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Dematerialized negotiations are increasing and tend to foster deceptive exchanges, while also limiting the ability to detect signs of deception. We therefore tested whether it was possible to deter negotiators from producing deceptive statements in the first place, by manipulating the mental conflict of lying (Dissonance factor) and increasing the perceived risk of being disbelieved if lying (Risk factor). A total of 458 participants were recruited online and placed in a buyer/supplier email negotiation scenario in one of eight experimental groups, manipulating the Dissonance factor (using, or not, a "you have the reputation of being honest and trustworthy" pro-social labeling technique), and Risk factor (three price levels of an alleged alternative offer and a control group). They were ultimately, as suppliers, asked their own purchasing price by the buyer—a highly sensitive piece of information. Results showed that the proportion of participants giving a true price in response to the question of their own purchasing price was significantly higher when they were exposed to our deception deterrence factors. Of the participants who did not dodge the question entirely, 38.1% of the control condition (no Dissonance, no Risk factor) gave their true purchasing price, compared to 80.8% in the combined Dissonance/Highest Risk factor level condition. Professionals can thus use simple theory-based deception deterrence factors to make their counterpart more honest in negotiations. [ABSTRACT FROM AUTHOR]

The current study investigates the combined effect of different dietary vitamins E and selenium (sodium selenite, Se) on the growth, survival, feed utilization, nutrients digestibility, body composition, activity test evaluation, intestinal bacterial load, and hematological indices of European seabass, Dicentrarchus labrax fry. A feeding experiment was conducted in D. labrax using five different diets with the same proximate composition. Introvit-ES100 oral® (ES) provides 50 mg/mL vitamin E and 0.5 mg/mL selenium, a source of VE and Se. The only distinction between the diets was the level of VE and SE. Each diet was fed to triplicate groups of fish (initial weight: 0.13 g) for 84 days. The control diet (ES0%) did not contain any added ES. Diets 2–5 included varying: 50: 0.5 mg/kg (ES1%), 100: 1.0 mg/kg (ES2%), 150: 1.5 mg/kg (ES3%), and 200: 2.0 mg/kg (ES4%). The water quality parameters were temperature 22, with a pH range of 7.9–8.2, the salinity range is 31.3–32.4 ppt, and the nitrogen concentrations are as follows: N at 0.54, NH3 at 0.73, and NH4 at 0.77. The results showed that seabass fry had the highest FBW, WG, SGR, FL, and K values when fed 150: 1.5 mg kg−1 of VE and Se, respectively (ES3%). Fish provided the ES4% diet had the highest survival (%) and showed inferior growth performance. Apparent digestibility coefficient analysis, which included protein, lipid, and carbohydrate digestibility, revealed that the highest values were recorded in fish fed the ES3% diets. The highest body protein was recorded in ES3%; the lowest lipid content value was recorded in ES4%. The highest white blood cell count, red blood cell count, and hematocrit values were recorded in ES3%. While the highest hemoglobin values were recorded in ES4%. The highest activity test value was recorded in ES2% and ES3% diets. The lowest Vibrio sp. count was recorded in ES3%. While the Aeromonas sp. was not detected in all experimental treatments. The results indicated that supplementing the diet with 150 mg kg−1 of VE and 1.5 mg kg−1 of Se improved growth performance, feed utilization, and survival rates, resulting in increased production of D. labrax fry after weaning in marine hatcheries. [ABSTRACT FROM AUTHOR]

Autologous transplantation remains the standard of care for eligible multiple myeloma (MM) patients, yet optimal CD34+ cell dose remains unclear. We conducted a retrospective study on MM patients undergoing upfront transplant between 2005 and 2021 and divided them into low (≤2.5 × 106 cells/kg) and high (>2.5 × 106 cells/kg) CD34+ dose groups. We included 2479 patients, 95 in the low CD34+ group and 2384 in the high CD34+ group. Patients in the low CD34+ group were older (63.2 vs 61.1 years, p = 0.013), more often had R-ISS III (19% vs 9%, p = 0.014), received plerixafor (60% vs 35%, p < 0.001) and transplanted after 2009 (88% vs 80%, p = 0.047). Time to neutrophil and platelet recovery was longer in the low CD34+ group. Median PFS and OS were lower in the low CD34+ group (31.6 vs. 43.6 months, p = 0.011 and 76.4 vs. 108.2 months, p < 0.001, respectively). Evaluation of incrementally higher CD34+ dose did not show significant improvement in survival at thresholds >2.5 × 106 cells/kg. Multivariable analysis affirmed that CD34+ >2.5 × 106 cells/kg was associated with better PFS (HR 0.71, p = 0.008) and OS (0.59, p < 0.001). After propensity score matching, a CD34+ dose >2.5 × 106 cells/kg remained a predictor of better OS (0.42, p < 0.001). In conclusion, CD34+ dose >2.5 × 106 cells/kg was associated with improved survival, without any additional benefit at incrementally higher doses. [ABSTRACT FROM AUTHOR]

Farming of red tilapia is one promising direction in aquaculture. The objective of this study was to investigate the impact of long-day photoperiod on the growth performance, reproductive parameters, maturity, sex ratio, β-carotene content, and skin coloration of red tilapia. Early life larvae were allocated into three treatment groups in triplicates: T1 = control group (12L:12D), T2 = long-day group (18L:6D), and T3 = continuous illumination group (24L:0D) for 90 days. By the end of the experiment, gonadosomatic index (GSI), relative fecundity, steroid hormones, maturity stages, sex ratio, and ovarian and testicular histology were examined; also, growth performance, survival rate, skin color, and total β-carotene content were measured. The results indicated that GSI% and serum testosterone (T) in T3 group significantly increased with greater amount of spermatozoa of male fish. Also, growth parameters and HSI% in female fish displayed significantly increased for T3 group. Females in group T2 showed significant elevation in GSI%, relative fecundity, and estradiol (E2) with higher number of mature stage. Continuous light group (T3) showed shifted male sex ratio, while female percentage was higher in T2 group. The total β-carotene content of T3 group showed significant elevation with less number of black spots. This study demonstrated that continuous light manipulation during red tilapia early life could stimulate the growth and enhance coloration by reducing black spots that significantly affects economic profitability. Long-day application was effective in female reproductive performance and maturity. This study also served as an important reference for red tilapia aquaculture. [ABSTRACT FROM AUTHOR]

Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p < 0.001), more often had <50% bone marrow plasma cells (67% vs. 58%; p = 0.018) and R-ISS stage I disease (43% vs. 34%). More patients in the LTR group received post-transplant maintenance (63% vs. 52%; p = 0.002). Patients in the LTR group had higher rates of complete response (CR) at day100 (41% vs. 27%; p < 0.001) and at best post-transplant response (70% vs. 37%; p < 0.001), compared to the non-LTR group. Patients in the LTR groups had a median PFS of 169.3 months and the median overall survival (OS) had not been reached. The leading cause of death in the LTR was disease progression. In conclusion, 15% of patients in the cohort were LTR after upfront autoHCT, with distinct characteristics and a median PFS of more than 14 years. [ABSTRACT FROM AUTHOR]

CLCN4-related disorder is a rare X-linked neurodevelopmental condition with a pathogenic mechanism yet to be elucidated. CLCN4 encodes the vesicular 2Cl−/H+ exchanger ClC-4, and CLCN4 pathogenic variants frequently result in altered ClC-4 transport activity. The precise cellular and molecular function of ClC-4 remains unknown; however, together with ClC-3, ClC-4 is thought to have a role in the ion homeostasis of endosomes and intracellular trafficking. We reviewed our research database for patients with CLCN4 variants and epilepsy, and performed thorough phenotyping. We examined the functional properties of the variants in mammalian cells using patch-clamp electrophysiology, protein biochemistry, and confocal fluorescence microscopy. Three male patients with developmental and epileptic encephalopathy were identified, with differing phenotypes. Patients #1 and #2 had normal growth parameters and normal-appearing brains on MRI, while patient #3 had microcephaly, microsomia, complete agenesis of the corpus callosum and cerebellar and brainstem hypoplasia. The p.(Gly342Arg) variant of patient #1 significantly impaired ClC-4's heterodimerization capability with ClC-3 and suppressed anion currents. The p.(Ile549Leu) variant of patient #2 and p.(Asp89Asn) variant of patient #3 both shift the voltage dependency of transport activation by 20 mV to more hyperpolarizing potentials, relative to the wild-type, with p.(Asp89Asn) favouring higher transport activity. We concluded that p.(Gly342Arg) carried by patient #1 and the p.(Ile549Leu) expressed by patient #2 impair ClC-4 transport function, while the p.(Asp89Asn) variant results in a gain-of-transport function; all three variants result in epilepsy and global developmental impairment, but with differences in epilepsy presentation, growth parameters, and presence or absence of brain malformations. [ABSTRACT FROM AUTHOR]

