The reasons for the unusually small Bi-Te-Bi bond angle of 86.6° observed in the crystal strucure of (Et₂ Bi)₂ Te are investigated by quantum chemical calculations. With the help of coupled cluster theory at the CCSD(T) level it is demonstrated that the structure of an isolated monomer should have a bond angle larger than 90°, despite a Bi-Bi distance in good agreement with the value of 4.09 Å found in the crystal structure. The discrepancy is resolved by a lengthening of the Bi-Te bond in the crystal, which is shown to be caused by partial electron transfer from neighbouring molecules to the Bi-Te σ* orbital. Through symmetry-adapted perturbation theory at the DFT-SAPT level it is shown that London dispersion interactions are highly important for the packing of molecules in the solid state and, in turn, for the small Bi-Te-Bi bond angle.

Keywords: bismuth; bond angles; charge transfer; dispersion interactions; telluride.

Background: Female patients undergoing anticancer treatment are at elevated risk of adverse ovarian outcomes including infertility and premature ovarian insufficiency (POI), which is associated with short- and long-term health risks. Anti-Müllerian hormone (AMH) is a key biomarker of ovarian reserve, but its role prior to and after cancer treatment is less well understood.

Objective and rationale: To conduct a systematic review evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment, which has become a pressing clinical issue in reproductive medicine. There are a large number of observational studies, but differences in patient groups, cancer diagnoses and study design make this a confusing field that will benefit from a thorough and robust review.

Search methods: A systematic literature search for AMH in women with cancer was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 April 2021. Bias review was conducted using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol along with qualitative assessment of quality. Exploratory subgroups were established based on age, cancer type and length of follow-up.

Outcomes: Ninety-two publications (N = 9183 patients) were included in this analysis after quality and bias review. Reduced/undetectable AMH was consistently identified in 69/75 studies (92%) following chemotherapy or radiotherapy, with reductions ranging from 42% to concentrations below the limit of detection, and many reporting mean or median declines of ≥90%. Where longitudinal data were analysed (42 studies), a majority (33/42 (79%)) of studies reported at least partial recovery of AMH at follow-up, however, effect estimates were highly variable, reflecting that AMH levels were strongly impacted by anticancer treatment (i.e. the chemotherapy regimen used and the number of treatment cycles need), with recovery and its degree determined by treatment regimen, age and pre-treatment AMH level. In 16/31 (52%) publications, oligo/amenorrhoea was associated with lower post-treatment AMH consistent with impending POI, although menstruation and/or pregnancy were reported in patients with low or undetectable AMH. Long-term (>5 years) follow-up of paediatric patients following cancer treatment also found significantly lower AMH compared with control groups in 14/20 (70%) of studies, with very variable effect sizes from complete loss of AMH to full recovery depending on treatment exposure, as in adult patients.

Wider implications: AMH can be used to identify the damaging effect of cancer treatments on ovarian function. This can be applied to individual women, including pre-pubertal and adolescent girls, as well as comparing different treatment regimens, ages and pre-treatment AMH levels in populations of women. While there was evidence for its value in the diagnosis of POI after cancer treatment, further studies across a range of diagnoses/treatment regimens and patient ages are required to clarify this, and to quantify its predictive value. A major limitation for the use of AMH clinically is the very limited data relating post-treatment AMH levels to fertility, duration of reproductive lifespan or time to POI; analysis of these clinically relevant outcomes will be important in further research.

Keywords: AMH; anti-Müllerian hormone; cancer; chemotherapy; fertility; gonadotoxicity; ovarian insufficiency; ovarian reserve.

Background: Identifying branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance.

Objective: We aimed to externally validate the previously developed Dutch-American Risk stratification Tool (DART-1; https://rtools.mayo.edu/DART/), which identifies cysts at low risk of developing worrisome features (WFs) or high-risk stigmata (HRS).

Methods: Three prospective cohorts of individuals under surveillance for BD-IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART-1, a multivariable Cox-proportional logistic regression model with five predictors for the development of WFs or HRS.

