We present two patients with history of recurrent respiratory infections, fatigue and sweating. They were diagnosed with absence of connection between the main pulmonary artery (MPA) and right pulmonary artery (RPA) and bilateral ductus arteriosus, with the RPA originating from the ductus arteriosus. Treatment was approached with a hybrid strategy: percutaneous intraluminal angioplasty with a right intraductal stent and device closure of the left ductus arteriosus and followed by surgical reconstruction with interposition of a graft from RPA to MPA. Both patients had a favorable outcome.
At a time where delivering the best quality of care is the raison d’être of the health service, outliers can pose a serious challenge to both clinicians and policy makers. Methods of outlier detection are highly variable. The collection and assimilation of outcome variables can also be very challenging. Despite this, the publication of surgeon specific data has brought the concept of outliers into the public eye and the consequent punitive action affected upon surgeons can be deleterious to clinician psychology and patient perception. Simultaneously, positive outliers are rarely mentioned and never rewarded. Moving forward, the use of more objective outcomes, including novel biomarkers and patient-centred data, as well as innovative statistical strategies and management cultures, can positively evolve the healthcare paradigm for the future.
Paz-Vinas et al. (2021) comment on methodological and data-related limits of our paper (Millette et al. 2020), which affect a small proportion of our datasets and analyses. These points do not refute our conclusions. We address their comments and support the call for the development of best practices for future macrogenetics research.
Background: Extracorporeal cardiopulmonary resuscitation (ECPR) has emerged as a rescue strategy for non-responders to conventional CPR (CCPR) in cardiac arrest. Definitive guidelines for ECPR deployment do not exist. Prior studies suggest that arrest rhythm and cardiac origin of arrest may be variables used to assess candidacy for ECPR. Aim: To describe a single center experience with ECPR and to assess associations between survival and physician-adjudicated origin of arrest and arrest rhythm. Methods: A retrospective review of all patients who underwent ECPR at a quaternary care center over a 7-year period was performed. Demographic and clinical characteristics were extracted from the medical record and used to adjudicate origin of cardiac arrest, etiology, rhythm, survival, and outcomes. Univariate analysis was performed to determine association of patient and arrest characteristics with survival. Results: Between 2010 and 2017, 47 cardiac arrest patients were initiated on extracorporeal membrane oxygenation (ECMO) at the time of active CPR. ECPR patient survival to hospital discharge was 25.5% (n=12). Twenty-six patients died on ECMO (55.3%) while 9 patients (19.1%) survived decannulation but died prior to discharge. Neither physician-adjudicated arrest rhythm nor underlying origin were significantly associated with survival to discharge, either alone or in combination. Younger age was significantly associated with survival. Nearly all survivors experienced myocardial recovery and left the hospital with a good neurological status. Conclusions: Arrest rhythm and etiology may be insufficient predictors of survival in ECPR utilization. Further multi-institutional studies are needed to determine evidenced based criteria for ECPR deployment.
Ecological processes often exhibit time lags. For plant invasions, lags of decades to centuries between species’ introduction and establishment in the wild (naturalisation) are common, leading to the idea of an invasion debt: accelerating rates of introduction result in an expanding pool of introduced species that will naturalise in the future. Here, I show how a concept from survival analysis, the hazard function, provides an intuitive way to understand and forecast time lags. For plant naturalisation, theoretical arguments predict that lags between introduction and naturalisation will have a unimodal distribution, and that increasing horticultural activity will cause the mean and variance of lag times to decline over time. These predictions were supported by data on introduction and naturalisation dates for plant species introduced to Britain. While increasing trade and horticultural activity can generate an invasion debt by accelerating introductions, the same processes could lower that debt by reducing lag times.
Increasing demands for protein-based therapeutics such as monoclonal antibodies, fusion proteins, bispecific molecules and antibody fragments require researchers to constantly find innovative solutions. To increase yields and decrease costs of next generation bioprocesses, highly concentrated cell culture media formulations are developed but often limited by the low solubility of amino acids such as tyrosine, cystine, leucine and isoleucine, in particular at physiological pH. This work sought to investigate highly soluble and bioavailable derivatives of leucine and isoleucine that are applicable for fed-batch processes. N-lactoyl-leucine and N-lactoyl-isoleucine sodium salts were tested in cell culture media and proved to be beneficial to increase the overall solubility of cell culture media formulations. These modified amino acids proved to be bioavailable for various Chinese hamster ovary (CHO) cells and were suitable for replacement of canonical amino acids in cell culture feeds. The quality of the final recombinant protein was studied in bioprocesses using the derivatives, and the mechanism of cleavage was investigated in CHO cells. Altogether, both N-lactoyl amino acids represent an advantageous alternative to canonical amino acids to develop highly concentrated cell culture media formulations to support next generation bioprocesses.