We evaluated the utility of genetic testing in the pre-surgical evaluation of pediatric patients with drug-resistant focal epilepsy. This single-center retrospective study reviewed the charts of all pediatric patients referred for epilepsy surgery evaluation over a 5-year period. We extracted and analyzed results of genetic testing as well as clinical, EEG, and neuroimaging data. Of 125 patients referred for epilepsy surgical evaluation, 86 (69%) had some form of genetic testing. Of these, 18 (21%) had a pathogenic or likely pathogenic variant identified. Genes affected included NPRL3 (3 patients, all related), TSC2 (3 patients), KCNH1, CHRNA4, SPTAN1, DEPDC5, SCN2A, ARX, SCN1A, DLG4, and ST5. One patient had ring chromosome 20, one a 7.17p12 duplication, and one a 15q13 deletion. In six patients, suspected epileptogenic lesions were identified on brain MRI that were thought to be unrelated to the genetic finding. A specific medical therapy choice was allowed due to genetic diagnosis in three patients who did not undergo surgery. Obtaining a molecular diagnosis may dramatically alter management in pediatric patients with drug-resistant focal epilepsy. Genetic testing should be incorporated as part of standard investigations in the pre-surgical work-up of pediatric patients with drug-resistant focal epilepsy. [ABSTRACT FROM AUTHOR]

This study provides comprehensive results on the growth, thyroid, liver, and gonadal condition, maturity, and sex ratio in red tilapia exposed to exogenous thyroxine and goitrogen. One-gram red tilapia fingerlings were reared in three groups: control, thyroxine (T4) (10 nM), and goitrogen (sodium perchlorate, 30 mg/L) for 30 days, followed by 30 days without treatment. After the first 30 days of treatment, liver enzymes and whole-body T4 and T3 were assessed. The gonadosomatic index (GSI), maturity stages and sex ratio were examined. Final body weight (FBW), weight gain (WG), specific growth rate (SGR), and survival rate were also measured. Results revealed insignificant differences among groups in FBW, WG, SGR, and GSI, but the hepatosomatic index (HSI) of the goitrogen group significantly increased. Exogenous thyroxine significantly increased whole-body T4. Liver enzymes were not affected. Thyroid follicles of the thyroxine-treated fish showed large thyroid follicles, whereas the goitrogen-treated fish showed degenerated and negligible thyroid follicles. Liver tissue of the thyroxine-treated fish group displayed a few fat vacuoles, while perchlorate-treated fish showed hydrophobic degenerated hepatocytes. At the end of 60 days, the thyroxine treatment significantly increased FBW, WG, SGR, female GSI, and male hepatosomatic index (HSI). Perchlorate and thyroxine exposure, respectively, skewed sex ratios toward males and females. Exogenous T4 enhanced the maturity stages of both females and males, while perchlorate exposure delayed their gonadal ripening. These results validated the significant role of T4 during early life of red tilapia as it could improve the growth and maturity, and affect its sex ratio, while T4 insufficiency could alter these factors. [ABSTRACT FROM AUTHOR]

The term Pontocerebellar Hypoplasia (PCH) was initially used to designate a heterogeneous group of fetal-onset genetic neurodegenerative disorders. As a descriptive term, PCH refers to pons and cerebellum of reduced volume. In addition to the classic PCH types described in OMIM, many other disorders can result in a similar imaging appearance. This study aims to review imaging, clinical and genetic features and underlying etiologies of a cohort of children with PCH on imaging. We systematically reviewed brain images and clinical charts of 38 patients with radiologic evidence of PCH. Our cohort included 21 males and 17 females, with ages ranging between 8 days to 15 years. All individuals had pons and cerebellar vermis hypoplasia, and 63% had cerebellar hemisphere hypoplasia. Supratentorial anomalies were found in 71%. An underlying etiology was identified in 68% and included chromosomal (21%), monogenic (34%) and acquired (13%) causes. Only one patient had pathogenic variants in an OMIM listed PCH gene. Outcomes were poor regardless of etiology, though no one had regression. Approximately one third of patients deceased at a median age of 8 months. All individuals had global developmental delay, 50% were non-verbal, 64% were non-ambulatory and 45% required gastrostomy feeding. This cohort demonstrates that radiologic PCH has heterogenous etiologies and the "classic" OMIM-listed PCH genes underlie only a minority of cases. Broad genetic testing, including chromosomal microarray and exome or multigene panels, is recommended in individuals with PCH-like imaging appearance. Our results strongly suggest that the term PCH should be used to designate radiologic findings, and not to imply neurogenerative disorders. [ABSTRACT FROM AUTHOR]

The goal of this paper is to examine the effect of high liquidity creation on systemic risk. We use a hand-collected dataset on 94 banks from 16 Western European countries over the 2004–2020 period, including the crisis (2008–2009) period and sound periods (2004–2007 and 2010–2020). We assess banks' systemic risk using two different proxies: banks' systemic risk exposure, measured by the marginal expected shortfall (MES), and banks' systemic risk contribution, measured by the delta conditional value at risk (ΔCoVaR). Based on panel regressions, our results mainly show that, during calm periods, high liquidity creation is associated with high systemic risk exposure. Moreover, we show that the effect of liquidity creation on banks' systemic risk exposure is stronger during turmoil periods. Interestingly, our results show that banks' liquidity creation increases the systemic contribution only during the financial crisis of 2008–2009. Our findings contribute to the literature and the regulatory debate by suggesting that regulators should pay more attention to high liquidity-creating banks as they may cause aggregate financial fragility. [ABSTRACT FROM AUTHOR]

Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and considered as participants of the cellular response to stress. Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs. We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions.Oligodendrocyte (OL) injury and loss is a pathologic hallmark of multiple sclerosis. Here, the authors show the presence of stress granules in OLs in multiple sclerosis lesions, and their in vitro studies in human OLs indicate that stress granules formation is a response to a combination of metabolic stress and pro-inflammatory conditions. [ABSTRACT FROM AUTHOR]