Results: Of 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART-1's discriminative ability (C-statistic 0.68) was similar to that in the development cohort (0.64-0.72) and showed moderate calibration. DART-1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3-year risk was 0%-0% versus 0%-3.7% for Q1; 0.3%-0.4% versus 3%-11% for Q2; and 2.6%-3% versus 2.4%-9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p < 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%).

Conclusions: The performance of DART-1 to predict the development of WFs or HRS in BD-IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD-IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles.

Keywords: intraductal papillary mucinous neoplasm; pancreatic cyst; prediction; prognosis; screening; surveillance.

Diabetic nephropathy is a microvascular complication of diabetes. Its etiology involves metabolic disorder-induced endothelial dysfunction. Endothelium-derived nitric oxide (NO) plays an important role in a number of physiological processes, including glomerular filtration and endothelial protection. NO dysregulation is an important pathogenic basis of diabetic nephropathy. Hyperglycemia and dyslipidemia can lead to oxidative stress, chronic inflammation and insulin resistance, thus affecting NO homeostasis regulated by endothelial nitric oxide synthase (eNOS) and a conglomerate of related proteins and factors. The reaction of NO and superoxide (O₂^.-) to form peroxynitrite (ONOO^-) is the most important pathological NO pathway in diabetic nephropathy. ONOO^- is a hyper-reactive oxidant and nitrating agent in vivo which can cause the uncoupling of eNOS. The uncoupled eNOS does not produce NO but produces superoxide. Thus, eNOS uncoupling is a critical contributor of NO dysregulation. Understanding the regulatory mechanism of NO and the effects of various pathological conditions on it could reveal the pathophysiology of diabetic nephropathy, potential drug targets and mechanisms of action. We believe that increasing the stability and activity of eNOS dimers, promoting NO synthesis and increasing NO/ONOO^- ratio could guide the development of drugs to treat diabetic nephropathy. We will illustrate these actions with some clinically used drugs as examples in the present review.

New findings: What is the central question of this study? Are there differences in blood pressure, arterial stiffness and indices of pressure waveforms between young oral contraceptive pill using and naturally menstruating women during lower and higher hormone phases of their cycles? What is the main finding and its importance? Blood pressure, arterial stiffness and indices of pressure waveforms are influenced similarly by exogenous and endogenous hormones. However, lower levels of exogenous hormones moderately increase blood pressure among OCP.

Abstract: Elevations in blood pressure (BP) are understood as having a bidirectional relationship with stiffening of central and peripheral arteries. Arterial stiffness is mitigated by oestrogen, which aides in arterial vasorelaxation. To evaluate whether BP, stiffness, and pressure waveforms were different between young healthy naturally menstruating (non-OCP) and oral contraceptive pill using women (OCP), we measured brachial and aortic BPs, carotid-to-femoral pulse wave velocity (cfPWV), carotid β-stiffness, elastic-modulus, central augmentation index (AIx and AIx75), and forward and backward pressure waveforms (Pf and Pb) in 22 women (22 (1) yr, OCP: n = 12). To assess phasic differences, women were studied during the early follicular (EF; ≤5 days of menstruation onset) and early luteal (EL; 4 (2) days post-ovulation) phases of non-OCP and compared to the placebo pill (PP; ≤5 days of onset) and active pill (AP; ≤5 days of highest-dose AP) phases of OCP. During the lower hormone phases, OCP have significantly higher brachial SBP (119.3 (8.3) vs. 110.2 (8.3) mmHg, P = 0.02) and aortic SBP (104.10 (7.44) vs. 96.80 (6.39) mmHg, P = 0.03) as compared to non-OCP; however, during the higher hormone phases, there are no differences in measures of brachial or aortic BP, arterial stiffness, or indices of BP waveforms between OCP and non-OCP (P≥0.05). In conclusion, exogenous and endogenous hormones have similar influences on BP and arterial stiffness; however, lower levels of exogenous hormones augment both central and peripheral BPs. This article is protected by copyright. All rights reserved.

Keywords: OCP; arterial stiffness; blood pressure; oestrogen; premenopausal; pulse wave velocity.

