Single-center outcome analysis of 46 fetuses with megacystis after intrauterine vesico-amniotic shunting with the Somatex®intrauterine shunt.

OBJECTIVES: To assess the spectrum of underlying pathologies, the intrauterine course and postnatal outcome of 46 fetuses with megacystis that underwent intrauterine vesico-amniotic shunting (VAS) with the Somatex® shunt in a single center. METHODS: Retrospective analysis of 46 fetuses with megacystis that underwent VAS either up to 14 + 0 weeks (early VAS), between 14 + 1 and 17 + 0 weeks (intermediate VAS) or after 17 + 0 weeks of gestation (late VAS) in a single tertiary referral center. Intrauterine course, underlying pathology and postnatal outcome were assessed and correlated with the underlying pathology and gestational age at first VAS. RESULTS: 46 fetuses underwent VAS, 41 (89%) were male and 5 (11%) were female. 28 (61%) fetuses had isolated and 18 (39%) had complex megacystis with either aneuploidy (n = 1), anorectal malformations (n = 6), cloacal malformations (n = 3), congenital anomalies overlapping with VACTER association (n = 6) or Megacystis-Microcolon Intestinal-Hypoperistalsis Syndrome (MMIHS) (n = 2). The sonographic 'keyhole sign' significantly predicted isolated megacystis (p < 0.001). 7 pregnancies were terminated, 4 babies died in the neonatal period, 1 baby died at the age of 2.5 months and 34 (74%) infants survived until last follow-up. After exclusion of the terminated pregnancies, intention-to-treat survival rate was 87%. Mean follow-up period was 24 months (range 1-72). The underlying pathology was highly variable and included posterior urethral valve (46%), hypoplastic or atretic urethra (35%), MMIHS or prune belly syndrome (10%) and primary vesico-ureteral reflux (2%). In 7% no pathology could be detected postnatally. No sonographic marker was identified to predict the underlying pathology prenatally. 14 fetuses underwent early, 24 intermediate and 8 late VAS. In the early VAS subgroup, amnion infusion prior to VAS was significantly less often necessary (7%), shunt complications were significantly less common (29%) and immediate kidney replacement therapy postnatally became less often necessary (0%). In contrast, preterm delivery ≤ 32 + 0 weeks was more common (30%) and survival rate was lower (70%) after early VAS compared to intermediate or late VAS. Overall, 90% of liveborn babies had sufficient kidney function without need for kidney replacement therapy until last follow-up, and 95% had sufficient pulmonary function without need for mechanical respiratory support. 18% of babies with complex megacystis suffered from additional health restrictions due to their major concomitant malformations. CONCLUSIONS: Our data suggest that VAS is feasible from the first trimester onward. Early intervention has the potential to preserve neonatal kidney function in the majority of cases and enables neonatal survival in up to 87% of cases. Despite successful fetal intervention, parents should be aware of the potential of mid- or long-term kidney failure and of additional health impairments due to concomitant extra-renal anomalies that cannot be excluded at time of intervention.

D-Transposition of the great arteries with restrictive foramen ovale in the fetus: the dilemma of predicting the need for postnatal urgent balloon atrial septostomy.

OBJECTIVE: Restrictive foramen ovale (FO) in dextro-transposition of the great arteries (d-TGA) with intact ventricular septum may lead to severe life-threatening hypoxia within the first hours of life, making urgent balloon atrial septostomy (BAS) inevitable. Reliable prenatal prediction of restrictive FO is crucial in these cases. However, current prenatal echocardiographic markers show low predictive value, and prenatal prediction often fails with fatal consequences for a subset of newborns. In this study, we described our experience and aimed to identify reliable predictive markers for BAS. METHODS: We included 45 fetuses with isolated d-TGA that were diagnosed and delivered between 2010 and 2022 in two large German tertiary referral centers. Inclusion criteria were the availability of former prenatal ultrasound reports, of stored echocardiographic videos and still images, which had to be obtained within the last 14 days prior to delivery and that were of sufficient quality for retrospective re-analysis. Cardiac parameters were retrospectively assessed and their predictive value was evaluated. RESULTS: Among the 45 included fetuses with d-TGA, 22 neonates had restrictive FO postnatally and required urgent BAS within the first 24 h of life. In contrast, 23 neonates had normal FO anatomy, but 4 of them unexpectedly showed inadequate interatrial mixing despite their normal FO anatomy, rapidly developed hypoxia and also required urgent BAS ('bad mixer'). Overall, 26 (58%) neonates required urgent BAS, whereas 19 (42%) achieved good O2 saturation and did not undergo urgent BAS. In the former prenatal ultrasound reports, restrictive FO with subsequent urgent BAS was correctly predicted in 11 of 22 cases (50% sensitivity), whereas a normal FO anatomy was correctly predicted in 19 of 23 cases (83% specificity). After current re-analysis of the stored videos and images, we identified three highly significant markers for restrictive FO: a FO diameter < 7 mm (p < 0.01), a fixed (p = 0.035) and a hypermobile (p = 0.014) FO flap. The maximum systolic flow velocities in the pulmonary veins were also significantly increased in restrictive FO (p = 0.021), but no cut-off value to reliably predict restrictive FO could be identified. If the above markers are applied, all 22 cases with restrictive FO and all 23 cases with normal FO anatomy could correctly be predicted (100% positive predictive value). Correct prediction of urgent BAS also succeeded in all 22 cases with restrictive FO (100% PPV), but naturally failed in 4 of the 23 cases with correctly predicted normal FO ('bad mixer') (82.6% negative predictive value). CONCLUSION: Precise assessment of FO size and FO flap motility allows a reliable prenatal prediction of both restrictive and normal FO anatomy postnatally. Prediction of likelihood of urgent BAS also succeeds reliably in all fetuses with restrictive FO, but identification of the small subset of fetuses that also requires urgent BAS despite their normal FO anatomy fails, because the ability of sufficient postnatal interatrial mixing cannot be predicted prenatally. Therefore, all fetuses with prenatally diagnosed d-TGA should always be delivered in a tertiary center with cardiac catheter stand-by, allowing BAS within the first 24 h after birth, regardless of their predicted FO anatomy.

