Accurate chemical kinetics are essential for reactor design and operation. However, despite recent advances in “big data” approaches, availability of kinetic data is often limited in industrial practice. Herein, we present a comparative proof-of-concept study for kinetic parameter estimation from limited data. Cross-validation (CV) is implemented to nonlinear least-squares (LS) fitting and evaluated against Markov chain Monte Carlo (MCMC) and genetic algorithm (GA) routines using synthetic data generated from a simple model reaction. As expected, conventional LS is fastest but least accurate in predicting true kinetics. MCMC and GA are effective for larger data sets but tend to overfit to noise for limited data. Cross-validation least-square (LS-CV) strongly outperforms these methods at much reduced computational cost, especially for significant noise. Our findings suggest that implementation of cross-validation with conventional regression provides an efficient approach to kinetic parameter estimation with high accuracy, robustness against noise, and only minimal increase in complexity.

Aim A robust and user-friendly software tool was developed for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone. This tool can facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. Methods Previously developed population pharmacokinetic (PPK) models for olanzapine and risperidone were combined with a PD model for D2 receptor occupancy (RO) and implemented in the R programming language. MAP Bayesian estimation was used to provide predictions of plasma concentration and receptor occupancy and based on sparse PK measurements. Results The average (standard deviation) response times of the tools were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (RMSE, 95% CI) of predicted versus observed concentrations were 3.73 ng/mL (-2.42 – 9.87) and 10.816 (6.71 – 14.93) for olanzapine, and 0.46 ng/mL (-4.56 – 5.47) and 6.68 (3.57 – 9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and RMSE of RO were -1.47% (-4.65 – 1.69) and 5.80 (3.89 – 7.72) for olanzapine and -0.91% (-7.68 – 5.85) and 8.87 (4.56 – 13.17) for risperidone. Conclusion Treatment of schizophrenia with antipsychotics offers unique challenges and requires careful monitoring to establish the optimal dosing regimen. Our monitoring software predicts RO in a reliable and accurate form.

The coexistence of granular liquid-like phase (cluster) and gas-like phase (void) in fluidization, a spontaneous symmetry-breaking dissipative state, contributes to excellent mixing behavior in multi-phase reactors. In present study, a universal granular state equation to describe phase coexistence far from critical point is developed, where both the inelastic solid-collision and asymmetrical instability is taken into consideration. Catastrophe theory is applied to find the stable boundary of phase coexistence, and verified by cold-flow experiment with different solid pressure. A phase diagram, based on both theoretical analysis and experimental study, is given as a useful guideline of design and operation of efficient multi-phase reactors.

This article proposes an analytical model to understand the rod-growth of eutectic in the bulk undercooled melt. Based on the previous derivations of the lamellar eutectic growth models, relaxing the assumptions of small Peclet numbers, the model is derived by considering melt kinetic and thermal undercoolings. The intent of this model is to predict the transitions in eutectic pattern for conditions of the low and high growth velocity. In addition to investigation of the transition between lamellar and rod eutectic pattern, mathematical simplifications of solving Bessel function are presented as well, which is the most important priority to model calculation.

In the development of personalized medicine, the ultrasensitive detection of point mutations that correlate with diseases is important to improve the efficacy of treatment and guide clinical medication. In this study, locked nucleic acid (LNA) was introduced as an amplification suppressor of a massive number of wild-type alleles in an amplification refractory mutation system (ARMS) to achieve the detection of low-abundance mutations with high specificity and sensitivity of at least 0.1%. By integrating the length of clamp, base type, number and position of LNA modifications, we have established a “shortest length with the fewest LNA bases” principle from which each LNA base would play a key role in the affinity and the ability of single base discrimination could be improve. Finally, based on this LNA design guideline, a series of the most important single point mutation sites of epidermal growth factor receptor (EGFR) was verified to achieve the optimal amplification state which as low as 0.1% mutation gene amplification was not affected under the wild gene amplification was completely inhibited, demonstrating that the proposed design principle has good applicability and versatility and is of great significance for the detection of circulating tumor DNA.

