Miracle-dz/UniFAR-FTUs huggingface dataset:
Behavioural outcome in twin–twin transfusion syndrome survivors treated with laser surgery

Objective Evaluate the incidence of and risk factors for behavioural problems in twin–twin transfusion syndrome (TTTS) survivors treated with fetoscopic laser coagulation. Design Observational cohort study. Setting National referral center for fetal therapy, Leiden University Medical Center, The Netherlands. Patients Behavioural outcome was assessed in 417 TTTS survivors, at the age of 2 years. Interventions Parents completed the Child Behavior Checklist for their twins. Antenatal, neonatal and follow-up data including Bayley III and a neurological exam were recorded from the medical database. Main outcome measures The incidence of and risk factors for behavioural problems. Results 332 twin pregnancies (664 fetuses) were treated with fetoscopic laser for TTTS between 2008 and 2015. For 517 children eligible for follow-up, 417 (81%) Child Behavior Checklist questionnaires were completed. The study group was born at a mean gestational age of 32.8 weeks±3.2. Total behavioural problems within the borderline to clinical range were reported in 8% (95% CI 5.9 to 11.2) of survivors, compared with 10% in the general Dutch population (p=0.12). No difference between donors and recipients was detected (p=0.84). Internalising and externalising problems were reported in 9.4% (95% CI 6.9 to 12.6) and 11.5% (95% CI 8.8 to 15.0), respectively. Severe neurodevelopmental impairment was more frequent in the children with behavioural problems. High maternal educational level was associated with lower behavioural problem scores. Conclusion Parents of twins treated with fetoscopic laser therapy for TTTS do not report more behavioural problems compared with general population norms. More behavioural problems are reported in children with severe neurodevelopmental impairment.
Educational interventions for primary care providers to improve clinical skin examination for skin cancer.

BACKGROUND AND PURPOSE Skin cancer, the most commonly diagnosed cancer in the United States, is a serious health care concern. Early skin cancer detection improves prognosis; most common early detection approach is a comprehensive clinical skin examination (CSE). A CSE consists of skin cancer risk assessment, head-to-toe skin examination, and skin lesion assessment. Nurse practitioners (NPs) currently lack adequate training and confidence to conduct CSE. The goal of this systematic review was to learn more about published interventions targeting CSE training for primary care NPs and/or other primary care providers. The findings were categorized based on the established procedures for intervention development. METHODS The databases PubMed, Google Scholar, CINAHL, and Web of Science were searched. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 10 articles were selected for data extraction. CONCLUSIONS There is a paucity of articles that report rigorously developed interventions aimed at educating primary care NPs to conduct CSE. Existing CSE interventions were not tested for efficacy or effectiveness, and the implementation methods were weak or not reported. A synthesis of the review findings revealed inadequately reported sample characteristics, vague intervention goals, unspecified frequency or duration of interventions, and lack of standardized intervention protocols. IMPLICATIONS FOR PRACTICE This review builds a foundation for more rigorously developed interventions to improve CSE and provides guidance for NPs to select education on CSE and other clinical foci. Future research will guide the development and evaluate the effectiveness of CSE education, which ultimately could improve skin cancer prognosis interventions and lack of standardized intervention protocols.
New Insight into Therapies Targeting Angiogenesis in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis that is determined by an augmented production of proangiogenesis factors by tumor and adjacent cells. This unbalanced angiogenesis process is a key feature of HCC carcinogenesis and progression. Proangiogenic factors also have a relevant role in the generation and maintenance of an immunosuppressive tumor microenvironment. Several therapeutic options for HCC treatment are based on the inhibition of angiogenesis, both in the early/intermediate stages of the disease and in the late stages of the disease. Conventional treatment options employing antiangiogenic approaches provide for the starving of tumors of their blood supply to avoid the refueling of oxygen and nutrients. An emerging alternative point of view is the normalization of vasculature leading to enhance tumor perfusion and oxygenation, potentially capable, when proposed in combination with other treatments, to improve delivery and efficacy of other therapies, including immunotherapy with checkpoint inhibitors. The introduction of novel biomarkers can be useful for the definition of the most appropriate dose and scheduling for these combination treatment approaches. The present review provides a wide description of the pharmaceutical compounds with an antiangiogenic effect proposed for HCC treatment and investigated in clinical trials, including antibodies and small-molecule kinase inhibitors.
Evidence-based recommendations for energy intake in pregnant women with obesity.