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung diseases (ILDs) are parenchymal lung conditions that are chronic, progressive, and have a high morbidity and mortality rate. Due to restrictions in their gas exchange and ventilatory dysfunction, ILD patients are probably at risk for sleep-disordered breathing (SDB). Methodology: Sixty-nine patients with diffuse parenchymal lung diseases identified by high-resolution computed tomography (HRCT) chest were included in the study. All patients were assessed by the STOP-BANG questionnaire (SBQ), Epworth sleepiness scale (ESS), and full-night polysomnography (PSG) for diagnosis and classification of SDB. The aim of the study is to examine the prevalence and risk factors for SDB in ILD. Results: Among the study group hypersensitivity pneumonitis (HP) was the most prevalent ILD, accounting for 63.8% of cases. Out of 69 individuals, 42 (60.9%) had SDB, 57.1% of those with SDB had obstructive sleep apnea (OSA), and the majority of those with OSA had mild degrees (21.7%, n = 15). Conclusion: OSA is significantly common in ILD patients. Higher left atrium diameter and oxygen desaturation index (ODI) are predictive factors of SDB. To facilitate early diagnosis and therapy, PSG should be performed on ILD patients at high risk (such as males, individuals with high ESS scores, SBQ scores, and left atrium diameter). Trial registration: Retrospectively registered, registration number is NCT06012526, date of registration August 25, 2023. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to describe and diagnose the difficulty in a long-term follow-up (eleven years) patient with a very early presentation of late-onset retinal degeneration (L-ORD) and the significance of electrophysiological examinations and follow-up in assessing undiagnosed inherited retinal diseases. Methods: This is an observational case report of a 56-year-old woman, with scattered multiple yellow–white retinal dots firstly diagnosed as fundus albipunctatus. Ten years after presentation, a deterioration in rod and cone responses in ff-ERG was detected, which allowed us to discard the first diagnostic hypothesis and proceed with a genetic testing. Results: Ten years after presentation, she presented a clear progression of the abnormal photoreceptor response with a cone and rod involvement in ff-ERG, which was not compatible with the previous suspicion of fundus albipunctatus. Six months later, genetic testing results together with the typical progression of atrophic patchy lesions in multimodal imaging allowed a certain diagnosis of L-ORD, caused by an already reported pathogenic variant in the C1QTNF5 gene (c.563C > T; p. Pro188 Leu). Conclusions: We demonstrate the importance of the ff-ERG examination and the follow-up (or ERG and imaging repetition) in the differential diagnosis of an incipient L-ORD, which can be easily misdiagnosed in the early stages, before the appearance of the characteristic chorioretinal atrophy seen with the progression of this rare disease. [ABSTRACT FROM AUTHOR]

The prognostic impact of additional copies of chromosome 1q (1q +) on outcomes of newly-diagnosed multiple myeloma (NDMM) patients undergoing autologous transplantation (autoSCT) is unclear. We conducted a retrospective single-center analysis of NDMM patients with 1q21 gain/amplification (3 or ≥4 copies of 1q, respectively) that received autoSCT between 2008–2018. 213 patients were included (79% 1q gain; 21% 1q amplification). The most commonly used induction regimen was bortezomib, lenalidomide, and dexamethasone (41%). At day100 post-autoSCT and at best post-transplant response, 78% and 87% of patients achieved ≥VGPR, and 38% and 50% achieved MRD-negative ≥VGPR, respectively. Median PFS and OS for the entire cohort were 35.5 months and 81.4 months, respectively. On multivariable assessment for PFS, MRD negative ≥VGPR before autoSCT (HR 0.52, p = 0.013) was associated with superior PFS, whereas 1q amplification was associated with inferior PFS (2.03, p = 0.003). On multivariate analysis for OS, achieving MRD negative ≥VGPR at best post-transplant response was associated with superior survival (0.29, p < 0.001), whereas R-ISS III and concomitant del17p or t(4:14) were associated with inferior survival (6.95, p = 0.030, 2.33, p = 0.023 and 3.00, p = 0.047, respectively). In conclusion, patients with 1q+ NDMM, especially 1q amplification, have inferior survival outcomes compared to standard-risk disease after upfront autoSCT, though outcomes are better than other high-risk cytogenetic abnormalities. [ABSTRACT FROM AUTHOR]

Daily eating/fasting cycles synchronise circadian peripheral clocks, involved in the regulation of the cardiovascular system. However, the associations of daily meal and fasting timing with cardiovascular disease (CVD) incidence remain unclear. We used data from 103,389 adults in the NutriNet-Santé study. Meal timing and number of eating occasions were estimated from repeated 24 h dietary records. We built multivariable Cox proportional-hazards models to examine their association with the risk of CVD, coronary heart disease and cerebrovascular disease. In this study, having a later first meal (later than 9AM compared to earlier than 8AM) and last meal of the day (later than 9PM compared to earlier than 8PM) was associated with a higher risk of cardiovascular outcomes, especially among women. Our results suggest a potential benefit of adopting earlier eating timing patterns, and coupling a longer nighttime fasting period with an early last meal, rather than breakfast skipping, in CVD prevention. The relation between daily meal and fasting timing with cardiovascular disease incidence remains unclear. Here, authors show that a later daily meal timing is associated with increased cardiovascular disease risk, especially in women. This study suggests that adopting earlier daily eating patterns may be beneficial for cardiovascular prevention. [ABSTRACT FROM AUTHOR]

In this study, the impact of adding samarium iron garnet (Sm3Fe5O12; SmIG) nanoparticles to the (Bi1.6Pb0.4)Sr1.9Ca0.9Y0.2Cu2.1O8+δ ((Bi, Pb)-2212) superconductor was investigated. The conventional solid-state reaction method was utilized to synthesize (SmIG)x(Bi, Pb)-2212 phase with different concentrations (x = 0, 0.25, 0.5, 0.75, 1, and 2 wt%). The structure, the morphology, and the elemental composition were tested using X-ray powder diffraction spectroscopy (XRD), scanning electron microscopy (SEM), and dispersive X-ray spectroscopy (EDX), respectively. Filling of pores and voids validated the impact of the added nano-SmIG on intergrain connections. The enhancement in oxygen content was verified by iodometric titration analysis. The superconducting transition temperature (Tc) and the critical current density (Jc) showed best enhancement with the addition of nano-SmIG up to x = 0.75 wt%, having values of 91.02 K and 373.95 A/cm2, respectively. The fluctuations in the superconducting properties were explained via X-ray photoelectron spectroscopy (XPS) by studying the elemental composition and oxidation states for all elements. Vickers microhardness (Hv) investigations were carried out at different applied loads and indentation time of 20 s, where Hv reached its highest value at x = 0.25 wt%. Based on Hv values, the modified proportional sample resistance (MPSR) model offered the most suitable theoretical model to elucidate the experimental data. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to describe the management of neovascular age-related macular degeneration (nAMD) in French patients between 2008 and 2018. Methods: This was a retrospective longitudinal cohort study using exhaustive nationwide health records from the French National Health Information database. Enrollment criteria were adults aged ≥ 50 years, nAMD diagnosis, or reimbursement for nAMD treatments (anti-vascular epithelial growth factor [VEGF] injection or dynamic phototherapy with verteporfin). Exclusion criteria were high myopia, diagnosis of other retinal diseases, and treatments for other macular diseases (dexamethasone implant, laser). Main outcome measures were consumption of medical care and nAMD treatments per calendar year and number of years of follow-up. Results: Between 2008 and 2018, we identified 342,961 patients who have been treated for nAMD. Median duration of ophthalmological follow-up exceeded 7 years (90 months). The median annual number of ophthalmology consultations decreased from nine visits in year 1 after treatment initiation to four visits from year 7 onwards. The median duration of nAMD treatment was 10.1 months for all patients, with 48.5% of patients undergoing treatment for < 1 year. Only 24.4% of patients had maintained treatment at year 11. Patients remaining under treatment had a median of four anti-VEGF treatments per year throughout the 10-year study period. Ranibizumab was the more common first-line treatment (67.5% of patients) compared to aflibercept (32.4%). About 20% of patients who initiated treatment switched treatment at least once. Conclusions: LANDSCAPE provides exhaustive nationwide data on the real-world management of nAMD in France over a 10-year period. Further investigation into short treatment duration is required, especially in terms of understanding its relation to visual outcomes. [ABSTRACT FROM AUTHOR]