The VQ protein family is plant-specific, and is involved in growth, development, and biotic and abiotic stress responses. In this study, we found that the gene expression of poplar VQ1(Potri.001G029700) from Populus trichocarpa varied remarkably under salt stress and hormones associated with disease. A subcellular localization experiment showed that VQ1 was localized in the nucleus and cytomembrane in tobacco. The overexpression of VQ1 in Arabidopsis thaliana enhanced its resistance to salt stress and disease, and was also responsive to it through abscisic acid (ABA). Compared with wild-type, transgenic Arabidopsis lines had significantly increased levels of ABA and salicylic acid. The expression of some stress-related genes, such as MPK6, NPR1, and PDF1.2, was significantly up-regulated by salt in transgenic plants, while WRKY70, ABI1, KUP6, and NCED2 were significantly down-regulated by Pseudomonas syringae pv. tomato DC3000 in transgenic plants. Together, these results demonstrate that VQ1 modulates hormonal signaling to confer multiple biotic and abiotic stress responses in transgenic Arabidopsis plants.

Keywords: VQ1; disease; hormone; salt.

A number of wetland ecosystem-services valuation studies around the world have been carried out, however, most of these studies have focused on wetlands in developed countries and few have been conducted in Africa, particularly in South Sudan. Thus, this study is conducted to value ecosystem services and identify the role and interests of stakeholders of the Machar Marshes and the Sudd wetlands for sustainable wetland management in the Nile basin. Market price and benefit transfer approaches have been applied to value the wetlands biodiversity and ecosystem services, by adjusting for income and price differences. In addition to environmental valuation methods, we conducted stakeholder analysis. Accordingly, Machar Marshes wetland provides an estimated per annum economic value of $200 million, of which the provisioning services contributed about $61 million, regulating services $132 million, and biodiversity services $7.35 million considering the 2015 price as a base year. Similarly, the Sudd wetland provides an estimated per annum economic value of 2.3 billion, of which regulating is about $1.2 billion, biodiversity $857 million, provisioning $209 million, and transportation service $293,400. The findings show that the ecosystem services from the wetlands have benefits beyond the local communities. Thus, to maintain and ensure sustainable wetlands ecosystem services, stakeholders should play a significant role to implement alternative wetland development options through managing the existing institutional challenges. Ecosystem-services assessment and wetland development options suffer from weak institutional capacity due to prolonged conflicts and instability and physical inaccessibility to critical natural resources in the wetlands.

Keywords: Institution; Machar Marshes; Stakeholder; Sudd; Valuation; Wetland Ecosystem Services.

Aim: There are mixed opinions on the influence of diabetes on the prognosis of patients receiving percutaneous coronary intervention (PCI). Therefore, in this study, the quantitative flow ratio (QFR), an emerging technology of functional evaluation, was used to explore the impact of diabetes on coronary physiology in patients who underwent PCI.

Materials and methods: Patients who underwent successful PCI and a one-year angiographic follow-up were retrospectively screened and analyzed by the QFR. Based on the presence or absence of diabetes, 677 enrolled patients (794 vessels) were classified into a diabetic group (211 patients, 261 vessels) and a nondiabetic group (466 patients, 533 vessels). The results of QFR analysis and clinical outcomes were compared between the two groups.

Results: The two groups reached a similar level of post-PCI QFR (0.95 ± 0.09 vs. 0.96 ± 0.06, p = 0.292). However, at the one-year follow-up, the QFR was lower (0.93 ± 0.11 vs. 0.96 ± 0.07, p < 0.001), and the degree of QFR decline was more obvious (-0.024 ± 0.090 vs. -0.008 ± 0.070, p = 0.023) in the diabetic group. Additionally, diabetes was independently associated with functional restenosis (OR: 2.164; 95% CI: 1.210-3.870, p = 0.009) and target vessel failure (TVF) (OR: 2.654; 95% CI: 1.405-5.012, p = 0.003).

Conclusion: As evaluated by the QFR, patients with diabetes received less coronary physiological benefit from PCI, which was consistent with their clinical outcomes.

Keywords: Diabetes; Percutaneous coronary intervention; Quantitative flow ratio.

