Objective To test equivalence of two doses of intravenous iron (ferric carboxymaltose) in pregnancy. Design Parallel, two-arm equivalence randomised controlled trial with an equivalence margin of 5%. Setting Single centre in Australia. Population 278 pregnant women with iron deficiency. Methods Participants received either 500 mg (n=152) or 1000mg (n=126) of intravenous ferric carboxymaltose in the second or third trimester. Main outcome measures The proportion of participants requiring additional intravenous iron (500mg) to achieve and maintain ferritin >30ug/L (diagnostic threshold for iron deficiency) at 4 weeks post-infusion, and at 6 weeks, and 3-, 6- and 12-months postpartum. Secondary endpoints included repeat infusion rate, iron status, birth, and safety outcomes. Results The two doses were not equivalent within a 5% margin at any timepoint. At 4 weeks post infusion, 26/73 (36%) participants required a repeat infusion in the 500 mg group compared with 5/67 (8%) in the 1000 mg group (difference in proportions, 0.283 95% confidence interval (0.177, 0.389)). Overall, participants in the 500 mg arm received twice the repeat infusion rate (0.81 (SD= 0.824 vs 0.40 (SD= 0.69), rate ratio 2.05, 95% CI (1.45, 2.91)). Conclusions Administration of 1000mg ferric carboxymaltose in pregnancy maintains iron stores and reduces the need for repeat infusions. A 500 mg dose requires ongoing monitoring to ensure adequate iron stores are reached and sustained.

Background and Objective: Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Anti-glycoprotein autoantibodies play a key role in the pathophysiology of ITP, but the relationship between platelet-specific antibodies and bleeding severity is unclear. This study aimed to analyze the relationship between anti-glycoprotein autoantibodies and bleeding severity in children with newly diagnosed ITP and platelet count <10×109/L. Method: This was a single-center prospective observational study that analyzed children with newly diagnosed ITP and platelet count <10×109/L between June 2018 and September 2021 at our hospital. The children were classified into the mild and severe groups based on the bleeding scores. The type and titer of anti-glycoprotein autoantibodies were detected using an ELISA kit (PAKAUTO). We analyzed the relationship between bleeding severity and anti-glycoprotein autoantibodies. Results: A total of 86 cases were enrolled, including 42 in the mild group and 44 in the severe group. Patients with anti-GPIIb/IIIa or anti-GPIb/IX antibodies suffered more severe bleeding than patients without them (c2=7.303, p=0.007; c2=3.875, p=0.049), but there was no significant difference between patients with or without anti-GPIa/IIa antibody (c2=0.745, p=0.388). When antibodies were analyzed together, patients with three antibodies suffered more severe bleeding than those without three antibodies (c2=5.053, p=0.025). Patients with higher antibody titer in the eluent, but not in the plasma, suffered more severe bleeding in all three antibodies (Z=-2.389, p=0.017; Z=-2.108, p=0.035; Z=-2.557, p=0.011). Conclusion: Anti-glycoprotein autoantibodies led to more severe bleeding in children under 18 years of age without drug treatment with newly diagnosed ITP and platelet count <10×109/L.

Background: Hemostatic disturbances with coronavirus disease 2019 (COVID-19) can predispose to tricuspid and right heart thrombi in very rare instances. Aim: We describe a 29-year-old female patient without previous cause of thrombosis who developed large tricuspid valve thrombus (TVT) and moderate-to-severe tricuspid regurgitation (TR) during the course of COVID-19 infection. Materials and methods: Persistant fever and tachycardia with thrombocytopenia and high D-dimer increased the index of suspicion. The diagnosis was made by bedside transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR). Surgery was performed for thrombectomy and tricuspid valve replacement with a tissue valve. Discussion and conclusion: Detection of TVT in COVID-19 patients on the basis of high index of suspicion, bedside TTE and non-invasive CMR helps early surgical treatment and subsequent reduction of mortality and hospital stay.

