Improved global access to novel age-appropriate formulations for paediatric subsets, either of new chemical entities or existing drugs, is a priority to ensure that medicines meet the needs of these patients. However, despite regulatory incentives, the introduction to the market of paediatric formulations still lags behind adult products. This is mainly caused by additional complexities associated with the development of acceptable age-appropriate paediatric medicines. This position paper proposes the use of a paediatric Quality Target Product Profile (pQTPP) as an efficient tool to facilitate early planning and decision making during the children-centric formulation design for new chemical entities, or to repurpose/reformulate off-patent drugs. Essential key attributes of a paediatric formulation are suggested and described. Moreover, greater collaboration between formulation experts and clinical colleagues, including healthcare professionals, is advocated to lead to safe and effective, age-appropriate medicinal products. Acceptability testing should be a secondary endpoint in paediatric clinical trials to ensure post-marketing adherence is not compromised by a lack of acceptability. Not knowing the indications and the related age groups and potential dosing regimens early enough is still a major hurdle for efficient paediatric formulation development; however the proposed pQTPP could be a valuable collaborative tool for planning and decision making to expedite paediatric product development.

Objective To analyze the effect of nasopharyngeal ventilation on the detection rate of colorectal polyps in 200 middle-aged and elderly overweight patients during painless colonoscopy. Methods A total of 100 patients aged 50-75 years, body mass index (BMI) ≥24 or abdominal circumference ≥85 cm in males and ≥82 cm in females, without underlying diseases, who underwent nasopharyngeal ventilation during painless colonoscopy at physical examinations in our hospital from 2019 to 2020, were selected as the observation subjects (n = 100). The control sample area was determined by propensity matching according to the basic information characteristics presented by the observation group. 100 patients received mask oxygen at physical examinations were randomly selected in the control group (n = 100). Results The verification analysis after matching indicated that there were no intraoperative and postoperative adverse reactions, the number of intraoperative limb movements was less than 1, and the intestinal peristalsis intervals were more than 5s in both groups, without atropine intervention. Colonoscopy was performed by senior endoscopists with a withdrawal time of 6-8 min. When the intraoperative SpO2 was lower than 90% but higher than 85%, the patients in the observation group underwent nasopharyngeal ventilation while those in the control group received mask oxygen assisted chin-lift. As a result, the SpO2 was maintained higher than 90%. The detection rate of colorectal polyps was compared between the two groups. Conclusion The detection rate of colorectal polyps in the observation group was higher than that in the control group, with a statistically significant difference. It may result from the reduction of ineffective respiratory movement and intraoperative intestinal peristalsis in middle-aged and elderly overweight patients.

The choice of patient for a single lung resection is challenging for the surgeon. This report is presenting our experience in surgical treatment for patient with metastatic synovial sarcoma who initially underwent total left pneumonectomy and to identify possible predictors for the selection of patients who may undergo surgical treatment.

Objective: Investigate the cardiorespiratory effects of non-invasive neurally adjusted ventilatory assist (NIV-NAVA), non-synchronized nasal intermittent positive pressure ventilation (NIPPV), and nasal continuous positive airway pressure (NCPAP) during the critical period shortly after extubation. Hypothesis: Levels of non-invasive pressure support provided and/or presence of synchronization can affect cardiorespiratory parameters. Study design: Randomized crossover trial. Patient-subject selection: Infants with birth weight (BW) ≤ 1250g undergoing their first planned extubation were randomly assigned to all 3 modes following extubation. Methodology: Electrocardiogram and electrical activity of the diaphragm (Edi) were recorded during 30min on each mode. Analysis of heart rate variability (HRV), diaphragmatic activity (Edi area, breath area, amplitude, inspiratory and expiratory times) and respiratory variability (RV) were compared between modes. Results: 23 enrolled infants had full data recordings and analysis: median [IQR] gestational age = 25.9 weeks [25.2-26.4], BW = 760g [595-900], and post-natal age 7 [4-19] days. There were no differences in HRV parameters between modes. During NIV-NAVA and NIPPV, diaphragmatic activity was significantly lower and RV higher than NCPAP. Delivered peak inflation pressures (PIPs) were lower during NIV-NAVA than NIPPV (14 cmH2O [13-16] vs cmH2O 16 [16-17]; p<0.001). However, due to a significantly higher proportion of assisted breaths (99% [92-103] vs. 51% [38-82]; p<0.001) NIV-NAVA provided a higher mean airway pressure (MAP)(9.4 cmH2O [8.2-10.0] vs. 8.2 cmH2O [7.6-9.3]; p=0.002). Conclusions: NIV-NAVA and NIPPV applied shortly after extubation were associated with positive cardiorespiratory effects. This effect was more evident during NIV-NAVA where patient-ventilator synchronization provided a higher MAP with lower PIPs.