Vascular endothelial growth factor-A (VEGF-A) is a critical angiogenic factor which is mainly secreted from podocytes and epithelial cells in kidney and plays an important role in renal pathophysiology. In recent years, functions of different isoforms of VEGF-A and the new secretion approach via extracellular vesicles (EVs) have been identified. Thus, further understanding are needed for the role of VEGF-A and its isoforms in renal injury and repair. In this review, we summarized the expression, secretion and regulation of VEGF-A, its biological function, and the role of different isoforms of VEGF-A in the development of different renal diseases. Meanwhile, the research progress of VEGF-A as diagnostic marker and therapeutic target for renal diseases were discussed.

Oral calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be effective in the acute and preventive treatment of migraine. CGRP receptor antagonists offer safety advantages over triptans because they are not active vasoconstrictors, which reduces cardiovascular risks. Bristol Myers Squibb discovered a high affinity CGRP receptor antagonist BMS-927711 for the treatment of migraine now FDA approved as Nurtec® ODT (rimegepant). Dual labeled [¹⁴ C]-BMS-927711 was prepared and used in a human absorption-distribution-metabolism-elimination (ADME) study. A dual labeled analog of BMS-927711 was required to fully track the compound's metabolic transformation. The carbon-14 labeled synthesis of both right side and left side portions of [¹⁴ C]-BMS-927711 are described.

Keywords: CGRP receptor antagonists; carbon-14 synthesis; human ADME study.

In this prospective study, we postulate that there is a difference between clearance of [99mTc]Tc- ethyl cysteinate dimer (ECD) in the seizure onset zone (SOZ) and other brain areas and thus SOZ localization by clearance patterns might become a potential novel method for SOZ localization in epilepsy. The parametric images of brain ECD clearance were generated by linear regression model analysis from serial brain SPECT scans from 30 to 240 min after ECD injection (7-times point) in 7 patients with drug-resistant epilepsy and 3 normal volunteers. Clearance patterns of the SOZ confirmed by good surgical outcome or consensus with other investigations were analyzed quantitatively and semi-quantitatively by visual grading (slower or faster washout than contralateral brain regions). The average [^99mTc]Tc-ECD clearance rates of SOZs were + 1.08% ± 2.57%/hr (wash in), -7.02% ± 2.56%/hr (washout), and -5.37% ± 1.71%/hr (washout) in ictal, aura and interictal states, respectively. Paired t-tests between the SOZ and contralateral regions showed statistically significant difference (p = 0.039 in interictal state). Clearance patterns that can define the SOZs were 1) wash in and slow washout on ictal slope, 2) fast washout on aura slope and interictal slope with 100% (6/6), 100% (2/2) and 75% (6/8) localization using ictal, aura, and interictal slope maps, respectively. Our study provided the evidence that clearance pattern methods are potential additive diagnostic tools for SOZ localization when routine one-time point SPECT are unable to define the SOZ.

Keywords: Brain SPECT; ECD clearance; Epilepsy; Ictal onset zone; Washout.

The thyroid transcription factor 1 (TITF-1) gene plays an important role in the development of the ventral forebrain, thyroid and lungs. Mutations of this gene are known to cause benign hereditary chorea (BHC) and can cause the full spectrum of abnormalities seen in the brain-thyroid-lung syndrome. Abnormalities of the ventral forebrain on imaging have been variably documented in the literature. Multiple previous reports describe a cystic pituitary mass, as well as duplication of the pituitary stalk and communication between an intrasellar cyst and the third ventricle. The initial MRI performed in our case was interpreted as an intrasellar cyst, but the high-resolution MRI performed later was able to resolve this as a persisting embryonal infundibular recess (PEIR), rather than the cystic pituitary mass which has previously been described. This case illustrates the role of the TITF-1 gene in the development of the pituitary and hypothalamus.

Keywords: Benign hereditary chorea; Hypothalamus; Persisting embryonal infundibular recess; TITF-1 gene mutation.

We explored the effects of the COVID-19 pandemic on people living with HIV (PLHIV) in Vietnam. In June 2020, we interviewed 32 PLHIV who identified as men who have sex with men, persons who inject drugs, female sex workers, or transgender after Vietnam's strict quarantine period. While most participants were knowledgeable regarding COVID-19 transmission and prevention, COVID-19 was perceived more as a threat to individual rather than community health. The pandemic affected PLHIV significantly. Many lost employment with reduced income and increased family stress and conflict. Travel restrictions and unemployment affected access to antiretroviral (ARV) medication, particularly for transgender PLHIV who obtain ARVs from unofficial sources. Participants recounted substantial mental health effects, including worry, stress, and boredom. However, some respondents reported positive effects on family relationships. After quarantine, most reported feeling better, although financial worries persisted. Preparation for social emergencies should include development of supports for PLHIV in vulnerable groups.