Wildlife population dynamics are modulated by abiotic and biotic factors, typically climate, resource availability, density-dependent effects, and predator-prey interactions. Understanding if human-caused disturbances shape these processes is needed for the conservation and management of ecological communtiies within increasingly human-dominated landscapes. Garnering this understanding is difficult due to lack of long-term longitudinal data on wildlife populations, human-mediated disturbances, climate and predator density on ungulate population dynamics has been under-studied. Using a 50-year time series (1962-2012) on mule deer (Odocoileus hemionus) demographics, seasonal weather, predator density, oil and gas development patterns from the North Dakota Badlands to investigate long-term effects of landscape-level disturbance. We aimed to evaluate if harsh weather conditions in-combination with energy development and predators affected fall mule deer recruitment. We found that density-dependent effects and harsh seasonal weather primarily drove recruitment in the North Dakota Badlands. Recruitment was further shaped by interacting effects of harsh seasonal weather and predator presence in the form of high coyote density. Additionally, we found that fall recruitment was subtly modulated by interactions between seasonal weather and energy development (i.e., lower recruitment when harsher weather was combined with higher density of active oil and gas wells), and that the combined effect of predator density and energy development was not interactive but rather additive. Our analysis demonstrates the effect of energy development by modulating mule deer recruitment fluctuations concurrent with main recruitment drivers being biotic (density-dependency, habitat, predation) and abiotic (harsh seasonal weather, woody vegetation encroachment). A pattern emerges of density dependence, presumably due to limited quality habitat, being the primary factor influencing fall fawn recruitment in mule deer. Secondarily, stochastic weather events periodically cause dramatic declines in recruitment. Finally, the interactions between human disturbance and predation can be additive to the aforementioned drivers of recruitment and subsequently cause further declines.

Cerebral Venous thrombosis can be caused by different conditions such as infectious, structural, hypercoagulable states, hematological, hormonal, collagen, vascular diseases, and oral contraceptive pills among other causes. Adenomyosis has been rarely associated with CVT. Increased CA-125 and Iron deficiency anemia in adenomyosis may predispose to CVT.

’Kissing molars’, were described by Van Hoof in 1973 as when the occlusal surfaces of impacted molars are united by the same follicular space and the roots point in the opposite direction[1]. There are very few published cases in the literature, it is an extremely rare form of impaction.

Title Page Title: Letter to the Editor: ” Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: A longitudinal, placebo- controlled study ”.Article type : Letter to the editor.

Plant metabolomics has been used widely in plant physiology, in particular to analyse metabolic responses to environmental parameters. Derivatization (via trimethylsilylation-methoximation) followed by GC-MS metabolic profiling is a major technique to quantify low molecular weight, common metabolites of primary carbon, sulphur and nitrogen metabolism. There are now excellent opportunities for new generation analyses, using high resolution, exact mass GC-MS spectrometers that are progressively becoming relatively cheap. However, exact mass GC-MS analyses for routine metabolic profiling are not common, there is no dedicated available database. Also, exact mass GC-MS is usually dedicated to structural resolution of targeted secondary metabolites. Here, we present a curated database for exact mass metabolic profiling (made of 336 analytes, 1,064 characteristic exact mass fragments) focused on molecules of primary metabolism. We show advantages of exact mass analyses, in particular to resolve isotopic patterns, localise S-containing metabolites, and avoid identification errors when analytes have common nominal mass peaks in their spectrum. We provide a practical example using leaves of different Arabidopsis ecotypes and show how exact mass GC-MS analysis can be applied to plant samples and identify metabolic profiles.

SRD5A3-CDG (MIM 612379) is an extremely rare congenital disease, with only 38 cases having been reported. Common manifestations are developmental delay, intellectual disability, ophthalmological abnormalities, cerebellar abnormalities, ataxia, and hypotonia. Here, we discuss a seven-year-old boy with SRD5A3-CDG (homozygous variant c.57G>A [p.Trp19Ter]), featuring the unprecedented finding of telangiectasia.