Background: Periventricular nodular heterotopia (PVNH) is a congenital brain malformation often associated with seizures. We aimed to clarify the spectrum of epilepsy phenotypes in PVNH and the significance of specific brain malformation patterns. Methods: In this retrospective cohort study, we recruited people with PVNH and a history of seizures, and collected data via medical record review and a standardized questionnaire. Results: One hundred individuals were included, aged 1 month to 61 years. Mean seizure onset age was 7.9 years. Ten patients had a self-limited epilepsy course and 35 more were pharmacoresponsive. Fifty-five had ongoing seizures, of whom 23 met criteria for drug resistance. Patients were subdivided as follows: isolated PVNH ("PVNH-Only") single nodule (18) or multiple nodules (21) and PVNH with additional brain malformations ("PVNH-Plus") single nodule (8) or multiple nodules (53). Of PVNH-Only single nodule, none had drug-resistant seizures. Amongst PVNH-Plus, 55% with multiple unilateral nodules were pharmacoresponsive, compared to only 21% with bilateral nodules. PVNH-Plus with bilateral nodules demonstrated the highest proportion of drug resistance (39%). A review of genetic testing results revealed eight patients with pathogenic or likely pathogenic single-gene variants, two of which were FLNA. Five had copy number variants, two of which were pathogenic. Conclusions: The spectrum of epilepsy phenotypes in PVNH is broad, and seizure patterns are variable; however, epilepsy course may be predicted to an extent by the pattern of malformation. Overall, drug-resistant epilepsy occurs in approximately one quarter of affected individuals. When identified, genetic etiologies are very heterogeneous. [ABSTRACT FROM AUTHOR]

Background Migraine is one of the most prevalent and disabling primary headache disorders. Migraine has many triggers factors as stress and irregular sleep pattern. Medical study in Egypt is so stressful with great psychological and physical burden; hence medical students are vulnerable to migraine. This study aims to determine the prevalence, characteristics, degree of disability, and psychological stress associated with migraine among medical students at different Egyptian universities. Results The overall prevalence of migraine was 17.27%, more in female (76.86%) than male. Sleeping disturbance and stress were the most common triggering factors associated with migraine (94.4%, 81.4% respectively). The majority of students with migraine (89.65%) had high psychological distress as measured by Kessler Psychological Distress Scale (K10) with moderate to severe disorder, while 76.8% had moderate to severe disability as assessed by Migraine Disability Assessment Score (MIDAS). Female gender was a potential predictor associated with higher psychological distress. There is negative correlation between degree of disability and academic performance. Conclusion Migraine is prevalent among medical students, with female predominance. It is associated with high level of psychological stress, moderate to severe disability, and negative impact on lifestyle and academic performance of the students. [ABSTRACT FROM AUTHOR]

Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC− in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC− (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p < 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC− groups, respectively (both p < 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS. [ABSTRACT FROM AUTHOR]

Introduction: Receipt of chemotherapy is associated with decreased satisfaction after breast surgery, but whether timing as adjuvant versus neoadjuvant (NAC) affects patient-reported outcomes (PROs) is unclear. We examined associations between chemotherapy timing and PROs after breast-conserving surgery (BCS) and mastectomy with immediate reconstruction (M-IR). Methods: In this retrospective cohort study of patients with stage I-III breast cancer undergoing chemotherapy between January 2017 and December 2019, we compared satisfaction with breasts (SABTR) and chest physical well-being (PWB-CHEST) between chemotherapy groups in BCS and M-IR cohorts. Median SABTR and PWB-CHEST scores (scale 0–100) were compared between chemotherapy groups at baseline and for 3 years postoperatively. Factors associated with SABTR and PWB-CHEST at 1 and 2 years were assessed with multivariable linear regression. Results: Overall, 640 patients had BCS and 602 had M-IR; 210 (33%) BCS patients and 294 (49%) M-IR patients had NAC. Following BCS, SABTR was higher than baseline at all postoperative timepoints, whereas 3-year SABTR remained similar to baseline following M-IR, independent of chemotherapy timing. In both surgical cohorts, PWB-CHEST was lowest after NAC at 6 months compared with baseline but was similar to adjuvant counterparts by 3 years. NAC was not a statistically significant predictor of SABTR or PWB-CHEST in either surgical cohort on multivariable analysis. Conclusions: For patients with breast cancer who require chemotherapy, neoadjuvant versus adjuvant timing does not impact long-term PROs in this study. These findings may inform shared decision making regarding the sequence of treatment in patients with operable disease. [ABSTRACT FROM AUTHOR]

Background: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive. Methods: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method. Results: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HRQ5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HRQ5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HRQ5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HRQ5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HRQ5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HRQ5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). Conclusions: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources. [ABSTRACT FROM AUTHOR]

ABO blood type has been reported as a potential factor influencing SARS-CoV-2 infection, but so far mostly in studies that involved small samples, selected population and/or used PCR test results. In contrast our study aimed to assess the association between ABO blood types and SARS-CoV-2 infection using seroprevalence data (independent of whether or not individuals had symptoms or sought for testing) in a large population-based sample. Our study included 67,340 French participants to the SAPRIS-SERO multi-cohort project. Anti-SARS-CoV-2 antibodies were detected using ELISA (targeting the proteins spike (S) and nucleocapsid (NP)) and seroneutralisation (SN) tests on dried blood spots collected in May–November 2020. Non-O individuals (and especially types A and AB) were more likely to bear anti SARS-CoV-2 antibodies (ELISA-S, 2964 positive cases: ORnon-Ovs.O = 1.09[1.01–1.17], ORAvs.O = 1.08[1.00–1.17]; ELISA-S/ELISA-NP/SN, 678 triple positive cases: ORnon-Ovs.O = 1.19 [1.02–1.39], ORAvs.O = 1.19[1.01–1.41], ORABvs.O = 1.43[1.01–2.03]). Hence, our results provided additional insights into the dynamic of SARS-CoV-2 infection, highlighting a higher susceptibility of infection for individuals of blood types A and AB and a lesser risk for blood type O. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) engenders traumatic necrosis and penumbra—areas of secondary neural injury which are crucial targets for therapeutic interventions. Segmenting manually areas of ongoing changes like necrosis, edema, hematoma, and inflammation is tedious, error-prone, and biased. Using the multi-parametric MR data from a rodent model study, we demonstrate the effectiveness of an end-end deep learning global-attention-based UNet (GA-UNet) framework for automatic segmentation and quantification of TBI lesions. Longitudinal MR scans (2 h, 1, 3, 7, 14, 30, and 60 days) were performed on eight Sprague–Dawley rats after controlled cortical injury was performed. TBI lesion and sub-regions segmentation was performed using 3D-UNet and GA-UNet. Dice statistics (DSI) and Hausdorff distance were calculated to assess the performance. MR scan variations-based (bias, noise, blur, ghosting) data augmentation was performed to develop a robust model. Training/validation median DSI for U-Net was 0.9368 with T2w and MPRAGE inputs, whereas GA-UNet had 0.9537 for the same. Testing accuracies were higher for GA-UNet than U-Net with a DSI of 0.8232 for the T2w-MPRAGE inputs. Longitudinally, necrosis remained constant while oligemia and penumbra decreased, and edema appearing around day 3 which increased with time. GA-UNet shows promise for multi-contrast MR image-based segmentation/quantification of TBI in large cohort studies. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is a progressive inflammatory process of the biliary tree resulting in biliary obstruction. No single known genetic or environmental factor has been established to cause BA. Cystic fibrosis (CF) is a rare cause of neonatal cholestasis, and it has never been described in familial BA cases. Here, we investigate two siblings of first-degree consanguineous parents presenting with neonatal BA. Shortly after the Kasai operation, the proband developed severe respiratory symptoms attributable to a missed CF diagnosis. This was discovered after re-investigating the family history, which revealed a first-degree cousin with CF who did not manifest BA. Afterwards, we identified a pathogenic variant (DeltaF508) in CFTR in both BA-affected siblings along with their cousin. This intrigued us to study the molecular etiology behind the familial BA presentations, which exclusively contributed to BA-pathogenesis in BA-CF-affected siblings and not in their CF-only affected cousin. We applied a multistep approach to investigate the variant profile of both siblings' and their cousin's exomes. We curated the genes whose variants were shared by the BA-CF siblings but absent or heterozygous in their CF-only-affected cousin. Consequently, we identified three candidate genes (SNAPC4, UCK1, and ZHX2) besides CFTR. We propose that these genes act cumulatively or individually in inducing BA-pathogenesis—either by aggravating the biliary damage in the context of CF or increasing the susceptibility of BA as a separate CF-comorbidity. To our knowledge, this is the first report of DeltaF508 in CFTR with familial neonatal BA cases. [ABSTRACT FROM AUTHOR]