Generations of cryoballoon transformed the atrial fibrillation ablation landscape. New advancements continue to make cryoballoon more successful and safer treatment. A new cryoballoon PolaRx from Boston Scientific has unique features compared to that of the Medtronic Arctic Front Advance system. Comparison of the two available cryoballoons will require ongoing larger trial and clinical experience.
Very late recurrences after ablation of AVNRT have been reported. Age related alterations of nodal tissues caused by fibrous and fatty tissue infiltration and changes of the sympathovagal influence on the AV node, in turn altering AV nodal conduction and refractoriness, could set the stage for a previously not present substrate for AVNRT. Consequently, the occurrence of AVNRT many years after an ablation procedure may perhaps not always implicate a recurrence but instead an arrhythmia caused by a new substrate.
The use of zolpidem has been driven by the still-widespread false belief among doctors that, since zolpidem is chemically not a benzodiazepine, it cannot lead to addiction and tolerance. We would like to contribute to better highlight certain characteristics of zolpidem and its potential as a substance of abuse due to the fact that our operating unit, which is entirely dedicated to medication abuse, has described among the most numerous cases of addiction to high doses of benzodiazepines and related hypnotics. - Zolpidem was in fourth place among the 29 molecules present on the Italian market; - We believe it’s now time to drop the term “Z-drugs”: zolpidem, zopiclone e zaneplon all have different chemical structures, they bind to different receptors and have completely different abuse potentials3. In our case history, both zopiclon and zaneplon were virtually absent, albeit being commonly used in Italy; - Istvan & colleagues highlight the fact that addiciton and abuse are prevalent in samples suffering from mental illness. In our case history this hasn’t been confirmed: about half of our patients had no history of psychiatric illnesses, nor a history of addiction to illicit substances or alcohol; - Lastly, regarding zolpidem’s hazardousness, we would like to report the fact that the drug was significantly preferred by addicts with a positive ADHD test result. In conclusion, the 2000s saw solid confirmation of the effectiveness of partial agonists in the treatment of some common addictions, such as buprenorphine, varenicline, cytisine. This didn’t happen for BZs
Higher risk of allergies at 4-6 years of age after systemic antibiotics in the first week of life To the editor,In humans, the first 100 days appear to be a ”critical window” of colonization during which microbial communities shape immune maturation.1,2. The use of antibiotics early in life may disrupt the normal maturation process leading to adverse health outcomes such as atopic disorders 1,3-5. The effects of antibiotic exposure immediately in the first week of life have rarely been investigated, nor the differences between treatment of 2-3 days and a prolonged treatment of 5-7 days. In the INCA study, a prospective birth cohort study of 151 infants receiving broad-spectrum antibiotics in their first week of life (AB+), and 285 healthy controls (AB-), we previously showed that antibiotic treatment in the first week of life was associated with an increased risk of wheezing, infantile colic and a trend towards more allergic sensitization in the first year of life6. The aim of this follow-up study in 418 eligible children was to determine if antibiotic treatment in the first week of life in term-born children was associated with an increase in atopic disorders at 4-6 years of age, using ISAAC questionnaires filled out by parents, ICPC codes derived from general physicians, and pharmaceutical records from local pharmacies. Detailed information regarding the subjects and methods is described in the online Appendix.In total, 341 of 418 (82%) questionnaires were filled out (114 AB+ and 227 AB-), Parental reported allergy was significantly higher in AB+ vs AB- children (23% vs 11% respectively, p=0.003) as was doctor-diagnosed allergy (12% vs 4% respectively, p=0.008). Confirmed food allergies were more common in AB+ children compared with AB- children (10 vs. 4% respectively, p=0.03). After correcting for sex, age, daycare attendance, family atopy, and parental level of education, parental-reported allergy was clearly associated with antibiotics use in the first week of life (aOR 2.40 [95%CI 1.22-4.72, p=0.01]). Additional adjustment for treatment duration showed that only 5-7 and not 2-3 days AB treatment was associated with a higher risk of parental reported allergy (aOR 2.85 [95%CI 1.37-5.91, p=0.005]). More importantly, this effect was independent of exposure to acid-suppressive drugs or additional antibiotics in the first two years of life (36% and 35% in AB- and AB+ group, respectively). The prevalence of eczema, wheezing/asthma, or allergic rhinitis was not different between AB+ and AB- children (Table 2).These results suggest that very early exposure to AB in the first week