The diet of an individual animal is subject to change over time, both in response to short-term food fluctuations and over longer time scales as an individual ages and meets different challenges over its life cycle. A metabarcoding approach was used to elucidate the diet of different life stages of a songbird, the Eurasian reed warbler (Acrocephalus scirpaceus) over the summer breeding season of 2017. The faeces of adult, juvenile and nestling warblers were screened for invertebrate DNA, enabling identification of prey species. Dietary analysis was coupled with monitoring of Diptera in the field using yellow sticky traps. Seasonal changes in warbler diet were subtle whereas age class had a greater influence on overall diet composition. Age classes showed high dietary overlap, but significant dietary differences were mediated through the selection of prey, i) from different taxonomic groups, ii) with different habitat origins (aquatic versus terrestrial) and iii) of different average approximate sizes. Our results highlight the value of metabarcoding data for enhancing ecological studies of insectivores in dynamic environments.

Background: Heart transplant from controlled donation after circulatory death (cDCD) is an emerging strategy that is rapidly expanding and may help increase the heart donor pool. Materials and Methods: The use of thoracoabdominal normothermic regional perfusion (TANRP) with extracorporeal membrane oxygenation device has allowed to perform cardiac transplantation after cDCD. Several experiences have been carried out in recent years, however the maximum cold ischemia time is still unknown. We present a successful case of heart transplantation using a graft from cDCD from another hospital with 201 minutes of cold ischemia time, the longest published in Europe. Discussion and conclusion: Heart transplant from cDCD could be a good alternative to brain dead donation. This experience suggests than nonlocal cardiac donation in controlled asystole could tolerate long periods of cold ischemia time and break the main barriers in cardiac donation after circulatory death.

Motivated by an important geophysical application, we analyze the nonlinear dynamics of the number of earthquakes per unit time in a given Earth’s surface area. At first, we consider a dynamical model of earthquakes describing their rhythmic behaviour with time delays. This model comprises different earthquake scenarios divided into three types (A, B, and C) accordingly to various system dynamics. We show that the deterministic system contains stable equilibria and a limit cycle whose size drastically depends on the production rate $\alpha$ of earthquakes and their time-delay effect. As this takes place, the frequency of earthquakes possesses an oscillatory behaviour dependent on $\alpha$. To study the role of $\alpha$ in more detail, we have introduced a white Gaussian noise in the governing equation. First of all, we have shown that the dynamical system is stochastically excitable, i.e. it excites larger-amplitude noise-induced fluctuations in the frequency of earthquakes. In addition, these large-amplitude stochastic fluctuations can alternate with small-amplitude fluctuations over time. In other words, the frequency of earthquakes can change its amplitude in an irregular manner under the influence of white noise. Another important effect is how close the current value of $\alpha$ is to its bifurcation point. The closer this value is, the less noise generates large-amplitude fluctuations in the earthquake frequency.

Viral infection in cell culture and tissue is modeled with delay reaction-diffusion equations. It is shown that progression of viral infection can be characterized by the viral replication number, time-dependent viral load and the speed of infection spreading. These three characteristics are determined through the original model parameters including the rates of cell infection and of virus production in the infected cells. The clinical manifestations of viral infection, depending on tissue damage, correlate with the speed of infection spreading, while the infectivity of a respiratory infection depends on the viral load in the upper respiratory tract. Parameter determination from the experiments on Delta and Omicron variants allows the estimation of the infection spreading speed and viral load. Different variants of the SARS-CoV-2 infection are compared confirming that Omicron is more infectious and has less severe symptoms than Delta variant. Within the same variant, spreading speed (symptoms) correlates with viral load allowing prognosis of disease progression.

Aim: To summarise the effectiveness of organisational interventions on appropriate opioid use for non-cancer pain upon hospital discharge. Methods: A systematic search was conducted on six electronic databases by two independent reviewers. We included original research articles reporting on quantitative outcomes of organisational interventions targeting appropriate opioid use on hospital discharge. Quality assessment was performed by two independent reviewers. The protocol for this review was prospectively registered on PROSPERO (ID: CRD42020156104). Results: Out of 173 full texts assessed for eligibility, 43 were included in this review. The majority of studies had a moderate to serious risk of bias (33 out of 43). Most of the studies implemented a multifaceted organisational intervention (16 studies). Other interventions included guideline implementation, prescriber education and default opioid prescribing quantity changes in electronic medical records. Multiple studies found that the dissemination of patient-specific and procedure-specific guidelines reduced the quantity of opioids prescribed by 44-57%. Prescriber education provided with feedback was implemented in four studies and resulted in a 33-44% decrease in prescribing rates. Lowering the default quantities in the electronic medical records produced a 40% decrease in opioids prescribed in one study. Conclusion: Guideline implementation, prescriber education and default opioid prescribing quantity changes all appear effective in improving the appropriate use of opioids on hospital discharge. However, the extent of reduction of opioid prescribing upon hospital discharge after the implementation of multifaceted intervention strategies appears similar to that of simpler interventions which require fewer resources.