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Background: Both the nutritional quality of the foods consumed (as nutrient composition) and their ultra-processed nature have been linked to health risks. However, the respective contribution of each of these correlated dimensions or their synergy to the overall diet quality has been rarely explored. Objective: To identify the respective effects of the nutritional quality of the foods consumed, the ultra-processed nature of foods and their cross-effect contributing to the overall quality of the diet. Design: Cross-sectional observational study. Setting: Web-based French NutriNet-Santé cohort study. Participants: Participants in the NutriNet-Santé cohort study with at least three available 24 h records as baseline dietary data (N = 98 454 participants). Main outcome measures: The overall quality of the diet (qualified using the adherence to the 2017 French national nutrition and health dietary recommendations dietary score PNNS-GS2) was broken down into: (1) an effect of the nutritional quality of the foods consumed (qualified using the modified Foods Standards Agency nutrient profile model (underlying the Nutri-Score) dietary index FSAm-NPS DI); (2) an effect of the ultra-processed nature of the foods consumed (qualified using the proportion of ultra-processed foods consumed UPFp using the NOVA classification), and (3) a cross-effect of both dimensions. Results: The overall effect from the 'nutritional quality of the foods consumed' (FSAm-NPS DI) was 1.10, corresponding to 26% of the total effect; the overall effect from ultra-processed foods consumption was 1.29, corresponding to 30% of the total effect; and cross-effect between nutritional quality of the foods consumed and ultra-processing was at 1.91, corresponding to 44% of total effects. Conclusions: Our study provides support to the postulate that nutritional quality and ultra-processing should be considered as two correlated but distinct and complementary dimensions of the diet. [ABSTRACT FROM AUTHOR]

Introduction: Patient-reported outcome measures (PROM) are used to assess value-based care. Little is known as to whether PROM response in breast cancer reflects the diverse patient population. The BREAST-Q, a validated measure of satisfaction and quality of life, and Recovery Tracker, a postoperative assessment tool, are PROM routinely delivered to all patients undergoing breast surgery at our institution. Here we determine whether response to PROM differs by age, race, language, or disease stage. Methods: All patients who had a breast operation between January 2020 and July 2021 were requested to complete the BREAST-Q and Recovery Tracker. Non-responders did not complete the PROM at any timepoint; responders completed 1 or more. Primary outcomes included rates of non-response versus response overall. Results: Of 6374 patients identified, 5653 (88.7%) responded to either PROM [4366/4751 (91.9%) BREAST-Q; 2746/3384 (81.1%) Recovery Tracker]. On univariate analysis, non-responders were older (60 years versus 55 years, p < 0.001) and more often non-English speaking (p < 0.001), Hispanic ethnicity (p = 0.031), and Black race (p < 0.001), versus responders. On multivariate analysis, non-responders were significantly more often Black race and non-English speaking (p < 0.001). Non-English speakers were significantly less responsive among all ethnicities and races except Black race. Although breast cancer stage did not reach significance for response, patients with malignant disease and those receiving neoadjuvant chemotherapy responded more often. Conclusions: Our findings demonstrate high patient engagement using 2 different PROM following breast surgery, but suggest that PROM results may not reflect the experience of the entire breast cancer population. Care process changes based solely on PROM should consider these findings to ensure that the views of the entire spectrum of patients with breast cancer are represented. [ABSTRACT FROM AUTHOR]

Opinion statement: For years, upfront autologous hematopoietic cell transplant (auto-HCT) has been the standard of care for younger and physically fit mantle cell lymphoma (MCL) patients after chemoimmunotherapy (CIT) induction. Bruton's tyrosine kinase (BTK) inhibitors have proven to be excellent salvage therapies, but their durability remains a question, especially in high-risk (HR) MCL. Allogeneic HCT (allo-HCT) was the only option for long-term remission and possibly cure for MCL relapse after auto-HCT and sometime as upfront consolidation for a young patient with HR MCL (debatable). We have seen a paradigm shift since the FDA approval in July 2020 of the brexucabtagene autoleucel chimeric antigen receptor T (CAR-T) cell therapy for relapsed and refractory (R/R) MCL with an preliminary evidence suggesting CAR-T may overcome known biological risk factors in MCL. Given its safety profile and excellent efficacy, the role of CAR-T among other approved therapies and HCT may need to be better defined. Based on the current evidence, auto-HCT remains a standard frontline consolidation therapy. CAR-T therapy is a preferred option for patients with relapsed/refractory (R/R) MCL, particularly those who failed BTK inhibitors. In certain high-risk MCL patients (such as high ki 67, TP53 alterations, complex karyotype, blastoid morphology, early relapse after initial diagnosis), CAR-T cell therapy may be considered before BTK inhibitors (preferably on a clinical trial). The role of allo-HCT is unclear in the CAR-T era, but remains a viable option for eligible patients who have no access or who have failed CAR-T therapy. Our review discusses current standards and the shifting paradigms in the indications for HCT and the role of CAR-T cell therapy for MCL. Prospective studies tailored based on risk factors are needed to better define the optimal sequences of HCT and cellular therapy and other approved novel therapies. [ABSTRACT FROM AUTHOR]

Purpose: To explore the relationships between clinical-radiological features and surgical outcomes in subjects with interhemispheric cysts (IHC) and corpus callosum anomalies. Methods: We reviewed the clinico-radiological and neurosurgical data of 38 patients surgically treated with endoscopic fenestration, shunting, or combined approaches from 2000 to 2018 (24 males, median age 9 years). Pre- and postoperative changes in IHC volume were calculated. Outcome assessment was based on clinico-radiological data. Group comparisons were performed using χ2, Fisher exact, Mann–Whitney U, and Kruskal–Wallis tests. Results: Median age at first surgery was 4 months (mean follow-up 8.3 years). Eighteen individuals (47.3%) required > 1 intervention due to IHC regrowth and/or shunt malfunction. Larger preoperative IHC volume (P =.008) and younger age at surgery (P =.016) were associated with cyst regrowth. At last follow-up, mean cystic volume was 307.8 cm3, with IHC volume reduction > 66% in 19/38 (50%) subjects. The neurological outcome was good in 14/38 subjects (36.8%), fair in 18/38 (47.3%), and poor in 6/38 (15.7%). There were no differences in the postoperative cyst volume with respect to either the type of first surgery or overall surgery type. Higher absolute postoperative IHC reduction was observed in subjects who underwent both IHC fenestration and shunting procedures (P <.0001). No differences in neurological outcome were found according to patient age at surgery or degree of IHC reduction. Conclusion: Endoscopic fenestration and shunting approaches are both effective but often require multiple procedures especially in younger patients. Larger IHC are more frequently complicated by cyst regrowth after surgery. [ABSTRACT FROM AUTHOR]

Previous studies have reported contradictory findings on the utility of remote physiological monitoring (RPM)-guided management of patients with chronic heart failure (HF). Multiple databases were searched for studies that evaluated the clinical efficacy of RPM-guided management versus standard of care (SOC) for HF patients. The primary outcome was HF-related hospitalization (HFH). The secondary outcomes were all-cause mortality, cardiovascular-related (CV) mortality, and emergency department (ED) visits. Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were calculated and combined using a random-effects model. A total of 16 randomized controlled trials, including 8679 HF patients (4574 managed with RPM-guided therapy vs. 4105 managed with SOC), were included in the final analysis. The average follow-up period was 15.2 months. There was no significant difference in HFH rate between the two groups (RR: 0.94; 95% CI: 0.84–1.07; P = 0.36). Similarly, there were no significant differences in CV mortality (RR 0.86, 95% CI 0.73–1.02, P = 0.08) or in ED visits (RR 0.80, 95% CI 0.59–1.08, P = 0.14). However, RPM-guided therapy was associated with a borderline statistically significant reduction in all-cause mortality (RR: 0.88; 95% CI: 0.78–1.00; P = 0.05). Subgroup analysis based on the strategy of RPM showed that both hemodynamic and arrhythmia telemonitoring–guided management can reduce the risk of HFH (RR: 0.79; 95% CI: 0.64–0.97; P = 0.02) and (RR: 0.79; 95% CI: 0.67–0.94; P = 0.008) respectively. Our study demonstrated that RPM-guided diuretic therapy of HF patients did not reduce the risk of HFH but can improve survival. Hemodynamic and arrhythmia telemonitoring–guided management could reduce the risk of HF-related hospitalizations. [ABSTRACT FROM AUTHOR]