of life has a higher impact on microbiota and immune development than when administered later in childhood. It also emphasizes the need for judicious use of AB in neonates, especially prolonged treatment of 5-7 days. Moreover, our findings accentuate the need for finding strategies to modify microbiome development after AB exposure to minimize aberrant immune development.Strengths of this study are the prospective design, the high response rate (82%), and the combined information collected from doctors and pharmacists, contributing to the reliability of the reported results, which allowed us to distinguish between the effect of antibiotics within and after the first week of life. A limitation of the study is the 4-6-year follow-up, which may have been too short for diagnosing asthma and allergic rhinitis.In conclusion, the risk of having an allergy at 4-6 years of age increased nearly 3-fold in children after antibiotic treatment for 5-7 days in their first week of life, independent of later AB treatment. These long-term adverse health effects of neonatal antibiotic use emphasize the need to implement AB stewardship programs to avoid AB overuse and reduce the duration of AB treatment where possible in the first week of life.
A 60-year-old female was referred to our clinic for evaluation of her rapidly progressive dyspnea, she had no previuos history of heart disease. A murmur was noted on her examination and transthoracic echocardiography was so difficult to be performed due to poor acoustic windows so she was referred to do a transesophageal echocardiography that showed an ostium primum atrial septal defect (ASD) with left to right shunt and a quadrileaflet mitral valve with severe regurgitation. Later on, she underwent surgery with Ostium Primum ASD closure by a patch and double cleft repair by suture after right heart catheterization.
Risk stratification of HPV positive women in routine cervical screeningHigh risk HPV primary screening is replacing organised cytology-based screening based on increased sensitivity to detect high grade intra-epithelial neoplasia and the very high negative predictive value which will allow extended screening intervals. The benefit of increased CIN detection and cancer prevention needs to balance against the disbenefits to screen positive women in over investigation not east the psychological impact. For colposcopy services, the English cervical screening programme reported a 80% increase in colposcopy referrals in the first round of screening, creating huge pressures on service capacity (Rebolj M et al BMJ 2019;364:l240). The lower positive predictive value also impacts on colposcopy performance with a different referral population wit proportionately less high grade CIN present. In this issue of BJOG, Gori M et al provide observational data from a large longitudinal study of routine primary HPV screening in an organised quality assured cervical screening programme in 3 regions of Italy. Whilst routinely collected data from real-world programmes will have limitations, they do provide an insight into disease detection and importantly impact on colposcopy provision. In a comparison of triage strategies, combined HPV genotyping for HPV16 and high-grade cytology offered an acceptable balance of risk of CIN3+ with number of colposcopies needed to detect one lesion. These results differ from the English pilot (Rebolj M et al 2019 BJC;121(6):455-463) where HPV16/18 genotyping detected only 1.2% more cases of CIN2+ with 5.9% additional colposcopies. Gori M et al did not combine HPV16/18 but they did report that HPV18 on genotyping was not as clinically useful at baseline or 12-month follow-up. Furthermore, 90% of women screened were aged over 35 years when HPV screening is more clinically effective whereas the English pilot started screening at age 25 years when HPV infection is more prevalent and less likely to be clinically significant. Longer follow-up, importantly at the next screening round, is not yet available when the relevance of non-HPV 16 types may be more apparent.The impact of the Covid 19 pandemic on health services and in particular screening, has sharpened the argument of risk stratification following primary screen positive testing both for service providers and those in the target population. Ciavattini A et al (2020 Int J Cancer 30(8):1097-1100) reported on suspension or postponement of cervical screening programmes across Europe relevant to both routine screening and onward referral to colposcopy. As services have needed to adapt to Covid infection rates and health service capacity, the ability to triage effectively and avoid unnecessary hospital visits is critical. Clinicians and women need information on their risk to inform clinical practice and provide reassurance. In the current second wave, the suspension of screening implemented in the first wave is no longer acceptable. Whilst data, such as these from Gori et al, continue to emerge from national and regional screening programmes, Covid has highlighted the need to be responsive and adaptive to allow cancer prevention to continue.