A type 1 diabetic patient with unilateral active thyroid-related eye disease was intolerant to systemic steroid therapy due to uncontrollable blood sugar levels. She was treated with low-dose methotrexate monotherapy which resulted in a marked improvement of her condition with no adverse events.

Background: Despite a proven mortality benefit in primary prevention (PP) patients, the utilization of implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy-defibrillators (CRT-D) remains low in many geographies. Purpose: The objective of this analysis was to examine the mortality benefit in PP patients by guideline-indicated device type: implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy-defibrillator (CRT-D). Methods: Improve SCA was a prospective, non-randomized, non-blinded multicenter trial that enrolled patients from regions where ICD utilization is low. PP patient’s CRT-D or ICD eligibility was based upon the 2008 ACC/AHA/HRS and 2006 ESC guidelines. Mortality was assessed according to guideline-indicated device type comparing implanted and non-implanted patients. Cox proportional hazards methods were used, adjusting for known factors affecting mortality risk. Results: Among 2,618 PP patients followed for a mean of 20.8 ± 10.8 months, 1,073 were indicated for a CRT-D, and 1,545 were indicated for an ICD. PP CRT-D-indicated patients who received CRT-D therapy had a 58% risk reduction in mortality compared to those without implant (adjusted HR 0.42, 95% CI: 0.28-0.61, P<0.0001). PP patients with an ICD indication had a 43% risk reduction in mortality with an ICD implant compared with no implant (adjusted HR 0.57, 95% CI: 0.41-0.81, P=0.002). Conclusions: This analysis confirms the mortality benefit of adherence to guideline-indicated implantable defibrillation therapy for PP patients in geographies where ICD therapy was underutilized. These results affirm that medical practice should follow clinical guidelines when choosing therapy for PP patients who meet the respective defibrillator device implant indication.

- Invited Commentary –

γ-Glutamyl carboxylase (GGCX) catalyses γ-carboxylation of 15 different vitamin K dependent (VKD) proteins. Pathogenic variants in GGCX cause a rare hereditary bleeding disorder called Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1). In addition to bleedings, some VKCFD1 patients develop skin laxity and skeletal dysmorphologies. However, the pathophysiological mechanisms underlying these non-haemorrhagic phenotypes remain elusive. Therefore, we analyzed the effect of 22 GGCX pathogenic variants on γ-carboxylation of six non-haemostatic VKD proteins (UCMA/GRP, MGP, BGLAP, GAS6, PRGP1, TMG4) in a GGCX-/- HEK293T cell line by a functional ELISA. We observed that biallelic deficiency to γ-carboxylate Gla-rich protein lead to the development of skin laxity. Markedly reduced level of γ-carboxylated MGP is crucial but not exclusive for causing facial dysmorphologies. Moreover, we identified the vitamin K hydroquinone binding site in GGCX in an in silico model by docking studies, which was further validated by functional assays. Variants affecting this site result into loss-of-function or severely diminished ability to γ-carboxylate VKD proteins and hence are involved in the most severe phenotypes. This genotype-phenotype analysis will help to develop new treatment options for VKCFD1 patients, where individualized therapy with γ-carboxylated VKD proteins may represent a promising strategy.

Background Guidelines standardise high-quality evidence-based management strategies for clinicians. Uterine fibroids are a highly prevalent condition and may exert significant morbidity. Objectives The purpose of this study was to appraise national and international uterine fibroid guidelines using the validated AGREE-II instrument. Selection Strategy An electronic database search of PubMed and EMBASE from inception to October 2020 for all published English-language uterine fibroid clinical practice guidelines was undertaken. Data Collection and Analysis 939 abstracts were screened for eligibility by two reviewers independently. Three reviewers used the AGREE-II instrument to assess guideline quality in six domains (scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability, and editorial independence). Recommendations were mapped to allow a narrative synthesis regarding areas of consensus and disagreement. Main Results Eight national (AAGL, SOGC 2014, ACOG, ACR, SOGC 2019, CNGOF, ASRM, and SOGC 2015) and one international guideline (RANZOG) were appraised. The highest scoring guideline was RANZOG 2001(score 56.5%). None of the guidelines met the a priori criteria for being high-quality overall (score >= 66%). There were 166 recommendations across guidelines. There were several areas of disagreement and uncertainty. Conclusions There is a need for high-quality fibroid guidelines given heterogeneity across individuals and a large range of treatment modalities available. There are also areas of controversy in the management of fibroids (e.g. Ulipristal acetate, power morcellation) which also should be addressed in any guidelines. Future guidelines should be methodologically robust to allow high-quality decision-making regarding fibroid treatments.