Keywords: COVID-19; HIV; Mental health; Vietnam; Vulnerable groups.

Aims: To investigate the predictive ability of direct plasma renin and aldosterone concentrations as well as their ratio (aldosterone-to-renin (ARR)) for incident hypertension in the general population.

Methods and results: Concentration of renin and aldosterone were measured by a chemiluminescence immunoassay (CLIA) using the fully-automated LIAISON® platform (DiaSorin) among 5,362 participants of the population-based Gutenberg Health Study, who were normotensive and had no clinically-overt CVD at baseline. During a follow-up period of five years, 18.6% (n = 996) developed a new-onset hypertension. Comparing extreme quartiles of biomarker distribution, the relative risk (RR) for incident arterial hypertension was found to be 1.58 (95% confidence interval (CI) 1.25-2.00; p = 0.00015; Q1 vs Q4ref) for renin; 1.29 (95% CI 1.05-1.59, p = 0.018; Q4 vs Q1ref) for aldosterone and 1.70 (95%CI 1.33-2.12; p < 0.0001; Q4 vs Q1ref) for ARR after multivariable adjustment in men. In females, only high ARR was independently predictive for incident hypertension over five years (RR 1.29 (95% CI 1.04-1.62); p = 0.024). Even in the subgroup of individuals having biomarker concentrations within the reference range, high ARR was predictive for new-onset hypertension in men (RR 1.44 (95%CI 1.13-1.83); p = 0.003). Finally, synergistic effects of co-prevalent obesity and ARR on incident hypertension were also demonstrated, resulting in markedly higher risk estimates as seen for biomarker alone (RR of 2.70 (95% 2.05-3.6) for Q4 of ARR and having BMI ≥ 30 kg/m2 vs low ARR (Q1ref) and normal weight; p < 0.0001).

Conclusion: Among normotensives from the general population ARR possesses a stronger predictive value for incident hypertension than renin or aldosterone alone. The prediction of arterial hypertension by ARR was even stronger in obese subjects.

Translational perspective: These findings may help in a better understanding of importance of aldosterone-renin imbalance for the development of new-onset hypertension among normotensive subject and identify individuals at greatest risk, who probably required more intensive preventive measures.

Keywords: aldosterone; aldosterone-to-renin ratio; general population; incident hypertension; renin.

Background & aim: Bystander response to out-of-hospital cardiac arrest (OHCA) may relate to area-level factors, including socioeconomic status (SES). We aimed to examine whether OHCA among individuals in more disadvantaged areas are less likely to receive bystander cardiopulmonary resuscitation (CPR) compared to those in more advantaged areas.

Methods: We analysed data on OHCAs in New South Wales, Australia collected prospectively through a statewide, population-based register. We excluded non-medical arrests; arrests witnessed by a paramedic; occurring in a medical centre, nursing home, police station; or airport, and among individuals with a Do-Not-Resuscitate order. Area-level SES for each arrest was defined using the Australian Bureau of Statistics' Index of Relative Socioeconomic Disadvantage and its relationship to likelihood of receiving bystander CPR was examined using hierarchical logistic regression models.

Results: Overall, 39% (6622/16,914) of arrests received bystander CPR (71% of bystander-witnessed). The OHCA burden in disadvantaged areas was higher (age-standardised incidence 76-87/100,000/year in more disadvantaged quintiles 1-4 versus 52 per 100,000/year in most advantaged quintile 5). Bystander CPR rates were lower (38%) in the most disadvantaged quintile and highest (42%) in the most advantaged SES quintile. In adjusted models, younger age, being bystander-witnessed, arresting in a public location, and urban location were all associated with greater likelihood of receiving bystander CPR; however, the association between area-level SES and bystander CPR rate was not significant.