Photochemical reactions of small molecules occur upon irradiation by ultraviolet or visible light, and they are a very important and controversial chemical process in the Earth’s atmosphere because they impact our quality of life and health. Small-unsaturated carbonyl compounds play an important role in the chemistry of the polluted troposphere. The fluorinated aldehydes are very reactive under the sunlight driving to species that trigger more atmospheric reactions. This paper is focused on a theoretical study of the photochemistry of difluoro-crotonaldehyde using static and dynamic calculations by combination of Global Reaction Route mapping (GRRM) and Trajectory Surface Hopping (TSH) approach. The static analysis of the electronic and geometrical structures at the critical points allowed to rationalize the possible pathways that interconnect the stationary and crossing points in order to get a map of the unimolecular photochemical reactions which take place. The time evolution of the electronic states and the degrees of freedom enabled the identification of the requirements to follow the most probable deactivation pathways. This article reports the unimolecular deactivation pathways after the electronic excitation of the trans and cis isomers. In both cases, the excitation energies were calculated and compared with the analogous in the crotonaldehyde in order to elucidate the effect of fluorine atoms on the electronic structure and stabilities. After the initial excitations to the ππ* excited states, the main deactivation channels follow non-adiabatic pathways via S1/S0 conical intersections. Ultrafast processes leading to the early activation of the S1 govern the decay of the difluoro-crotonaldehyde. Depending on the nature of the S1 state before the crossing with the S0, the system can follow several reaction pathways. The main photochemical processes observed were the cis-trans isomerization, the Norrish type I reaction (α-cleavage), Norrish type II reaction (γ-hydrogen abstraction) and fluorine photodissociation. The time scale, the molecular deformations and the electronic states implied for the different photochemical processes, as well as how these compete with the photophysical deactivation are discussed.
Atrial tachycardia (AT) in the right atrium often occurs following open-heart surgery. Catheter ablation for these AT is challenging and can lead to unintended conduction block. We performed late-gadolinium enhancement magnetic resonance imaging prior to catheter ablation and predicted wavefront propagation during SR as well as the slow conduction zone
Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID-19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post-authorization and post-marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research.
We are reporting a case of neurofibromatosis type 1 in a genotype-phenotype correlation and chromosomal microarray test revealed a submicroscopic deletion on the long arm of chromosome 17, which is associated with a more severe phenotype. The presence of a more severe phenotype warrants precise monitoring of complications.
Background: Therapeutic drug monitoring for busulfan is important to prevent adverse events and improve outcomes in stem cell transplantation. We investigated intravenous busulfan pharmacokinetics and evaluated the utility of limited sampling strategy (LSS) as a simple method to estimate the area under the concentration-time curve (AUC). Procedure: The study comprised 87 busulfan measurements in 54 children who received intravenous busulfan between August 2015 and May 2020. AUCs were calculated from 3–5 blood sampling points in each patient, and the correlation between AUC and plasma concentrations (ng/mL) at 1, 2, 3, 4, and 6 h after initiating busulfan infusion (C1, C2, C3, C4, and C6, respectively). Results: By one-point sampling strategy, the most accurate predicted AUC was based on C6 (r2 = 0.789; precision, 11.0%) in all patients. The predicted AUC based on C6 was highly precise (r2 = 0.937; precision, 5.9%) in adolescent patients weighing > 23 kg, but the correlation was poor in infants and young children weighing ≤23 kg (r2 = 0.782; precision, 11.4%). By two-point sampling strategy, the predicted AUC based on C3 and C6 showed the most favorable performance (r2 = 0.943; precision, 6.4%), even in infants and young children, whereas the predicted AUC based on C3 and C6 was acceptable (r2 = 0.963; precision, 5.7%). Conclusions: The AUC of busulfan can be predicted based on C6 in adolescent patients. However, there was substantial inter-individual variation in busulfan pharmacokinetics in infants and young children, in whom two-point LSS was necessary for accurate AUC prediction.