Background: Several new variants of SARS-CoV-2 have emerged since fall 2020 which have multiple mutations in the receptor binding domain (RBD) of the spike protein. It is unclear which mutations affect receptor affinity versus immune recognition. Methods: We produced RBD with single mutations (E484K, K417N or N501Y) or with all three mutations combined and tested their binding to ACE2 by biolayer interferometry (BLI). The ability of convalescent sera to recognize RBDs and block their interaction with ACE2 was tested as well. Results: We demonstrated that single mutation N501Y increased binding affinity to ACE2 but did not significantly affect its recognition by convalescent sera. In contrast, single mutation E484K had almost no impact on the binding kinetics, but essentially abolished recognition of RBD by convalescent sera. Interestingly, combining mutations E484K, K417N and N501Y resulted in a RBD with both features: enhanced receptor binding and abolished immune recognition. Conclusion: Our data demonstrate that single mutations either affect receptor affinity or immune recognition while triple mutant RBDs combine both features.

Significant changes or cancellation of MCIT could result in limiting access to breakthrough medical technologies that could improve the health and well-being of Medicare beneficiaries. For these reasons, we encourage federal agencies to work together and CMS to implement the MCIT rule without delay to ensure timely access to breakthrough technologies

Lentigines are brown macules which represent increased proliferation of melanocytes at the dermo-epidermal junction. We report three cases of acral lentiginosis in children following chemotherapy for acute lymphoblastic leukaemia (ALL) which have persisted following cessation of chemotherapy, despite avid photoprotection.

1. The balance between risk and benefit of exploiting resources drives life history evolution. Predators are naturally recognized as major drivers of the life history evolution of their prey. The concept of an evolutionary arms race posits that prey also influence the life history evolution of their predators. There is far more evidence on the role of predators than of prey. 2. The goal of this study was to investigate the role of prey in life history evolution of predators using ladybird beetle predators either of aphids or coccids. These particular organisms were chosen because literature shows that the pace of life of aphids is faster than that of coccids and this difference is reflected in the life histories of the ladybirds that specialize on feeding on aphids or coccids. 3. Thirty-four species of ladybird predators of aphids and eight of coccids belonging to five different tribes were collected and reared in the laboratory. The females were weighed as well as their eggs, and their reproductive investment calculated as the number of ovarioles multiplied by the average mass of an egg. Phylogenetic relatedness was controlled for in the statistical analyses. 4. Controlling for female mass revealed that ladybird predators of aphids lay bigger eggs and have a higher reproductive investment than ladybird predators of coccids. These differences are not influenced by phylogenetic relatedness but only by the type of prey. We suggest that ladybird predators of coccids lay smaller eggs because neonate larvae do not have to search, catch and subdue prey, and that they have a smaller reproductive investment because they need to allocate more resources to locate prey. 5. Recognizing the influence of prey on the life history evolution of predators is important for understanding food web dynamics.

Biodiversity inventory remains limited in marine systems due to unbalanced access to the three ocean dimensions. The use of environmental DNA (eDNA) for metabarcoding allows fast and effective biodiversity inventory and is forecast as a future biodiversity research and biomonitoring tool. However, in poorly understood ecosystems, eDNA results remain difficult to interpret due to large gaps in reference databases and PCR bias limiting the detection of some major phyla. Here, we aimed to circumvent these limitations by avoiding PCR and recollecting larger DNA fragments to improve assignment of detected taxa through phylogenetic reconstruction. We applied capture by hybridization (CBH) to enrich DNA from deep-sea sediment samples and compared the results with those obtained through an up-to-date metabarcoding PCR-based approach (MTB). Originally developed for bacterial communities by targeting 16S rDNA, the CBH approach was applied to 18S rDNA to improve the detection of species forming benthic communities of eukaryotes, with particular focus on metazoans. The results confirmed the possibility of extending CBH to metazoans with two major advantages: i) CBH revealed a broader spectrum of prokaryotic, eukaryotic, and particularly metazoan diversity, and ii) CBH allowed much more robust phylogenetic reconstructions of full-length barcodes with up to 1900 base pairs. This is particularly important for taxa whose assignment is hampered by gaps in reference databases. This study provides a database and probes to apply 18S CBH to diverse marine systems, confirming this promising new tool to improve biodiversity assessments in data-poor ecosystems like those in the deep sea.