Conclusions: There are lower rates of bystander CPR in less advantaged areas, however after accounting for patient and location characteristics, area-level SES was not associated with bystander CPR. Concerted efforts to engage with communities to improve bystander CPR in novel ways could improve OHCA outcomes.

Keywords: Administrative data; Bystander cardiopulmonary resuscitation; Health equity; Out-of-hospital cardiac arrest; Socioeconomic status.

Long-term exposure to primary air pollutants, such as sulphur dioxide (SO₂) and nitrogen oxides (NO_x), alters the structure and functions of forest ecosystems. Many biochemical and biogeochemical processes discriminate against the heavier isotopes in a mixture; thus, the values of δ¹³C and δ¹⁵N (i.e. the ratio of stable isotopes ¹³C to ¹²C and that of ¹⁵ N to ¹⁴ N, respectively) may give insights into changes in ecosystem processes and identify the immediate drivers of these changes. We studied sources of variation in the δ¹³C and δ¹⁵N values in the foliage of eight boreal forest C3 plants at 10 sites located at the distance of 1-40 km from the Monchegorsk nickel-copper smelter in Russia. From 1939‒2019, this smelter emitted over 14,000,000 metric tons (t) of SO₂, 250,000 t of metals, primarily nickel and copper, and 140,000 t of NO_x. The δ¹³C value in evergreen plants and the δ¹⁵N value in all plants increased near the smelter independently of the plant mycorrhizal type. We attribute the pollution-related increase in the foliar δ¹³C values of evergreen species mainly to direct effects of SO₂ on stomatal conductance, in combination with pollution-related water stress, which jointly override the potential opposite effect of increasing ambient CO₂ concentration on δ¹³C values. Stomatal uptake of NO_x and root uptake of ¹⁵N-enriched organic N compounds and NH₄⁺ may explain the increased foliar δ¹⁵N values and elevated foliar N concentrations, especially in the evergreen trees (Pinus sylvestris), close to Monchegorsk, where the soil inorganic N supply is reduced due to the impact of long-term SO₂ and heavy metal emissions on plant biomass. We conclude that, despite the uncertainties in interpreting δ¹³C and δ¹⁵N responses to pollution, the Monchegorsk smelter has imposed and still imposes a great impact on C and N cycling in the surrounding N-limited subarctic forest ecosystems.

Keywords: Heavy metals; Kola Peninsula; Leaf longevity; Mycorrhiza; Stable isotopes; Sulphur dioxide.

Introduction: We aimed to describe healthcare resource utilization (HCRU) patterns and costs in patients with fibrosing interstitial lung disease (ILD) and those with a progressive phenotype of fibrosing ILD in a US claims database.

Methods: Data from the IBM^® MarketScan^® databases (1 October 2011-30 September 2015) were used. Diagnosis codes documented on medical claims on two occasions (without any claims during the 12 months prior) identified patients with incident fibrosing ILD. Patients with chronic fibrosing ILD with a progressive phenotype were identified by proxies for progression. Patients aged ≥ 18 years with 365 days of continuous coverage before the index date were eligible for inclusion. Data were analyzed for 12 months prior to identification of fibrosing ILD/progressive phenotype (baseline) and 12 months after (follow-up). Outcomes included treatment patterns, outpatient and inpatient claims, and costs.

Results: We identified 23,577 patients with incident fibrosing ILD and 14,722 with the progressive phenotype. Follow-up data were available for 9986 and 5840 patients, respectively. The most frequent ILD-related medications during baseline were corticosteroids (49.4% and 56.6%). Mean (± standard deviation [SD]) annualized number of outpatient claims was 30.0 (± 26.4) and 34.1 (± 27.7) in the baseline period and 36.2 (± 28.6) and 41.9 (± 30.2) in the follow-up in fibrosing ILD and with a progressive phenotype, respectively. Mean (SD) number of all-cause hospitalizations was 0.5 (± 1.1) and 0.7 (± 1.2) during baseline and 0.6 (± 1.1) and 0.7 (± 1.2) during follow-up. Mean (SD) total costs were $40,907 (± 92,496) and $49,561 (± 98,647) during baseline and $46,157 (± 102,858) and $54,215 (± 116,833) during follow-up. Inpatient mortality during follow-up was 53.50 and 77.44 per 1000 patient-years.