Background: The high incidence of postoperative pulmonary venous obstruction (PVO) is a major mortality-associated concern in patients with right atrial isomerism and extracardiac total anomalous pulmonary venous connection (TAPVC). We evaluated new anatomical risk factors for reducing the space behind the heart after TAPVC repair. Methods: 18 patients who underwent TAPVC repair between 2014 and 2020 were enrolled. Sutureless technique was used in 12 patients and conventional repair in six patients. The angle between the line perpendicular to the vertebral body and that from the vertebral body to the apex was defined as the “vertebral-apex angle (V-A angle).” The ratio of post- and preoperative angles, indicating the apex’s lateral rotation, was compared between patients with and without PVO. Results: The median (interquartile range) age and body weight at repair were 102 (79-176) days and 3.8 (2.6-4.8) kg, respectively. The 1-year survival rate was 83% (median follow-up, 29 [11-36] months). PVO occurred in seven patients (39%), who showed an obstruction of one or two branches in the apex side. The postoperative V-A angle (46° [45°-50°] vs. 36° [29°-38°], P = 0.001) and the ratio of post- and preoperative V-A angles (1.27 [1.24-1.42] vs. 1.03 [0.98-1.07], P = 0.001) were significantly higher in the PVO group than in the non-PVO group. The cut-off values of the postoperative V-A angle and ratio were 41° and 1.17, respectively. Conclusions: A postoperative rotation of the heart apex into the ipsilateral thorax was a risk factor for branch PVO after TAPVC repair.

Abstract Background Subaortic stenosis (SAS) was a rare congenital heart disease of left ventricular outflow tract (LVOT), ranging from “isolated” lesions to “tunnel” or “diffuse” lesions. We conducted a retrospective study to describe the characteristics of patients with different lesions and analyze the risk factors for reoperation. Methods In this study, we examined a single-center retrospective cohort of SAS patients undergoing resection from 2010 to 2019. Patients were classified as simple lesion group (n = 37) or complex lesion group (n = 28). Demographics, perioperative findings, and clinical data were analyzed. Results The surgical effect of the two groups was significantly lower than that before the operation (p <0.05). The median age at operation was 6(3-11.8) years. There was no operative mortality. In complex lesion group, extracorporeal circulation time (CPB time), aortic cross clamp time (ACC time), mechanical ventilation time and ICU stay time were longer. The median follow-up period was 2.8 years (range 1-3.8), with two late death. Six patients (9.2%) required reoperation due to restenosis or severe aortic insufficiency. The freedom from reoperation rates at 5 years was 66.7% for simple lesion but only 52.3% for complex lesion (p = 0.036). Conclusions Although the lesions include many forms, subaortic stenosis resection was still satisfactory. However, the reoperation after initial surgical treatment was not infrequent, especially in patients with complex lesion.

Background: This study aims at better defining the profile of patients with a complicated versus non-complicated postoperative course following isolated tricuspid valve (TV) surgery to identify predictors of a favourable/unfavourable hospital outcome. Methods: All patients treated with isolated tricuspid surgery from March 1997-January 2020 at our institution were retrospectively reviewed. Considering the complexity of most of these patients, a regular postoperative course was arbitrarily defined as a length-of-stay in intensive care unit <4 days and/or postoperative length-of-stay <10days. Patients were therefore divided accordingly in two groups. Results: 172 patients were considered, among whom 97 (56.3%) had a regular (REG) and 75 (43.6%) a non-regular (NEG) postoperative course. The latter had worse baseline clinical and echocardiographic characteristics, with higher rate of renal insufficiency, previous heart failure hospitalizations, cardiac operations, and right ventricular dysfunction. NEG patients more frequently needed tricuspid replacement and experienced a greater number of complications (p<0.001) and higher in-hospital mortality (13% vs 0%, p<0.001). The majority of these complications were related to more advanced stage of the tricuspid disease. Among most important predictors of a negative outcome univariate analysis identified chronic kidney disease, ascites, previous right heart failure hospitalizations, right ventricular dysfunction, previous cardiac surgeries, TV replacement and higher MELD scores. At multivariate analysis, liver enzymes and diuretics’ dose were predictors of complicated postoperative course. Conclusions: In isolated TV surgery a complicated postoperative course is observed in patients with more advanced right heart failure and organ damage. Earlier surgical referral is associated to excellent outcomes and should be recommended.

Objective: to evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. Design and setting: multicentre retrospective cohort study between 2008-2021 Population: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis Methods and main outcome measures: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. Results: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 at term age (79% of live births and 60% of pregnancies). No maternal deaths were observed, one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. Conclusions: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contra-indication for pregnancy. Individualized, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population.