BACKGROUND In women with obesity, excess gestational weight gain (≥270 g/week) occurs in two out of three pregnancies and contributes to metabolic impairments in both mother and baby. To improve obstetrical care, objectively assessed information on energy balance is urgently needed. The objective of this study was to characterize determinants of gestational weight gain in women with obesity. METHODS This was a prospective, observational study of pregnant women with obesity. The primary outcome was energy intake calculated by the energy intake-balance method. Energy expenditure was measured by doubly-labeled water and whole-room indirect calorimetry and body composition as 3-compartment model by air displacement plethysmography and isotope dilution in early (13-16 weeks) and late pregnancy (35-37 weeks). RESULTS In pregnant women with obesity (n=54), recommended weight gain (n=8, 15%) during the second and third trimesters was achieved when energy intake was 125±52 kcal/d less than energy expenditure. In contrast, women with excess weight gain (67%) consumed 186±29 kcal/d more than they expended (P<0.001). Energy balance affected maternal adiposity (recommended: -2.5±0.8 kg fat mass, excess: +2.2±0.5, inadequate: -4.5±0.5, P<0.001), but not fetal growth. Weight gain was not related to demographics, activity, metabolic biomarkers, or diet quality. We estimated that energy intake requirements for recommended weight gain during the second and third trimesters were not increased as compared to energy requirements early in pregnancy (34±53 kcal/d, P=0.83). CONCLUSIONS We here provide the first evidence-based recommendations for energy intake in pregnant women with obesity. Contrary to current recommendations, energy intake should not exceed energy expenditure. FUNDING This study was funded by the National Institutes of Health (R01DK099175; Redman, U54GM104940 and P30DK072476; Core support). TRIAL REGISTRATION clinicaltrials.gov: NCT01954342.
Prognostic value of FDG-PET in patients with mantle cell lymphoma: results from the LyMa-PET Project

Mantle cell lymphoma (MCL) is an incurable aggressive non-Hodgkin lymphoma (NHL), which accounts for approximately 5% of all NHL. Novel agents and rituximab maintenance therapy (RM) have greatly improved patient outcomes, but most patients still experience recurrent relapses. This highlights the need for riskadapted therapies. The prognostic value of [(18)F]fluorodeoxyglucose positron-emission-tomography (FDG-PET) has already been demonstrated in various lymphoma entities, but its utility in MCL remains unclear. In the LyMa-PET project, we centrally reviewed PET results from patients enrolled in the LyMa trial, a prospective, multicenter, international, randomized phase III trial (NCT00921414) that investigated RM after autologous stem-cell transplantion (ASCT) in young previously untreated MCL patients. Our aim was to investigate the prognostic value of the image-derived FDG-PET quantitative indices. In the LyMa trial, FDG-PET was optional at diagnosis, before ASCT (iPET) and after-ASCT (eotPET), and not used in the decision-making strategy. FDG-PET images were acquired in voluntary centers participating in the LyMa trial, according to the local protocol and following the rules of good practice. FDG-PET data were centrally collected and analyzed on a dedicated workstation (PLANET®Onco-Solution, Dosisoft, France) and evaluated by two experienced readers (CBM and CB) who were blinded to clinical information, treatment arm and follow-up. For the initial staging, a positive FDG-PET signal was defined as an area of increased uptake thought to be lymphoma-related. Different quantitative metrics were extracted from the FDG-PET data set, measured as volume of interest (VOI) covering the entire nodal and extranodal lesions as visualized by increased FDG uptake:
Entry-Prohibited Effect of kHz Pulsed Magnetic Field Upon Interaction Between SPIO Nanoparticles and Mesenchymal Stem Cells

Objective: The interaction between superparamagnetic iron oxide (SPIO) nanoparticles and mesenchymal stem cells (MSCs) in the presence of pulsed magnetic field (PMF) has become an important area of research in recent years. Methods: A parameter-adjustable pulsed magnetic field was developed based on the principle of insulated gate bipolar translator transistor-controlled discharge of large capacitances. The internalizations of SPIO nanoparticles by MSCs were investigated under the treatment of PMF in both intermittent stimulation mode and continuous stimulation mode. Results: The intensities and frequencies of pulsed magnetic field can be adjustable in the range of 1.9–4.6 mT and 3–5 kHz, respectively. This PMF was safe to the MSCs. However, the uptake of SPIO nanoparticles by MSCs was significantly prohibited under the treatment of kHz-ranged PMF while the 10 Hz PMF enhanced the cellular uptake of nanoparticles. This phenomenon was relative with the magnetic effect of the PMF with different frequency. Conclusion: The PMF can be used to effectively regulate the cellular uptake of SPIO nanoparticles and the mechanism lies in the magnetic effect. Significance: The interaction between SPIO nanoparticles and the MSCs is a fundamental and important issue for nanomedicine and stem cell research. Our results demonstrate that the external magnetic field can be used to regulate their interaction. We believe that this safe, facile, and flexible method will greatly promote the development and clinical translation of regenerative medicine and nanomedicine.
Dmrt factors determine the positional information of cerebral cortical progenitors via differential suppression of homeobox genes