Conclusion: HCRU and costs were high in patients with chronic fibrosing ILD with a progressive phenotype, likely reflecting the disease severity and the need for close monitoring and acute care. Outpatient claims accounted for a substantial proportion of the total costs.

Keywords: Claims database; Costs; Healthcare resource utilization; Hospitalization; Interstitial lung disease; Progressive fibrosing ILD; Pulmonary fibrosis.

The lipase catalyzed polycondensation of azelaic acid and glycerol was investigated according to a Design of Experiment approach that allowed to understand the effect of the experimental variables on monomer conversion, M n and regioselectivity of acylation of glycerol. The chemometric analysis showed that after 24h the reaction proceeds regardless of the presence of the enzyme. Accordingly, the biocatalyst was removed after a first step of synthesis and the chain elongation continued at 80°C. That allowed the removal of the biocatalyst and the preservation of its activity: pre-requites for efficient applicability at industrial scale. The experimental study, combined with docking based computational analysis, provided rational guidelines for the optimization of the regioselective acylation of glycerol. Overall, the process was scaled up to 73.5 g of monomer. The novelty of the present study stays in the rigorous control of the reaction conditions and of the integrity of the immobilized biocatalyst, thus avoiding any interference of free enzyme or fines released in the reaction mixture. The quantitative analysis of the effect of the experimental conditions and the overcoming of the major technical bottlenecks for the scalability of enzymatic polycondensation opens new scenarios for its industrial exploitation.

Keywords: azelaic acid oligoesters lipase CalB solvent-free polycondensation.

Hybrid photochromic materials (HPMs) have potential applications in numerous fields, such as display, protection, and information storage. The generation of HPMs with tunable photochromic performance is meaningful for the availability of smart photoresponsive materials. As a good platform, crystalline HPMs (CHPMs) provide possibilities to generate desirable products because of their synthetic tunability. To achieve this goal, how to introduce predesigned organic ligands as electron acceptors (EAs) into suitable electron donor (ED) systems is significant for yielding products with hybrid ED-EA structure triggering electron transfer (ET) after photo-stimulus. In this study, inserting protonated 1,10-phenanthroline (phen) (as EAs) and its monosubstituted derivatives 5-Cl-phen and 5-NH₂-phen to the interchain voids of anionic halometallate units (as EDs) generated three CHPMs, namely [H-phen][BiCl₄] (1), [H-5-Cl-phen][BiCl₄]·H₂O (2), and [H-5-NH₂-phen][BiCl₄]·H₂O (3). The obtained products featured the same anionic inorganic chains with main differences in the protonated organic guests. As expected, compounds 1-3 displayed apparent photochromism because of the ET from the anionic chains to protonated organic units. Interestingly, the photochromic performance of complexes 1-3 could be tuned by inserting phenanthroline-derivative-guests. This research offers a universal way to engineer the photochromic performance of halometallate-based CHPMs under the guidance of the organic EA design.

Mixed outcome endpoints that combine multiple continuous and discrete components are often employed as primary outcome measures in clinical trials. These may be in the form of co-primary endpoints, which conclude effectiveness overall if an effect occurs in all of the components, or multiple primary endpoints, which require an effect in at least one of the components. Alternatively, they may be combined to form composite endpoints, which reduce the outcomes to a one-dimensional endpoint. There are many advantages to joint modeling the individual outcomes, however in order to do this in practice we require techniques for sample size estimation. In this article we show how the latent variable model can be used to estimate the joint endpoints and propose hypotheses, power calculations and sample size estimation methods for each. We illustrate the techniques using a numerical example based on a four-dimensional endpoint and find that the sample size required for the co-primary endpoint is larger than that required for the individual endpoint with the smallest effect size. Conversely, the sample size required in the multiple primary case is similar to that needed for the outcome with the largest effect size. We show that the empirical power is achieved for each endpoint and that the FWER can be sufficiently controlled using a Bonferroni correction if the correlations between endpoints are less than 0.5. Otherwise, less conservative adjustments may be needed. We further illustrate empirically the efficiency gains that may be achieved in the composite endpoint setting.