Key Points • Transnasal Oesophagoscopy (TNO) is an approach to inspect the upper aerodigestive tract, especially in the head and neck cancer (HNCA) population that present with dysphagia. • Twenty-five (25) office-based TNO procedures were performed, with a same-day discharge rate of 96% (24/25) and no reported complications. • This case series is the first to compare preoperative and postoperative outcomes (EAT-10) following stricture dilatation using TNO in the UK. Our results show a statistically significant improvement in symptom severity (EAT-10 scores) (n=11, P=0.001). In the majority of these patients, strictures were due to post-radiation complications. Biopsy in 4/5 cases was sufficient for diagnosis/ruling out disease. Of these patients, 80% had a previous HNCA. • This study identifies the remit for a new ‘one-stop’ TNO service for suspected cancer referrals, of which a large proportion are patients with a previous HNCA. Surveillance, therapeutics and diagnostics can be achieved in a single visit. • Earlier staging or treatment may be achieved due to a fast turnover in clinic

BJOG-20-2353.R2 What should we believe when systematic reviews disagree?For many years, uterine balloon tamponade (UBT) has been used to treat severe postpartum haemorrhage (PPH), despite a lack of randomised trials to demonstrate its effectiveness. With commercial devices being expensive, clinicians in low resource settings have made their own using 2 low-cost, widely available items (Foley catheters and condoms). Public health experts have been so confident of their benefit that large programmes have been set up to disseminate the necessary skills worldwide.Recently, however, the global maternal health community has been thrown into disarray when not one, but two randomised controlled efficacy trials suggested that outcomes with condom catheter UBTs were actuallyworse than normal care in low resource settings. The Cochrane meta-analysis concluded that “in [low resource] settings, balloon tamponade [should be] only introduced alongside multi‐system improvements in PPH care” (Kellie et al. Cochrane Database of Systematic Reviews 2020(7): CD013663).Systematic reviews may be the pinnacle of evidence-based medicine, but even they can differ in how to interpret evidence. And so, proponents of the condom catheter conducted their own systematic review with far wider inclusion criteria – they not only included the randomised trials but examined success rates from 15 non-randomised trials and 69 case series (Suarez et al. Am J Obstet Gynecol 2020;222(4):293.e1–e52). Furthermore, the primary outcome was the success rate of the technique (overall 86%) rather than the risk of morbidity and mortality compared to controls, as used in the Cochrane review. This is problematic, as reported ‘success rates’ without controls can be very difficult to interpret: in initial case series misoprostol showed similar success rates against life-threatening haemorrhage before RCTs eventually showed it to be less effective than oxytocin.A third version of the same review is published today by a WHO team (Pingray et al. BJOG 2021;XXX,XXX). This time they include only 4 high quality studies in which UBT was compared to standard care. With a composite maternal morbidity / mortality outcome, they found no evidence of benefit and concluded that “the effect … is unclear, as is the role of the type of device and the setting”. WHO studies are now underway to address this uncertainty.But why is this all so important? The difficulty comes because the World Health Organisation has been updating its guidance on PPH management, and had to declare a position on UBT. The recently-published guideline, drawn up by independent experts, accepts the validity of the RCTs but recognises that there is wide acceptability of the technique and that the evidence of harm is only for condom catheters and onlyin resource-poor settings. They put a high emphasis on minimising harm and conclude that UBTs should only be used in settings where there is already a good standard of care, including recourse to blood transfusion and surgery if needed (WHO. Geneva: World Health Organization; 2021).Until further studies are published, the debate will continue. But this episode shows how the choice of inclusion criteria and outcomes in systematic reviews are critical, both for their conclusions, and for global policy.

Is the patient choice the best choice?

Pulmonary cryptococcosis presents as various radiological manifestations depending on the immunological status of the host. The most common chest radiographic findings include single or multiple nodules. Herein, we present a rare case of pulmonary cryptococcosis in a patient with rheumatoid arthritis presenting as multiple cystic lesions that enlarged after treatment.