Introduction: Correct inhaler technique is essential for the optimal delivery of inhaled medicines and the successfully management of respiratory conditions. The general practitioner (GP), the prescriber of inhaled medicines, plays a crucial role in educating patients on inhaler technique. However, in the real-world setting, there are barriers. For the GP, it is time and competence and for the patient, it is their ability to recognise inhaler technique as an issue and their ability to maintain correct inhaler technique over time. This study aimed to determine GPs' experience, skills and priority placed on inhaler technique and to identify factor(s) associated with inhaler technique competence. Methods: This cross-sectional observational study design surveyed GPs' perspectives on inhaler use and preferences for inhaler prescribing within their practice setting. GP inhaler technique was assessed. GPs were recruited through an established network of GP practices. Data collected include (i) practice demographics, (ii) inhaler technique opinions and experience, (iii) inhaler prescribing preferences and (iv) inhaler education history data. Data were analysed descriptively and multivariate logistic regression modelling was used to explore the relationship between outcomes and GPs' ability to use devices correctly. Results: A total of 227 GPs completed the inhaler survey. Sixty-three percent of GPs reported receiving previous inhaler education and 73.3% educated or checked their patients' inhaler technique; 64.5% felt they were somewhat competent in doing so. GPs who reported not demonstrating inhaler technique believed that a pharmacist or a practice nurse would do so. When prescribing new inhaler devices, GPs considered the disease being treated first and then patient's experience with inhalers; they often already have an inhaler preference and this was related to familiarity and perceived ease of use. For GPs, inhaler competence was not associated with their previous inhaler education or the priority placed on inhaler technique. Conclusion: GPs do recognise the importance of inhaler technique in respiratory management but their technique can be better supported with regular educational updates to inform them about new inhalers and management practices and to support appropriate inhaler choices for their patients. [ABSTRACT FROM AUTHOR]

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2′-pyrrolidine-3′,3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties. [ABSTRACT FROM AUTHOR]

A study of archaeobotanical samples recovered from excavations by the German Archaeological Institute (2013–2019) in late Middle Kingdom (1750–1650 bc) house 169 on Elephantine Island (Egypt) yielded an assemblage of exceptionally well-preserved desiccated and charred plant macro-remains. In order to determine patterns within the assemblage of 208,493 plant items from 123 archaeological contexts, we applied a novel approach to multivariate statistical analyses, making use of machine learning methods. A combination of cluster analysis and evolutionary decision trees out-performed traditional correspondence analysis and principal components analysis techniques, allowing for the discovery that whilst the assemblage was generally homogeneous, it was possible to identify certain types of deposits as being locations of plant “waste” disposal. The analysis also allowed identification of possible storage of barley and flax processing in one room, and some fireplaces in which the inhabitants chose to burn specific selected materials. [ABSTRACT FROM AUTHOR]

Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5, while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them. The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments. [ABSTRACT FROM AUTHOR]

Heat shock proteins (HSPs) work in response to a variety of external and internal stresses to maintain homeostasis and are upregulated upon cellular damage. This study aimed to determine the effect of maximal aerobic effort test ( max test) on the expression of genes related to heat shock proteins' (HSPs) cycle (HSP90AA1, HSP90AB1, PTGES3). Eleven black-belt taekwondo male athletes participated in this study and performed a max test on a treadmill connected to the Cortex gas analyzer till the point of physical exhaustion. Gene expression was analyzed by real-time PCR, while the physiological parameters were measured spectrophotometrically or by immune assays using serum form the blood Before the test (Bf), Immediately After (IA), and Two Hours After (2HA) the max test. The levels of fold change expression were affected by the VO2max test. HSP90AA1, HSP90AB1 and PTGES3 mRNA levels were significantly higher IA the test (P ≤ 0.05). HSPs surpassed the cut-off value (1.5-fold) IA showed (M = 2.29 times for HSP90AA1), (M = 1.68 times for HSP90AB1), while PTGES3 did not reach the cut-off value (M = 1.12 times). The expression levels of the three genes were significantly decreased 2HA and returned to the baseline values. Moreover, physiological parameters including growth hormone, creatinine kinase, white blood cells, platelets count, and blood lactate showed a peak in their levels IA the test and then dropped 2HA (P ≤ 0.05). Our findings demonstrate that genetic expressions of HSP90AA1 and HSP90AB1 genes were significantly elevated IA the test and decreased 2HA. The same applied on most of the physiological parameters; strongly suggesting the possible utility of using those parameters as a reference to confirm evidence of exercise-induced cell stress. [ABSTRACT FROM AUTHOR]

Relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (allo-HCT) in myeloid malignancies. Additional strategies have been devised to further maximize the immunologic effect of allo-HCT, notably through maintenance therapy with hypomethylating agents such as 5-azacytidine (AZA). We conducted a single-center retrospective study to investigate the efficacy of AZA after allo-HCT for high-risk myeloid malignancies. All patients transplanted between Jan 2014 and Sept 2019 for high-risk acute myeloid leukemia (n = 123), myelodysplastic syndrome (n = 51), or chronic myelomonocytic leukemia (n = 11) were included. Patients who died, relapsed, or developed grade ≥ 2 acute graft-versus-host disease before day + 60 were excluded, as well as those who were eligible for anti-FMS-like tyrosine kinase 3 maintenance. Of the 185 included patients, 65 received AZA while 120 did not. Median age at transplant was 59 years; 51.9% of patients were males. The median follow-up was 24 months for both groups. Regarding main patient characteristics and transplantation modalities, the two groups were comparable. In multivariate analyses, there were no significant differences between the two groups in terms of 2-year cumulative incidence of relapse (HR = 1.19; 95% confidence interval (CI) 0.67–2.12; p = 0.55), overall survival (HR = 0.62; 95%CI 0.35–1.12; p = 0.12) and event-free survival (HR = 0.97; 95%CI 0.60–1.58; p = 0.91) rates. In conclusion, single-agent AZA does not appear to be an optimal drug for preventing post-transplant relapse in patients with high-risk myeloid malignancies. This study highlights the need for prospective studies of alternative therapies or combination approaches in the post-transplant setting. [ABSTRACT FROM AUTHOR]

Pulmonary edema is a leading cause of hospital admissions, morbidity, and mortality in heart failure (HF) patients. A point-of-care lung ultrasound (LUS) is a useful tool to detect subclinical pulmonary edema. We performed a comprehensive literature search of multiple databases for studies that evaluated the clinical utility of LUS-guided management versus standard care for HF patients in the outpatient setting. The primary outcome of interest was HF hospitalization. The secondary outcomes were all-cause mortality, urgent visits for HF worsening, acute kidney injury (AKI), and hypokalemia rates. Pooled risk ratio (RR) and corresponding 95% confidence intervals (CIs) were calculated and combined using random-effect model meta-analysis. A total of 3 randomized controlled trials including 493 HF patients managed in the outpatient setting (251 managed with LUS plus physical examination (PE)–guided therapy vs. 242 managed with PE-guided therapy alone) were included in the final analysis. The mean follow-up period was 5 months. There was no significant difference in HF hospitalization rate between the two groups (RR 0.65; 95% CI 0.34–1.22; P = 0.18). Similarly, there was no significant difference in all-cause mortality (RR 1.39; 95% CI 0.68–2.82; P = 0.37), AKI (RR 1.27; 95% CI 0.60–2.69; P = 0.52), and hypokalemia (RR 0.72; 95% CI 0.21–2.44; P = 0.59). However, LUS-guided therapy was associated with a lower rate for urgent care visits (RR 0.32; 95% CI 0.18–0.59; P = 0.0002). Our study demonstrated that outpatient LUS-guided diuretic therapy of pulmonary congestion reduces urgent visits for worsening symptoms of HF. Further studies are needed to evaluate LUS utility in the outpatient treatment of HF. [ABSTRACT FROM AUTHOR]

