Estrogen receptor (ER) and human epidermal growth factor 2 (HER2) expression guide the use of neoadjuvant chemotherapy (NACT) in patients with early breast cancer. We evaluate the independent ...predictive value of adding a multigene profile (CIT256 and PAM50) to immunohistochemical (IHC) profile regarding pathological complete response (pCR) and conversion of positive to negative axillary lymph node status. The cohort includes 458 patients who had genomic profiling performed as standard of care. Using logistic regression, higher pCR and node conversion rates among patients with Non-luminal subtypes are shown, and importantly the predictive value is independent of IHC profile. In patients with ER-positive and HER2-negative breast cancer an odds ratio of 9.78 (95% CI 2.60;36.8), P < 0.001 is found for pCR among CIT256 Non-luminal vs. Luminal subtypes. The results suggest a role for integrated use of up-front multigene subtyping for selection of a neoadjuvant approach in ER-positive HER2-negative breast cancer.
We apply first principles computational techniques to analyze the two-electron, multistep, electrochemical reduction of CO(2) to CO in water using cobalt porphyrin as a catalyst. Density functional ...theory calculations with hybrid functionals and dielectric continuum solvation are used to determine the steps at which electrons are added. This information is corroborated with ab initio molecular dynamics simulations in an explicit aqueous environment which reveal the critical role of water in stabilizing a key intermediate formed by CO(2) bound to cobalt. By use of potential of mean force calculations, the intermediate is found to spontaneously accept a proton to form a carboxylate acid group at pH < 9.0, and the subsequent cleavage of a C-OH bond to form CO is exothermic and associated with a small free energy barrier. These predictions suggest that the proposed reaction mechanism is viable if electron transfer to the catalyst is sufficiently fast. The variation in cobalt ion charge and spin states during bond breaking, DFT+U treatment of cobalt 3d orbitals, and the need for computing electrochemical potentials are emphasized.
The reduction of carbon dioxide by cobalt porphyrins is thought to be a multistep reaction with several possible intermediates and reaction pathways. We here investigate a number of possible ...intermediates in this reaction using density functional theory, including both hybrid (B3LYP) and pure (PBE and BP86) functionals. Optimum structures are located, and harmonic vibrational frequencies and thermal corrections are computed for the low-lying electronic states for all intermediates. Free energies of solvation are predicted for all species, providing a reaction profile in the aqueous phase, which enables identification of likely pathways. Finally, the reaction energy for the binding of carbon dioxide to the cobalt porphine cation is determined in the gas phase and in solution.
Abstract
STUDY QUESTION
How common is bleeding in early pregnancy after Hormone Replacement Therapy (HRT) Frozen Embryo Transfer (FET) and does bleeding affect the reproductive outcome?
SUMMARY ...ANSWER
A total of 47% of HRT-FET patients experience bleeding before the eighth week of gestation, however, bleeding does not affect the reproductive outcome.
WHAT IS KNOWN ALREADY
Bleeding occurs in 20% of spontaneously conceived pregnancies, although most will proceed to term. However, our knowledge regarding bleeding in early pregnancy after HRT-FET and the reproductive outcome is sparse.
STUDY DESIGN, SIZE, DURATION
We performed a systematic review of the existing literature on early pregnancy bleeding after assisted reproductive technology (ART) to evaluate the bleeding prevalence and resulting reproductive outcome in this population. A random-effects proportional meta-analysis was conducted. Subsequently, we performed a prospective cohort study including 320 pregnant patients undergoing HRT-FET and a secondary analysis of the cohort study was performed to evaluate bleeding prevalence and reproductive outcome. The trial was conducted from January 2020 to November 2022 in a public fertility clinic.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A systematic literature search was performed, using MESH terms and included studies with data from ART patients and with early pregnancy bleeding as a separate outcome. The cohort study included patients with autologous vitrified blastocyst transfer treated in an HRT-FET protocol. In the event of a positive HCG-test, an early pregnancy scan was performed around 8 weeks of gestation. During this visit, patients answered a questionnaire regarding bleeding or spotting and its duration after the positive pregnancy test. The information was verified through medical files, and these were used to obtain information on reproductive outcomes.