Objective: Arterial stiffness refers to arterial wall rigidity, particularly in central vessels, and is an independent predictor of cardiovascular disease. 25-Hydroxy (OH) vitamin D has beneficial effects on blood pressure, vascular endothelial function, and arterial stiffness. Therefore, we aimed to elucidate the role of 25-OH vitamin D deficiency in arterial stiffness development and its relationship with arterial stiffness in healthy children. Methods: This study included 80 patients with low levels of 25-OH vitamin D and 40 healthy control. The study participants were then divided into three groups: group 1 consisted of patients with a deficient 25-OH D level of < 19.9 ng/mL, group 2 with an insufficient 25-OH D level between 20-29.9 ng/mL; group 3 were considered control group with a sufficient serum 25-OH vitamin D level of ≥30 ng/mL. Aortic strain, distensibility, stiffness index, and standard left ventricular measurements were calculated using M-mode echocardiographic data. Results: Left ventricular mass index (LVMI) and interventricular septal diastolic thickness (IVSTd) appeared to increase in group 1 compared to groups 2 and 3. Aortic strain and distensibility were significantly decreased in group 1, whereas aortic stiffness index and elastic modulus were significantly increased. The aortic stiffness index was negatively correlated with serum 25-OH vitamin D levels; however, aortic strain, aortic distensibility, and LVMI were positively correlated. Conclusions: Our study results revealed a significant relationship between 25-OH vitamin D levels indicative of a deficiency and aortic stiffness. We suggest that arterial stiffness may also occur in healthy children with a 25-OH vitamin D deficiency.

Objectives Possibility of reinfection with SARS-CoV-2 changes our view on herd immunity and vaccination, and can impact worldwide quarantine policies. We performed RT-PCR follow-up studies on recovered patients to assess possible development of reinfections and re-positivity. Method During a 6-month period, 202 PCR-confirmed recovering COVID-19 patients entered this study. Follow-up RT-PCR tests and symptoms assessment were performed one month after the initial Positive results. patients who tested negative were tested again one and three months later. The Serum IgG and IgM levels were measured in the last follow-up session. Results In the first two follow-up sessions, 82 patients continued their participation, of which four patients tasted positive. In the second follow-up 44 patients participated, three of whom tested positive. None of the patients who tested positive in the first and second follow-up session were symptomatic. In the last session, 32 patients were tested and four patients were positive, three of them were mildly symptomatic and all of them were positive for IgG. Conclusion A positive RT-PCR in a recovering patient may represent reinfection. While we did not have the resources to prove reinfection by genetic sequencing of the infective viruses, we believe presence of mild symptoms in the three patients who tested positive over 100 days after becoming asymptomatic, can be diagnosed as reinfection. The IgG may have abated the symptoms of the reinfection, without providing complete protection.

Since the start of the SARS-CoV-2 pandemic, it has been difficult to differentiate between SARS-CoV-2 re-infection and prolonged RNA shedding. In this report, we identified patients with positive rtPCR results for SARS-CoV-2 ≥70 days apart. Clinical and laboratory data were collected and criteria were applied to discern whether the presentation was consistent with SARS-CoV-2 re-infection or prolonged viral RNA shedding. Eleven individuals met the initial testing criteria, of which, seven met at least one criteria for re-infection and four were consistent with prolonged RNA shedding. These data demonstrate the need for criteria to differentiate SARS-CoV-2 re-infection from prolonged RNA shedding.

A 62-year-old man with rare blood type exhibited severe respiratory failure due to novel coronavirus. Extracorporeal membrane oxygenation was inapplicable, which requires numerous blood products with the same blood type. We thoroughly restricted fluid volumes by sacrificing renal function. He was discharged with complete recovery of respiratory and renal functions.

How variations in carbon supply affect wood formation remains poorly understood in particular in mature forest trees. To elucidate how carbon supply affects carbon allocation and wood formation, we attempted to manipulate carbon supply to the cambial region by phloem girdling and compression during the mid- and late-growing season and measured effects on structural development, CO2 efflux, and nonstructural carbon reserves in stems of mature white pines. Wood formation and stem CO2 efflux varied with location relative to treatment (i.e., above or below the restriction). We observed up to twice as many tracheids formed above versus below the treatment after the phloem transport manipulation, whereas cell-wall area decreased only slightly below the treatments, and cell size did not change relative to the control. Nonstructural carbon reserves in the xylem, needles, and roots were largely unaffected by the treatments. Our results suggest that low and high carbon supply affects wood formation, primarily through a strong effect on cell proliferation, and respiration, but local nonstructural carbon concentrations appear to be maintained homeostatically. This contrasts with reports of a decoupling of source activity and wood formation at the whole-tree or ecosystem level, highlighting the need to better understand organ-specific responses, within-tree feedbacks, as well as phenological and ontological effects on sink-source dynamics.