OBJECTIVES: The frozen elephant trunk (FET) technique has become an important tool in the treatment of acute type A aortic dissection. The aim of this study was to evaluate the effect of long FET on spinal cord injury (SCI) and distal aortic remodeling after acute type A aortic dissection based on clinical and radiological outcomes. METHODS: From January 2018 to November 2019, 158 patients [mean age 51.8 years (range 32 - 78 years), 88.6% male] with acute type A aortic dissection were treated by FET with 100 mm (n=113) or 150 mm (n=45) open hybrid stent graft prosthesis. Patients were divided into two groups according to the length of FET. The clinical and radiological outcomes of the patients were reviewed retrospectively. RESULTS: Postoperative outcomes did not differ significantly: in-hospital mortality (9.7% vs 6.7%, P=0.758) and SCI (5.3% vs 2.2%, P=0.674). Aortic remodeling, which was evaluated by aortic diameter, true lumen diameter, false lumen diameter and the rate of false lumen complete thrombosis, was more positive in long FET group in the descending thoracic aorta during the follow-up period. At the abdominal level, there was no statistically significant difference between the two groups. CONCLUSIONS: The long version of FET does not increase the risk of SCI in patients with acute type A aortic dissection. The application of long FET can achieve better results in terms of remodeling of the thoracic aorta in the short- and medium-term follow-up.

Infectious endocarditis (IE) is a rare condition with an estimated yearly incidence of 3 to 10 cases per 100,000 people[1]. Its in-hospital mortality rate hovers around 18%, with one-year mortality reaching up to 40%[2]. Although nearly 50% of IE cases now undergo surgical intervention, it does not appear to elevate the in-hospital mortality risk[3]. Wei et al conducted a study on the relationship between red blood cell distribution width (RDW) value and postoperative death of IE patients. Their most remarkable finding was the in-hospital mortality rate was significantly higher in the High RDW group(55.6%vs.2.7%)[4]. Their results suggestted that RDW may become a valuable biomarker for estimating poor postoperative outcome in patients with IE. RDW reflects the variable size of circulating red blood cells and is routinely used to narrow the differential diagnosis of anemia. However, many studies had revealed that RDW maybe a new prognostic marker to predict the cardiovascular event. The increased value have been always linked with inflammatory and oxidative states. Further studies are required to explore the mechanism for the relationship between the RDW and adverse clinical outcomes.

Inadequate pasture management causes land degradation and negative impacts on the socio-economic development of agricultural regions. Given the importance for Brazil and the World of pasture-based livestock production, the recognition of pasture degradation is essential. The use of remote sensing satellite systems to detect degraded pastures increased in the recent past, because of their capability to survey large portions of Earth’s surface. A struggle nowadays is to improve detection accuracy and to implement high-resolution surveys at farmland scale using unmanned aerial vehicles (UAVs). The satellite sensors capture reflectance from the visible spectrum and near infrared bands, which allows estimating plant’s vigor vegetation indices. The NDVI is a widely accepted index, but to generate an NDVI map using a UAV a relatively high-cost multispectral sensor is required, while most UAVs are equipped with low-cost RGB cameras. In the present study, a script developed on the Google Earth Engine image-processing platform manipulated images from the Landsat 8 satellite, and compared the performances of NDVI and an improved color index that we coined “Total Brightness Quotient” of red (TBQR), green (TBQG) and blue (TBQB) bands. An efficient detection of pasture degradation using the TBQs would be a good prognosis for the surveys at farm scale where environmental authorities are progressively using UAVs and forcing landowners towards pasture restoration. When compared to NDVI, the TBQG showed a correlation of 0.965 and an accuracy of 88.63%. Thus, the TBQG proved as efficient as the NDVI in the diagnosis of degraded pastures.

Current guidelines do not adequately acknowledge the potential acute consequences in patients receiving both rituximab and COVID-19 vaccination. We report a case of rituximab-induced lympholysis and pancytopenia in a patient who received Moderna COVID-19 vaccine ten days before rituximab infusion. These observations highlight the urgent need to update current guideline.