MAIN RESULTS AND THE ROLE OF CHANCE
The review revealed a total of 12 studies of interest. The studies reported a prevalence of early pregnancy bleeding ranging from 2.1% to 36.2%. The random effects proportional meta-analysis resulted in a pooled effect estimate of the prevalence of early pregnancy bleeding in the ART population of 18.1% (95% CI (10.5; 27.1)). Four of the included studies included data on miscarriage rate following an episode of bleeding. All four studies showed a significantly increased risk of miscarriage in patients with early pregnancy bleeding as compared to patients with no history of bleeding. No studies investigated bleeding after HRT-FET specifically. In our HRT-FET cohort study, we found that a total of 47% (149/320) of patients with a positive pregnancy test experienced bleeding before 8 weeks of gestation. Generally, the bleeding was described as spotting with a median of 2 days (range 0.5–16 days). Out of 149 patients with one or several bleeding episodes, a total of 106 patients (71%) had an ongoing pregnancy at 12 weeks of gestation. In comparison, 171 patients reported no bleeding episodes and a total of 115 (67%) of these patients had an ongoing pregnancy at 12 weeks of gestation. This difference was not significant (P = 0.45). Furthermore there was no difference in the live birth rate between the two groups (P = 0.29).
LIMITATIONS, REASONS FOR CAUTION
Most studies included in the review were older and not all studies specified the type of ART. Moreover, the studies were of moderate methodological quality. The patients in the cohort study were treated in a personalized HRT-FET protocol using a rectal supplementary rescue regimen if serum progesterone levels were <35 nmol/l at embryo transfer. The results may not be applicable to other FET protocols, and the present data were based on self-reported symptoms. The systematic review revealed an increased risk of miscarriage following an episode of early pregnancy bleeding. However our cohort study found no such association. This discrepancy can partly be due to the fact, that the four studies in the review only included episodes of heavy bleeding. Also, none of the four studies included data on HRT-FET cycles making them unfit for direct comparison.
WIDER IMPLICATIONS OF THE FINDINGS
Episodes of early bleeding during pregnancy are associated with distress for the pregnant woman, especially in a cohort of infertile patients. Our cohort study showed that at least minor bleeding seems to be a common adverse event of early pregnancy after HRT-FET. From the systematic review, it seems that this prevalence is higher than what has previously been described in relation to other types of ART. However, minor bleeding during early pregnancy after HRT-FET does not seem to affect the reproductive outcome. Knowledge regarding the frequent occurrence of bleeding during early pregnancy after HRT-FET and the fact that this should not be used as a prognostic parameter will help the clinician in counselling patients.
STUDY FUNDING/COMPETING INTEREST(S)
Gedeon Richter Nordic supported this investigator-initiated study with an unrestricted grant as well as study medication (Cyclogest). B.A. has received an unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA, and Marckyrl Pharma. P.H. received honoraria for lectures from Merck, Gedeon Richter, Institut Biochimique SA (IBSA), and Besins as well as unrestricted research grants from Merck, Gedeon Richter, and Institut Biochimique SA (IBSA). The other authors have no conflict of interest to declare.
TRIAL REGISTRATION NUMBER
EudraCT no.: 2019-001539-29.
Self-organization in many solution-processed, semiconducting conjugated polymers results in complex microstructures, in which ordered microcrystalline domains are embedded in an amorphous matrix. ...This has important consequences for electrical properties of these materials: charge transport is usually limited by the most difficult hopping processes and is therefore dominated by the disordered matrix, resulting in low charge-carrier mobilities ( 10-5 cm2 V-1 s-1). Here we use thin-film, field-effect transistor structures to probe the transport properties of the ordered microcrystalline domains in the conjugated polymer poly(3-hexylthiophene), P3HT. Self-organization in P3HT results in a lamella structure with two-dimensional conjugated sheets formed by interchain stacking. We find that, depending on processing conditions, the lamellae can adopt two different orientations-parallel and normal to the substrate-the mobilities of which differ by more than a factor of 100, and can reach values as high as 0.1 cm2 V-1 s-1 (refs 3, 4). Optical spectroscopy of the field-induced charge, combined with the mobility anisotropy, reveals the two-dimensional interchain character of the polaronic charge carriers, which exhibit lower relaxation energies than the corresponding radical cations on isolated one-dimensional chains. The possibility of achieving high mobilities via two-dimensional transport in self-organized conjugated lamellae is important for applications of polymer transistors in logic circuits and active-matrix displays.