Changes in atmospheric circulation and evapotranspiration are reducing rainfall in the Brazilian Cerrado.

Here we analyze the trends of rainfall and the frequency of rainy days over the Brazilian Cerrado between 1960 and 2021 in four distinct periods according to the seasonal patterns over the region. We also evaluated trends in evapotranspiration, atmospheric pressure, winds, and atmospheric humidity over the Cerrado to elucidate the possible reasons for the detected trends. We recorded a significant reduction in rainfall and frequency of rainy days in the northern and central Cerrado regions for all periods except at the beginning of the dry season. The most pronounced negative trends were recorded during the dry season and the beginning of the wet season, where we recorded reductions of up to 50% in total rainfall and the number of rainy days. These findings are associated with the intensification of the South Atlantic Subtropical Anticyclone, which has been shifting atmospheric circulation and raising regional subsidence. Moreover, during the dry season and the beginning of the wet season, there was a reduction in regional evapotranspiration, which also potentially contributed to the rainfall reduction. Our results suggest an expansion and intensification of the dry season in the region, potentially bringing broad environmental and social impacts that transcend the Cerrado boundaries.

A multiple linear regression approach to the estimation of carboxylic acid ester and lactone alkaline hydrolysis rate constants.

Pesticides, pharmaceuticals, and other organic contaminants often undergo hydrolysis when released into the environment; therefore, measured or estimated hydrolysis rates are needed to assess their environmental persistence. An intuitive multiple linear regression (MLR) approach was used to develop robust QSARs for predicting base-catalyzed rate constants of carboxylic acid esters (CAEs) and lactones. We explored various combinations of independent descriptors, resulting in four primary models (two for lactones and two for CAEs), with a total of 15 and 11 parameters included in the CAE and lactone QSAR models, respectively. The most significant descriptors include pKa, electronegativity, charge density, and steric parameters. Model performance is assessed using Drug Theoretics and Cheminformatics Laboratory's DTC-QSAR tool, demonstrating high accuracy for both internal validation (r2 = 0.93 and RMSE = 0.41-0.43 for CAEs; r2 = 0.90-0.93 and RMSE = 0.38-0.46 for lactones) and external validation (r2 = 0.93 and RMSE = 0.43-0.45 for CAEs; r2 = 0.94-0.98 and RMSE = 0.33-0.41 for lactones). The developed models require only low-cost computational resources and have substantially improved performance compared to existing hydrolysis rate prediction models (HYDROWIN and SPARC).

Phaeohyphomycosis due to Exophiala in Aquarium-Housed Lumpfish (Cyclopterus lumpus): Clinical Diagnosis and Description.

Phaeohyphomycosis caused by Exophiala species represents an important disease of concern for farmed and aquarium-housed fish. The objective of this study was to summarize the clinical findings and diagnosis of Exophiala infections in aquarium-housed Cyclopterus lumpus. Clinical records and postmortem pathology reports were reviewed for 15 individuals from 5 public aquaria in the United States and Canada from 2007 to 2015. Fish most commonly presented with cutaneous ulcers and progressive clinical decline despite topical or systemic antifungal therapy. Antemortem fungal culture of cutaneous lesions resulted in colonial growth for 7/12 samples from 8 individuals. Amplification of the internal transcribed spacer region (ITS) of nuclear rDNA identified Exophiala angulospora or Exophiala aquamarina in four samples from three individuals. Postmortem histopathologic findings were consistent with phaeohyphomycosis, with lesions most commonly found in the integument (11/15), gill (9/15), or kidney (9/15) and evidence of fungal angioinvasion and dissemination. DNA extraction and subsequent ITS sequencing from formalin-fixed paraffin-embedded tissues of seven individuals identified E. angulospora, E. aquamarina, or Cyphellophora sp. in four individuals. Lesion description, distribution, and Exophiala spp. identifications were similar to those reported in farmed C. lumpus. Antemortem clinical and diagnostic findings of phaeohyphomycosis attributable to several species of Exophiala provide insight on the progression of Exophiala infections in lumpfish that may contribute to management of the species in public aquaria and under culture conditions.

Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

An epidemiologic retrospective study of maxillofacial traumatology in the elderly.

INTRODUCTION: The elderly population, which is more active than before, is increasingly suffering from trauma (loss of reflexes and systemic pathologic conditions). Surgical management may be more controversial due to the potential consequences of general anesthesia and the sometimes negligible consequences of functional management. The main objective of this study was to analyze the causes and location of facial fractures in subjects older than 65 years. The secondary objective was to evaluate the management of these fractures (surgical or functional) according to comorbidities. MATERIAL & METHODS: In this retrospective study (over a five-year period), we analyzed the causes and management of facial fractures in patients aged over 65 years, and the medical history of each patient was investigated. RESULTS: One hundred and nineteen patients with 198 facial fractures were included. The main cause of fractures was a fall (50%). The zygomatic region (39.9%) and mandible (27.8%) were the sites of the most frequent fractures. Comorbidities were found in 84.9% of patients, the majority of which were cardiovascular diseases (82.3%). 75.8% of fractures were treated surgically and 4.8% of patients had complications. DISCUSSION: This work is a help to understanding the causes and consequences of facial trauma in the elderly population. The management of these facial fractures requires a multidisciplinary assessment, taking into account the patient's medical history and evaluating the risks and benefits of a surgical procedure with general anesthesia.

Suppression of black-hole growth by strong outflows at redshifts 5.8-6.6.

Bright quasars, powered by accretion onto billion-solar-mass black holes, already existed at the epoch of reionization, when the Universe was 0.5-1 billion years old1. How these black holes formed in such a short time is the subject of debate, particularly as they lie above the correlation between black-hole mass and galaxy dynamical mass2,3 in the local Universe. What slowed down black-hole growth, leading towards the symbiotic growth observed in the local Universe, and when this process started, has hitherto not been known, although black-hole feedback is a likely driver4. Here we report optical and near-infrared observations of a sample of quasars at redshifts 5.8 ≲ z ≲ 6.6. About half of the quasar spectra reveal broad, blueshifted absorption line troughs, tracing black-hole-driven winds with extreme outflow velocities, up to 17% of the speed of light. The fraction of quasars with such outflow winds at z ≳ 5.8 is ≈2.4 times higher than at z ≈ 2-4. We infer that outflows at z ≳ 5.8 inject large amounts of energy into the interstellar medium and suppress nuclear gas accretion, slowing down black-hole growth. The outflow phase may then mark the beginning of substantial black-hole feedback. The red optical colours of outflow quasars at z ≳ 5.8 indeed suggest that these systems are dusty and may be caught during an initial quenching phase of obscured accretion5.

Surviving a global pandemic: The experience of depression, anxiety, and loneliness among individuals with multiple sclerosis.

BACKGROUND: The world has been experiencing one of the most significant worldwide health pandemics in modern history. The result has been increased depression, anxiety, and loneliness in the general population. However, populations who demonstrated pre-pandemic emotional disturbance and social isolation, such as individuals with multiple sclerosis (MS), are likely uniquely vulnerable to such symptoms. OBJECTIVE: The purpose of the present investigation was to examine the emotional outcomes, including reports of loneliness, in individuals with MS during the COVID-19 pandemic. We additionally sought to examine how individuals' experiences during the pandemic may contribute to a specific COVID-19-related depression or anxiety. METHODS: 142 individuals with MS who previously participated in a national, online, survey-based study were asked to complete an online survey assessing their current level of depression, anxiety, loneliness, and perceived impact of the COVID-19 pandemic. RESULTS: Increases in the rates of depression and anxiety were noted, with approximately 54% and 33% reporting "new" depression or anxiety, respectively. Given this increase, we examined how individuals with "new" depression or anxiety differed from those without depression and anxiety and those with pre-pandemic depression and/or anxiety. Significant differences in person-specific factors (e.g., personality, self-efficacy) were noted between the groups. Increased loneliness was also found among both those with depression or anxiety regardless of whether "new" or pre-pandemic. Finally, all those depressed or anxious reported greater disruption and distress related to the COVID-19 pandemic with a trend for increased anxiety specifically related to the pandemic (e.g., fear or dying due to COVID-19) among those with new depression or anxiety when compared to those with existing depression or anxiety, suggesting an influence of the pandemic that is specific to reports of new depression or anxiety. CONCLUSION: Findings suggest increased depression, anxiety, and loneliness among individuals with MS following the COVID-19 pandemic, with reports of "new" depression or anxiety, which appears to be related to the pandemic, specifically. Moreover, factors commonly associated with depression or anxiety in MS (e.g., personality, self-efficacy) were more common among those with existing depression or anxiety but not among those experiencing new depression or anxiety. These differences should be considered when attempting to ameliorate the impact of the COVID-19 among those experiencing emotional distress.