ABSTRACT The spatiotemporal identity of neural progenitors and the regional control of neurogenesis are essential for the development of cerebral cortical architecture. Here, we report that mammalian DM domain factors (Dmrt) determine the identity of cerebral cortical progenitors. Among the Dmrt family genes expressed in the developing dorsal telencephalon, Dmrt3 and Dmrta2 show a medialhigh/laterallow expression gradient. Their simultaneous loss confers a ventral identity to dorsal progenitors, resulting in the ectopic expression of Gsx2 and massive production of GABAergic olfactory bulb interneurons in the dorsal telencephalon. Furthermore, double-mutant progenitors in the medial region exhibit upregulated Pax6 and more lateral characteristics. These ventral and lateral shifts in progenitor identity depend on Dmrt gene dosage. We also found that Dmrt factors bind to Gsx2 and Pax6 enhancers to suppress their expression. Our findings thus reveal that the graded expression of Dmrt factors provide positional information for progenitors by differentially repressing downstream genes in the developing cerebral cortex. Summary: Mammalian Dmrt factors orchestrate the development of the dorsal telencephalon, a primordium of the cerebral cortex, via dose-dependent suppression of developmental patterning factors such as Pax6 and Gsx2.
Response to Confounding Factors on the Prediction of Opioid Usage after Thyroidectomy and Parathyroidectomy Surgery

I read with great interest the article of Tharakan and colleagues in a recent issue of the journal. The authors conducted a study on 209 patients who underwent total thyroidectomy, hemithyroidectomy, or parathyroidectomy and concluded that the number of pain pills meeting the opioid needs of 80% of these patients was 10 pills and that older age was associated with lower odds of opioid use. The authors should be applauded for performing a well-designed study in an important topic (eg, acute pain) in patients undergoing elective surgery. The need to reduce opioid prescription and diversion is currently an important public health issue. Nonetheless, some critical points need to be clarified by the authors to determine the validity of the findings. First, the authors did not report the use of intraoperative opioids in their analysis as this can directly affect the use of postoperative opioids. Second, the authors included the use of nonopioid analgesics in their statistical model; however, they did not quantify the amount or the type of opioid analgesic consumed by patients as this can also alter the study results. Last, the authors had fewer than 50 events (ie, patients taking more than 10 pills), but they constructed predictive models using more than 10 dependent variables, potentially resulting in substantial model overfitting. I would welcome some comments by the authors as this would help to further support the findings of this important clinical study.
Relations between catechol-O-methyltransferase Val158Met genotype and inhibitory control development in childhood.

The Val158Met rs4680 single-nucleotide polymorphism (SNP) at the catechol-O-methyltransferase (COMT) gene, primarily involved in dopamine breakdown within prefrontal cortex, has shown relations with inhibitory control (IC) in both adults and children. However, little is known about how COMT genotype relates to developmental trajectories of IC throughout childhood. Here, our study explored the effects of the COMT genotype (Val/Val, Val/Met, and Met/Met) on IC trajectories between the ages of 5 and 10 years. Children (n = 222) completed a Go/Nogo task at ages 5, 7, and 10; IC was characterized using signal detection theory to examine IC performance (d') and response strategy (RS) (criterion). COMT genotype was not related to initial levels of IC performance and RS at age 5 or change in RS from ages 5 to 10. In contrast, COMT genotype was related to change in IC performance between 5 and 10 years. While Val/Val children did not differ from Val/Met children in development of IC performance, children with the Met/Met genotype exhibited more rapid development of IC performance when compared with Val/Met peers. These results suggest that COMT genotype modulates the development of IC performance in middle childhood.
Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.
A New Insight into the Comonomer Effect through NMR Analysis in Metallocene Catalysed Propene–co–1-Nonene Copolymers