In this study, an attempt was made to understand the hydrogeochemical processes controlling water resources (surface and groundwater) evolution in El Fayoum depression, Egypt. Hydrochemical, inverse geochemical modeling integrated with environmental isotopes was applied. Forty-three surface and groundwater samples were collected and analyzed for major chemistry (cations, anions) and environmental stable isotopes (δ18O, δD). The ionic sequence based on relative molar proportions for cations was Na+ > Ca2+ > Mg2+ > K+ and Na+ > Mg2+ > Ca2+ > K+ for surface and groundwater, respectively and for anions was HCO3− > Cl− > SO42− for all water samples. δ18O and δD relationship plot on a typical evaporation line, enhance potential evaporation of recharging water prior to infiltration. Saturation index estimation revealed that water resources were affected by carbonate and evaporites minerals dissolution and supersaturated with Goethite, Gibbsite and Barite minerals. Inverse geochemical modeling using PHREEQC was used to identify water resources evolution in the study area through two flow paths A, B. The inverse model was constrained so the primary mineral phase including calcite, Aragonite, Anhydrite and Gypsum with Carbon dioxide (gas) are constrained to dissolve until they reach saturation, Whereas H2(g), hydrogen sulphide (gas) and O2(g) are constrained to out gas in all models for flow path (A). For flow path (B), Dolomite, Anhydrite and Gypsum are tend to dissolve with carbon dioxide (gas), H2(g) and O2(g) gases tend to outgassed. Finally, two processes controlling water resource evolution; carbonate and evaporites dissolution and development of cation exchange process through the aquifer system. [ABSTRACT FROM AUTHOR]

Biological age is an important risk factor for chronic diseases. We examined the associations between five markers of unhealthy ageing; Growth Differentiation Factor-15 (GDF-15), N-terminal pro-brain natriuretic peptide (NT-proBNP), glycated hemoglobin A1c (HbA1C), C-Reactive Protein (CRP) and cystatin-C; with risks of cancer and cardiovascular disease (CVD). We used a case-cohort design embedded in the EPIC-Heidelberg cohort, including a subcohort of 3792 participants along with 4867 incident cases of cancer and CVD. Hazard ratios (HRs) were computed and the strongest associations were used to build weighted multi-marker combinations, and their associations with cancer and CVD risks were tested. After adjusting for common confounders, we observed direct associations of GDF-15 with lung cancer risk, NT-proBNP with breast, prostate and colorectal cancers, HbA1C with lung, colorectal, and breast cancer risks, and CRP with lung and colorectal cancer risks. An inverse association was observed for GDF-15 and prostate cancer risk. We also found direct associations of all 5 markers with myocardial infarction (MI) risk, and of GDF-15, NT-proBNP, CRP and cystatin-C with stroke risk. A combination of the independently-associated markers showed a moderately strong association with the risks of cancer and CVD (HRQ4-Q1 ranged from 1.78[1.36, 2.34] for breast cancer, when combining NT-proBNP and HbA1C, to 2.87[2.15, 3.83] for MI when combining NT-proBNP, HbA1C, CRP and cystatin-C). This analysis suggests that combinations of biomarkers related to unhealthy ageing show strong associations with cancer risk, and corroborates published evidence on CVD risk. If confirmed in other studies, using these biomarkers could be useful for the identification of individuals at higher risk of age-related diseases. [ABSTRACT FROM AUTHOR]

Introduction: The Commission on Cancer (CoC) issues Cancer Program Practice Profile Reports (CP3R) that set standards for high-quality care. Three metrics for breast cancer include radiation within 1 year for women < 70 years of age receiving breast-conserving surgery, radiation within 1 year after mastectomy for women with four or more positive lymph nodes (MASTRT), and hormonal therapy within 1 year of a stage IB–III hormone receptor-positive breast cancer (HT). Our study evaluates national trends in quality metric compliance. Methods: The National Cancer Database was queried from 2004 to 2014 to identify patients who met the criteria for the three quality metrics. National trends in compliance were compared. Results: Overall, 1,094,264 patients qualified for BCSRT (n = 534,147), MASTRT (n = 66,291), or HT (n = 493,826). In 2014, 91.1% of patients met BCSRT, 88.4% met MASTRT, and 90.7% met HT. BCSRT, MASTRT, and HT compliance rates were lower in community hospitals compared with Integrated Network Cancer Programs (INCP) (BCSRT: 89.0% vs. 92.8%, p < 0.01; MASTRT: 85.5% vs. 90.6%, p < 0.01; HT: 87.3% vs. 93.7%, p < 0.01). On multivariate analysis, patients receiving care at an INCP facility [odds ratio (OR) 1.47, 95% confidence interval (CI) 1.37–1.58] and insured patients (OR 1.70, 95% CI 1.54–1.87) had higher odds of BCSRT compliance, and minorities (OR 0.76, 95% CI 0.73–0.80) had lower odds. Similar results were seen for MASTRT and HT. Conclusion: In more recent years, overall compliance rates for breast cancer quality metrics of BCSRT and HT by Comprehensive Community Cancer Programs, Academic/Research Programs, and INCPs have increased to meet the 90% CoC standards, while MASTRT has regressed. Community programs were least compliant with meeting the CoC standards. [ABSTRACT FROM AUTHOR]

Introduction: Biomarker changes in patients with residual disease (RD) after neoadjuvant systemic therapy (NAT) have unclear consequences. This study examined the prevalence of biomarker [hormone receptor (HR) and HER2] change and its effect on disease-free survival (DFS) and overall survival (OS). Patients and Methods: A total of 303 patients treated with NAT from 2008 to 2016 were identified from a prospective database. Biomarker status at diagnosis was determined and retested after NAT in patients with RD. DFS and OS were compared among three groups: no biomarker change, clinically insignificant change in either ER or PR without alteration in HR status, and clinically significant change in at least one biomarker with resultant change in HR or HER2 status. Subgroups with no change and HR change were examined [HR+HER2− no change, triple negative (TN) no change, HR+HER2− to TN, TN to HR+HER2]. Results: Overall, 61.4% of patients had RD. Of these, 32.8% had changes in at least one biomarker. At median follow up of 5.48 years, no biomarker change was associated with improved DFS compared with changes in HR or HER2 status (p = 0.043). In addition, no biomarker change (p = 0.005) and clinically insignificant changes in biomarker status (p = 0.019) were associated with improved OS compared with clinically significant changes in HR or HER2 status. Among subgroups, HR+HER2− to TN was associated with worse DFS (p = 0.029) and OS (p = 0.008) compared with HR+HER2− no change. Conclusions: Among those with RD, biomarker status change was common and impacted survival in subgroups of HR+ or TN disease. Retesting biomarkers after NAT has prognostic implications. [ABSTRACT FROM AUTHOR]

A series of (Cu0.5−xTl0.5−y)-1223 superconductor samples, doped with varying amounts of (CuF2)x and (TlF)y compounds with x = y = 0.0, 0.1, 0.2, 0.3 and 0.4, were synthesized via a single-step solid-state reaction. X-ray diffraction (XRD) revealed that all the samples have a tetragonal symmetry of (Cu0.5Tl0.5)-1223 phase. Additionally, with increasing fluorine content up to x = 0.2 CuF2 and y = 0.1 TlF, the phase fraction and the superconducting transition Tc were enhanced. The scanning electron microscopy (SEM) images exhibited mainly plate-like rectangular shape grains confirming the formation of (Cu0.5Tl0.5)-1223 phase. The Fourier transform infrared (FTIR) spectra of CuF2- and TlF-substituted (Cu0.5−xTl0.5−y)-1223 show a slight softening and hardening in few peaks related to the apical oxygen atoms and CuO2 planar modes. The stoichiometry of elemental composition for all prepared samples has been confirmed using ion beam analysis (IBA) methods. The excess conductivity Δσ above Tc was analyzed through the Aslamasov–Larkin (AL) approach. Using the Ginzburg–Landau (GL) number (NG) and equations, the coherence length, the effective layer thickness, the lower critical field Bc1(0), the upper critical field Bc2(0) and the critical current density Jc(0) were estimated. It was found that the addition of an optimum concentration of CuF2 and TlF, controlled the microstructure, the grains coupling and hence enhanced the physical properties of (Cu0.5Tl0.5)-1223 phase. [ABSTRACT FROM AUTHOR]

