater harvesting. All these require high-resolution weather and climate information. Toward this end, we have undertaken a multipronged research and development activity in which we are developing an integrated data-driven regional coupled modeling system. The telescopically nested components include 5-km- to 600-m-resolution atmospheric models to address weather and climate challenges, 4-km- to 50-m-resolution ocean models with regional and coastal configurations to simulate and predict the general and mesoscale circulation, 4-km- to 100-m-resolution ecosystem models to simulate the biogeochemistry, and 1-km- to 50-m-resolution wave models. In addition, a complementary probabilistic transport modeling system predicts dispersion of contaminant plumes, oil spill, and marine ecosystem connectivity. Advanced ensemble data assimilation capabilities have also been implemented for accurate forecasting. Resulting achievements include significant advancement in our understanding of the regional circulation and its connection to the global climate, development, and validation of long-term Red Sea regional atmospheric–oceanic–wave reanalyses and forecasting capacities. These products are being extensively used by academia, government, and industry in various weather and marine studies and operations, environmental policies, renewable energy applications, impact assessment, flood forecasting, and more.</jats:p