The “comonomer effect” is an intriguing kinetic phenomenon in olefin copolymerization that still remains without a detailed explanation. It typically relates to the rate of enhancement undergone in ethylene and propene catalytic polymerization just by adding small fractions of an alpha-olefin. The difficulty lies in the fact that changes caused by the presence of the comonomer in reaction parameters are so conspicuous that it is really difficult to pin down which of them is the primary cause and which ones are side factors with marginal contribution to the phenomenon. Recent investigations point to the modification of the catalyst active sites as the main driving factor. In this work, the comonomer effect in the metallocene copolymerization of propene and 1-nonene is analysed and correlated to the comonomer role in the termination of the chain-growing process. The associated termination mechanisms involved furnish most of chain-free active sites, in which the selective interaction of the comonomer was proposed to trigger the insertion of monomers. A thorough characterisation of chain-end groups by means of the 1H NMR technique allows for detailing of specific transfer processes, ascribed to comonomer insertions, as well as evidencing the influence of the growing chain’s microstructure over the different termination processes available.
Right-to-left shunts and hormonal therapy influence cerebral vasomotor reactivity in patients with migraine with aura

Patent Foramen Ovale and impaired cerebral hemodynamics were proposed among the pathophysiological mechanisms explaining the increased risk for stroke in patients with Migraine with Aura (MA). Our study aimed at comparing the vasomotor reactivity (VMR) of the anterior and the posterior cerebral circulation in patients with Migraine with Aura, in patients with acute vascular ischemic accidents, and in controls. We hypothesized that VMR in MA patients is preserved in the anterior circulation and reduced in the posterior circulation. We prospectively assessed with Transcranial Doppler the vasomotor reactivity to breath holding of the Middle and Posterior Cerebral Arteries (MCA, PCA) in MA patients, in acute vascular patients and healthy controls. We also evaluated the possible effect of clinical characteristics of MA (attack frequency, aura length or type, disease history), vascular factors and the presence of right-to-left shunt on VMR. Diverging from our hypothesis, MA patients displayed a higher breath-holding index (BHI) than controls in the MCA (1.84±0.47%/s vs 1.53±0.47%/s, p = .001) as well as in the PCA (1.87±0.65%/s vs 1.47±0.44%/s, p < .001). In MA patients, MCA BHI was higher in those with large right-to-left shunts (2.09±0.42 vs 1.79±0.47, p = .046) and lower in those taking estrogens (1.30±0.30%/s vs 1.9±0.45%/s, p = .009). We did not observe an effect of MA characteristics on BHI. The increased BHI in MA patients with large right-to-left shunts could be explained by the vasoactive effect in the cerebral circulation of substances bypassing the deactivating pulmonary filters or by a constitutional trait of the vascular system associating persistent right-to-left shunts and hyper-reactive hemodynamics. Our results discourage the hypothesis that altered hemodynamics contribute to increasing the stroke risk in all MA patients. However, estrogens can lower VMR, curtailing the hemodynamic resources of MA patients.
Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies)

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.
Trimethylamine-N-oxide metabolites in the early pregnancy and risk of gestational diabetes: a nested case control study.

AIMS This study aimed to investigate the associations between TMAO and related metabolites in the early pregnancy and risk of GDM. MATERIALS AND METHODS A prospective cohort of 22,302 pregnant women from 2010 to 2012 in Tianjin, China, was used to perform a nested case-control study. 243 women with GDM and 243 women without GDM matched with maternal age (+/-1 year) were used as cases and controls respectively. Conditional logistic regression and restricted cubic spline were used to examine the full-range risk associations between individual TMAOs at the first antenatal care visit with GDM. Trimethylamine ratio (TMAR) was defined as TMA/its precursors while TMAO ratio (TMAOR) was defined as TMAO/TMA. An additive interaction between high TMAR and low TMAOR indicates a state of TMA accumulation while a mathematical interaction between high TMAR and high TMAOR indicates accumulation of TMAO. RESULTS TMA was linearly associated with GDM while TMA precursors and TMAO were inversely associated with GDM with clear threshold effects, i.e., 16 nmol/mL for TMAO, 200 nmol/mL for betaine, 112 nmol/mL for L-carnitine, and 110 and 270 nmol/mL for cholinechloride (a U-shaped relationship). Co-presence of TMAR >0.35 and TMAOR ≤0.15 was associated with markedly higher odds ratio of 11.16 (5.45-22.8), compared to TMAR >0.35 only (1.71, 0.42-6.95) or TMAOR ≤0.15 only (2.06, 1.09-3.90), with a significant additive interaction. However, the mathematical interaction was non-significant. CONCLUSIONS TMAO metabolites in the early pregnancy were associated with the risk of GDM, while TMA was more likely to play a causal role in GDM.