The MitraClip technique has been increasingly used for correction of mitral valve regurgitation in patients in whom surgical mitral repair is considered contraindicated or very risky, but off label use occurs often. Failure of the procedure, translated into moderate to severe rates of residual or recurrent mitral regurgitation, is observed in up to one-third of the patients, and surgery has been used to correct it in a number of cases, in what can be called an “operation for the inoperable”. That is precisely the subtitle of a paper published in this issue of the JOCS by Gerfen and colleagues, who analyse their institutional experience with a series of 17 patients. In this Editorial, I comment on this series and the possible reasons for failure of the MitraClip, and on the indications for reintervention and its constraints, which I hope can contribute to the discussion about “further exploration and refinement of patient selection criteria and identify predictors for MitraClip failure”, as the authors suggest.

The dominant method for generating Chinese hamster ovary (CHO) cell lines that produce high titers of biotherapeutic proteins utilizes selectable markers such as dihydrofolate reductase (Dhfr) or glutamine synthetase (Gs), alongside inhibitory compounds like methotrexate (MTX) or methionine sulfoximine (MSX), respectively. Recent work has shown the importance of asparaginase (Aspg) for growth in media lacking glutamine–the selection medium for Gs-based selection systems. We generated a Gs/Aspg double knockout CHO cell line and evaluated its utility as a novel dual selectable system via co-transfection of Gs-Enbrel and Aspg-Enbrel plasmids. Using the same selection conditions as the standard Gs system, the resulting cells from the Gs/Aspg dual selection showed substantially improved specific productivity and titer compared to the standard Gs selection method, however, with reduced growth rate and viability. Following adaptation in selection medium, the cells improved viability and growth while still achieving ~5-fold higher specific productivity and ~3-fold higher titer than Gs selection alone. We anticipate that with further optimization of culture medium and selection conditions this approach would serve as an effective addition to workflows for the industrial production of recombinant biotherapeutics.

Objective: To evaluate the functional capacity, pulmonary function and quality of life of children and adolescents with sickle cell anemia (SCA) and to test the reproducibility of functional capacity tests in this population. Method: Cross-sectional study with  volunteers with SCA genotype Hb-SS (SCAG), aged 6 to 18 years matched in age and  gender to the control group (CG). Spirometry, 5-repetition sit-to-stand test (5STS-test),  modified shuttle walk test (MSWT), and Pediatric Quality of Life Questionnaire (PedsQL) were performed. The reproducibility of 5STS-test and MSWT was evaluated:   Results: 48 volunteers of SCAG and 48 of CG were evaluated. Pulmonary function of SCAG (FVC: 92 ± 15% pred.; FEV 1 /FVC: 84 ± 8% pred.) was worse than the CG (104 ± 15% pred.; FEV 1 /FVC: 90 ± 6% pred.) p < 0.05. SCAG had worse functional capacity registered by distance walked: 576m (515-672m) and 5STS-test: 8 seconds (7.4-8.9seconds) compared to the CG who showed distance walked: 1010m (887- 1219m) and 5STS-test: 7 seconds (7.0-8.1seconds), p < 0.001. SCAG had worse quality compared to CG, p < 0.05. The reproducibility was good of MSWT (ICC 0.99 (0.98-0.99 IC-95%)) and 5STS-test (ICC 0.80 (0.69 – 0.88), p < 0.001 . Conclusion: Children and adolescents with sickle cell anemia showed worse capacity to walk or run, and to perform sit-to-stand test. Additionally, they have poor quality of life when compared with their control peers. The MSWT and 5STS-test showed reproducible to be applied in pediatric individual with SCA.

Remdesivir can precipitate fatal acute necrotizing pancreatitis especially in patients who previously suffer from hypertriglyceridemia.