Cerebellar hypoplasia (CH) refers to a cerebellum of reduced volume with preserved shape. CH is associated with a broad heterogeneity in neuroradiologic features, etiologies, clinical characteristics, and neurodevelopmental outcomes, challenging physicians evaluating children with CH. Traditionally, neuroimaging has been a key tool to categorize CH based on the pattern of cerebellar involvement (e.g., hypoplasia of cerebellar vermis only vs. hypoplasia of both the vermis and cerebellar hemispheres) and the presence of associated brainstem and cerebral anomalies. With the advances in genetic technologies of the recent decade, many novel CH genes have been identified, and consequently, a constant updating of the literature and revision of the classification of cerebellar malformations are needed. Here, we review the current literature on CH. We propose a systematic approach to recognize specific neuroimaging patterns associated with CH, based on whether the CH is isolated or associated with posterior cerebrospinal fluid anomalies, specific brainstem or cerebellar malformations, brainstem hypoplasia with or without cortical migration anomalies, or dysplasia. The CH radiologic pattern and clinical assessment will allow the clinician to guide his investigations and genetic testing, give a more precise diagnosis, screen for associated comorbidities, and improve prognostication of associated neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Red and processed meats are recognized by the International Agency for Research on Cancer as probably carcinogenic and carcinogenic to humans, respectively. Heme iron has been proposed as a central factor responsible for this effect. Furthermore, anxiety affects the intestinal barrier function by increasing intestinal permeability. The objective of this work was to assess how anxiety modifies the association between red and processed meat consumption and cancer risk in the NutriNet-Santé prospective cohort (2009–2019). Methods: Using multi-adjusted Cox models in a sample of 101,269 subjects, we studied the associations between the consumption of red and processed meat, the amount of heme iron coming from these meats and overall, colorectal, prostate, and breast cancer risks, overall and separately among participants with and without anxiety. Results: An increase in red and processed meat consumption was associated with an increased risk of developing colorectal cancer in the total population (HR for an increase of 50 g/day = 1.18 (1.01–1.37), p = 0.03). After stratification on anxiety, the HR 50 g/day was 1.42 (1.03–1.94, p = 0.03) in anxious participants and 1.12 (0.94–1.33, p = 0.20) in other participants. Similar trends were observed for overall cancer risk. Analyses conducted with heme iron also provided similar results. Conclusions: Our results strengthen the existing body of evidence supporting that red and processed meat consumption and heme iron intake are associated with an increased risk of overall and more specifically colorectal cancer, and suggest that anxiety modifies these associations, with an increased risk in anxious participants. [ABSTRACT FROM AUTHOR]

Introduction: Interventions aimed at optimizing parents' ability to manage their children's asthma could be strengthened by better understanding the networks that influence these parents' choices when managing asthma. This study aimed to explore the asthma networks of parents of children with asthma—specifically to gain insights into whom parents select to be within their networks and why; how individuals within parents' networks influence the way in which they manage their children's asthma medications, and factors driving the development of these networks. Methods: A qualitative research methodology utilizing semi-structured interviews with parents of children with asthma was employed to fulfil the objectives of this study. Results: Twenty-six face-to-face interviews with parents of children with asthma were conducted, recorded, and transcribed. Transcriptions were independently coded for concepts and themes by the research team. Asthma medications was a dominant theme identified, and revealed that parents actively sought advice and support from a series of complex and multidimensional relationships with people and resources in their health network. These not only included health care professionals (HCPs) but also personal connections, lay individuals, and resources. The composition and development of these asthma networks occurred over time and were determined by several key factors: satisfaction with their HCP provider; need for information; convenience; trust and support; self-confidence in management; and parents' perceptions of their children's asthma severity. Conclusions: By exploring parents' asthma network, this study uncovers the complex relationship between HCPs, family and friends of parents of children with asthma, and provides new insight into the intimate and parallel influence they have on parent's decision-making. [ABSTRACT FROM AUTHOR]

Background: Radioactive seed localization (RSL) and the Savi Scout® radar (SSR) are newer alternatives to wire-guided localization (WL) for nonpalpable breast lesions. Objective: The aim of this study was to compare three localization devices when multiple devices were used for preoperative localization for breast surgery. Methods: Between July 2017 and July 2018, 68 patients had a partial mastectomy (n = 54) or breast biopsy (n = 14) with preoperative image-guided localization using multiple wires or device placement for nonpalpable lesions. Operative timing, outcomes, and 30-day complications were evaluated. Results: Overall, 41 patients (60%) had WL, 11 patients (16%) had RSL, and 16 patients (24%) had SSR localization. Fifty-four patients (79.4%) had localization of two lesions and 13 patients (19.1%) had localization of three lesions. Twenty-three patients (33.8%) had a lesion that was bracketed. There was no difference in retained biopsy clip among the groups (average 7.4%; p = 0.962). For operations performed in the hospital, there was no difference in operative time among the groups, with a median of 77.5 min (p = 0.705) or total perioperative time of 508 min (p = 0.210). Among operations with delayed start times, there was a longer average delay of 95.5 min in WL, compared with 42 min in SSR (p = 0.004). A greater volume of tissue was excised in the WL group (29.5 g WL vs. 15.9 g RSL vs. 12.1 g SSR; p = 0.022). There was no difference in positive margin rate and 30-day complications among groups. Conclusion: SSR and RSL can be used to localize multiple breast lesions, with no difference in positive margin rates or complications and less tissue excised compared with WL. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer is a multifactorial disease whose aetiology is still not fully understood. Metabolomics, by measuring several hundred metabolites simultaneously, could enhance knowledge on the metabolic changes involved and the potential impact of external factors. Objectives: The aim of the present study was to investigate whether pre-diagnostic plasma metabolomic profiles were associated with the risk of developing a prostate cancer within the following decade. Methods: A prospective nested case-control study was set up among the 5141 men participant of the SU.VI.MAX cohort, including 171 prostate cancer cases, diagnosed between 1994 and 2007, and 171 matched controls. Nuclear magnetic resonance (NMR) metabolomic profiles were established from baseline plasma samples using NOESY1D and CPMG sequences. Multivariable conditional logistic regression models were computed for each individual NMR signal and for metabolomic patterns derived using principal component analysis. Results: Men with higher fasting plasma levels of valine (odds ratio (OR) = 1.37 [1.07–1.76], p =.01), glutamine (OR = 1.30 [1.00–1.70], p =.047), creatine (OR = 1.37 [1.04–1.80], p =.02), albumin lysyl (OR = 1.48 [1.12–1.95], p =.006 and OR = 1.51 [1.13–2.02], p =.005), tyrosine (OR = 1.40 [1.06–1.85], p =.02), phenylalanine (OR = 1.39 [1.08–1.79], p =.01), histidine (OR = 1.46 [1.12–1.88], p =.004), 3-methylhistidine (OR = 1.37 [1.05–1.80], p =.02) and lower plasma level of urea (OR =.70 [.54–.92], p =.009) had a higher risk of developing a prostate cancer during the 13 years of follow-up. Conclusions: This exploratory study highlighted associations between baseline plasma metabolomic profiles and long-term risk of developing prostate cancer. If replicated in independent cohort studies, such signatures may improve the identification of men at risk for prostate cancer well before diagnosis and the understanding of this disease. [ABSTRACT FROM AUTHOR]