Climate extremes cause significant winter wheat yield loss and can cause much greater impacts than single extremes in isolation when multiple extremes occur simultaneously. Here we show that compound ...hot-dry-windy events (HDW) significantly increased in the U.S. Great Plains from 1982 to 2020. These HDW events were the most impactful drivers for wheat yield loss, accounting for a 4% yield reduction per 10 h of HDW during heading to maturity. Current HDW trends are associated with yield reduction rates of up to 0.09 t ha
per decade and HDW variations are atmospheric-bridged with the Pacific Decadal Oscillation. We quantify the "yield shock", which is spatially distributed, with the losses in severely HDW-affected areas, presumably the same areas affected by the Dust Bowl of the 1930s. Our findings indicate that compound HDW, which traditional risk assessments overlooked, have significant implications for the U.S. winter wheat production and beyond.
Objective The aim of this study was to determine the impact of three different office designs (cellular office, shared office, and open-plan workspace) on the risk of medically certified sickness ...absence and the number of days, respectively, of medically certified sickness absence over a 12-month follow-up period. Methods The study relied on a combination of self-report survey questionnaire data on office design supplemented with official registry data number of days with sickness absence from the Norwegian Labor and Welfare Administration. The sample comprised 6328 Norwegian office workers (57% women, age range: 19-70 years, mean age: 44 years). Results Adjusting for survey year, employees working in a shared office risk ratios (RR) 1.18, 95% confidence interval (CI) 1.10-1.27 and an open-plan workspace (RR 1.12, 95% CI 1.02-1.22) had significantly higher risk of having had medically instances of certified sickness absence when compared to employees working in a cellular-office. Office design was not related to the number of days with absence. The associations were consistent across organizational affiliation, age, gender, whether the respondent had leadership responsibility, and educational level. Conclusion The use of shared offices and open-plan workspaces is a risk factor for medically certified sickness absence. Providing employees with the opportunity to work in cellular offices may reduce absence rates.
Recent studies have suggested the possibility of significantly obscuring supersoft X-ray sources in relatively modest amounts of local matter lost from the binaries themselves. If correct, then this ...would have explained the paucity of observed supersoft X-ray sources and would have significance for the search for single-degenerate Type Ia supernova progenitors. We point out that earlier studies of circumbinary obscuration ignored photoionizations of the gas by the emission from the supersoft X-ray source. We revisit the problem using a full, self-consistent calculation of the ionization state of the circumbinary material photoionized by the radiation of the central source. Our results show that the circumstellar mass-loss rates required for obscuration of supersoft X-ray sources is about an order of magnitude larger than those reported in earlier studies, for comparable model parameters. While this does not entirely rule out the possibility of circumstellar material obscuring supersoft X-ray sources, it makes it unlikely that this effect alone can account for the majority of the missing supersoft X-ray sources. We discuss the observational appearance of hypothetical obscured nuclear-burning white dwarfs and show that they have signatures making them distinct from photoionized nebulae around supersoft X-ray sources imbedded in the low-density interstellar medium.
To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investigated the secretion of the incretin hormones, glucagon-like peptide-1 and glucose- dependent ...insulinotropic polypeptide and measured nonesterified fatty acids, and plasma concentrations of insulin, C peptide, pancreatic polypeptide, and glucose during a 4-h mixed meal test in 54 heterogeneous type 2 diabetic patients, 33 matched control subjects with normal glucose tolerance, and 15 unmatched subjects with impaired glucose tolerance. The glucagon-like peptide-1 response in terms of area under the curve from 0-240 min after the start of the meal was significantly decreased in the patients (2482 +/- 145 compared with 3101 +/- 198 pmol/liter.240 min; P = 0.024). In addition, the area under the curve for glucose-dependent insulinotropic polypeptide was slightly decreased. In a multiple regression analysis, a model with diabetes, body mass index, male sex, insulin area under the curve (negative influence), glucose-dependent insulinotropic polypeptide area under the curve (negative influence), and glucagon area under the curve (positive influence) explained 42% of the variability of the glucagon-like peptide-1 response. The impaired glucose tolerance subjects were hyperinsulinemic and generally showed the same abnormalities as the diabetic patients, but to a lesser degree. We conclude that the meal-related glucagon-like peptide-1 response in type 2 diabetes is decreased, which may contribute to the decreased incretin effect in type 2 diabetes.
Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain <25% of SQTS cases. ...Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pH
, short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3. Mechanistic analyses suggest that an increase in pH
and decrease in Cl
shortened the action potential duration. However, other mechanisms may also play a role. Altered anion transport represents a mechanism for development of arrhythmia and may provide new therapeutic possibilities.
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