Keywords: latent variable modeling; mixed outcome endpoints; sample size estimation.

We report the case of a 79-year-old woman with hepatocellular carcinoma (HCC) who presented with creatine kinase (CK)-MM elevation. On admission, her serum CK-MM level exceeded 4000 IU/L (normal, 44-206 IU/L), and computed tomography revealed two HCCs in hepatic segment VIII (23 mm, 86 mm). The patient denied experiencing muscular symptoms such as weakness or pain. Hypothyroidism, ischemic heart disease, muscular dystrophy, autoimmune myopathy, drug-induced rhabdomyolysis, and paraneoplastic inflammatory myositis syndrome (PIMS) were included in the differential diagnosis for high CK-MM, but none were suspected. Although the cause of elevated CK-MM was not elucidated, an HCC-related mechanism was considered and the tumor was resected. The CK-MM levels declined gradually to 300 IU/L postoperatively without any special perioperative management. Nineteen cases of HCC-associated CK-MM elevation have been reported in English thus far, in all of which, inflammatory myositis was concluded as the cause of CK-MM elevation. However, in this case, the elevation of CK-MM was associated with HCC-related mechanisms distinct from PIMS, suggesting HCC-related mechanisms should not be excluded as a cause of high CK-MM, even though PIMS is negative.

Keywords: CK-MM; Creatine kinase; Hepatocellular carcinoma; Paraneoplastic syndrome.

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10^-8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10^-10; OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10^-16; OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.

Keywords: CTNNA3; FOXF1/FOXC2/FOXL1; HNF1B; esophageal atresia (EA); genome-wide association study (GWAS); multifactorial diseases.

Hypertension is one of the strongest risk factors for cardiovascular diseases, cerebral stroke, and kidney failure. Lifestyle and nutrition are important factors that modulate blood pressure. Hypertension can be controlled by increasing physical activity, decreasing alcohol and sodium intake, and stopping tobacco smoking. Chronic kidney disease patients often have increased blood pressure, which indicates that kidney is one of the major organs responsible for blood pressure homeostasis. The decrease of renal sodium reabsorption and increase of diuresis induced by high potassium intake is critical for the blood pressure reduction. The beneficial effect of a high potassium diet on hypertension could be explained by decreased salt reabsorption by sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT). In DCT cells, NCC activity is controlled by with-no-lysine kinases (WNKs) and its down-stream target kinases, Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress-responsive 1 (OSR1). The kinase activity of WNKs is inhibited by intracellular chloride ([Cl^-]_i) and WNK4 is known to be the major WNK positively regulating NCC. Based on our previous studies, high potassium intake reduces the basolateral potassium conductance, decreases the negativity of DCT basolateral membrane (depolarization), and increases [Cl^-]_i. High [Cl^-]_i inhibits WNK4-SPAK/OSR1 pathway, and thereby decreases NCC phosphorylation. In this review, we discuss the role of DCT in the blood pressure regulation by dietary potassium intake, which is the mechanism that has been best dissected so far.

We previously generated Brassica juncea lines overexpressing either glyoxalase I (gly I) or γ-tocopherol methyltransferase (γ-TMT) involved in the glyoxalase system and tocopherol biosynthesis, respectively. These transgenic plants showed tolerance to multiple abiotic stresses. As tolerance is a complex trait that can be improved by pyramiding of several characteristics in a single genotype, we generated in this study B. juncea plants coexpressing gly I and γ-TMT by crossing the previously generated stable transgenic lines. The performance of the newly generated B. juncea lines coexpressing gly I and γ-TMT was compared with that of wild-type and the single transgenic lines under non-stressed and NaCl and mannitol stress conditions. Our results show a more robust antioxidant response of B. juncea plants coexpressing gly I and γ-TMT compared to the other lines in terms of higher chlorophyll retention, relative water content, antioxidant enzyme and proline levels, and photosynthetic efficiency and lower oxidative damage. The differences in response to the stress of the different lines were reflected in their yield parameters. Overall, we demonstrate that the pyramiding of multiple genes involved in antioxidant pathways could be a viable and useful approach for achieving higher abiotic stress tolerance in crop plants.