Dysfunction of proprioceptive sensory synapses is a pathogenic event and therapeutic target in mice and humans with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that SMA patients exhibit impaired proprioception, and their proprioceptive sensory synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex (H-reflex). We further show that loss of excitatory afferent synapses and altered potassium channel expression in SMA motor neurons are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory SMA patients and mouse models treated with SMN-inducing drugs correlate with increased function of sensory-motor circuits that can be accurately captured by the H-reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the H-reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.

BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.

Utility of cranial MRI in non-traumatic headache patients with prior negative head CT within 1 month.

AIM: To investigate the importance of additional cranial magnetic resonance imaging (cMRI) in non-traumatic headache patients with a prior negative head computed tomography (CT) examination within 1 month. MATERIALS AND METHODS: This retrospective study analysed 162 adult patients with non-traumatic headache who underwent cMRI within 1 month of a negative initial head CT at the emergency department (ED). The diagnostic yield and false-referral rate were analysed according to the revisit duration (early [≤1 week] versus late [>1-4 weeks] revisits), patient care settings (ED versus outpatient clinics [OPC]), and clinical variables. Subsequent patient management change (PMC), such as admission and treatment (AT) or outpatient clinic treatment (OT), were also investigated. RESULTS: The overall diagnostic yield of cMRI was 17.3% (28/162) and the false-referral rate was 1.2% (2/162). The diagnostic yield of cMRI was significantly different according to the patient care settings (ED, 24.7% [21/85] versus OPC, 9.1% [7/77]; p=0.02). The diagnostic yield was highest in the ED-early-revisit group (25.4% [18/71]), 45% (9/20) in those with systemic signs, and 46.7% (14/30) in those with symptom change. Among patients with positive cMRI findings, 90% (27/30) received AT and 3.3% (1/30) received OT. Among OPC-revisit-negative cMRI patients, PMC occurred in 0% (0/50). CONCLUSION: The diagnostic yield of cMRI was relatively high for headache patients who revisited the ED earlier, especially in those with systemic signs or symptom change. Most positive cMRI cases experienced PMC. Negative cMRI in OPC-revisit patients might help clarify the benign nature of a condition.

Review on fate, transport, toxicity and health risk of nanoparticles in natural ecosystems: Emerging challenges in the modern age and solutions toward a sustainable environment.

In today's era, nanoparticles (NPs) have become an integral part of human life, finding extensive applications in various fields of science, pharmacy, medicine, industry, electronics, and communication. The increasing popularity of NP usage worldwide is a testament to their tremendous potential. However, the widespread deployment of NPs unavoidably leads to their release into the environmental matrices, resulting in persistence in ecosystems and bioaccumulation in organisms. Understanding the environmental behavior of NPs poses a significant challenge due to their nanoscale size. Given the current environmental releases of NPs, known negative consequences, and the limited knowledge available for risk management, comprehending the toxicity of NPs in ecosystems is both awaiting and crucial. The present review aims to unravel the potential environmental influences of nano-scaled materials, and provides in-depth inferences of the current knowledge and understanding in this field. The review comprehensively summarizes the sources, fate, transport, toxicity, health risks, and remediation solutions associated with NP pollution in aquatic and soil ecosystems. Furthermore, it addresses the knowledge gaps and outlines further investigation priorities for the sustainable control of NP pollution in these environments. By gaining a holistic understanding of these aspects, we can work toward ensuring the responsible and sustainable use of NPs in today's fast-growing world.

[Genetic counselling and testing in pulmonary arterial hypertension - A consensus statement on behalf of the International Consortium for Genetic Studies in PAH - French version]. / Conseil génétique et dépistage de l'hypertension artérielle pulmonaire ­ consensus du Consortium international pour les études génétiques dans l'HTAP ­ version française.

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.

Occurrence, fate, and potential risk of pharmaceutical pollutants in agriculture: Challenges and environmentally friendly solutions.

In recent years, pharmaceutical active compounds (PhACs) have attained global prevalence. The behavior of PhACs in agricultural soils is complex and depends on several factors, such as the nature of the compounds and their physicochemical characteristics, which affect their fate and potential threats to human health, ecosystems, and the environment. The detection of residual pharmaceutical content is possible in both agricultural soils and environmental matrices. PhACs are commonly found in agricultural soil, with concentrations varying significantly, ranging from as low as 0.048 ng g-1 to as high as 1420.76 mg kg-1. The distribution and persistence of PhACs in agriculture can lead to the leaching of these toxic pollutants into surface water, groundwater, and vegetables/plants, resulting in human health risks and environmental pollution. Biological degradation or bioremediation plays a critical role in environmental protection and efficiently eliminates contamination by hydrolytic and/or photochemical reactions. Membrane bioreactors (MBRs) have been investigated as the most recent approach for the treatment of emerging persistent micropollutants, including PhACs, from wastewater sources. MBR- based technologies have proven to be effective in eliminating pharmaceutical compounds, achieving removal rates of up to 100%. This remarkable outcome is primarily facilitated by the processes of biodegradation and metabolization. In addition, phytoremediation (i.e., constructed wetlands), microalgae-based technologies, and composting can be highly efficient in remediating PhACs in the environment. The exploration of key mechanisms involved in pharmaceutical degradation has revealed a range of approaches, such as phytoextraction, phytostabilization, phytoaccumulation, enhanced rhizosphere biodegradation, and phytovolatilization. The well-known advanced/tertiary removal of sustainable sorption by biochar, activated carbon, chitosan, etc. has high potential and yields excellent quality effluents. Adsorbents developed from agricultural by-products have been recognized to eliminate pharmaceutical compounds and are cost-effective and eco-friendly. However, to reduce the potentially harmful impacts of PhACs, it is necessary to focus on advanced technologies combined with tertiary processes that have low cost, high efficiency, and are energy-saving to remove these emerging pollutants for sustainable development.

Orbital angular momentum densities in the astigmatic transformation of Lissajous geometric laser modes.

Orbital angular momentum densities in the astigmatic transformation of Lissajous geometric laser modes are originally and systematically investigated. The quantum theory of the coherent state is exploited to derive an analytical wave representation for the transformed output beams. The derived wave function is further employed to numerically analyze the propagation dependent orbital angular momentum densities. The parts of the negative and positive regions in the orbital angular momentum density are found to rapidly change in the Rayleigh range behind the transformation.

Facile preparation of porphyrin@g-C3N4/Ag nanocomposite for improved photocatalytic degradation of organic dyes in aqueous solution.

In the quest of improving the photocatalytic efficiency of photocatalysts, the combination of two and more semiconductors recently has garnered significant attention among scientists in the field. The doping of conductive metals is also an effective pathway to improve photocatalytic performance by avoiding electron/hole pair recombination and enhancing photon energy absorption. This work presented a design and fabrication of porphyrin@g-C3N4/Ag nanocomposite using acid-base neutralization-induced self-assembly approach from monomeric porphyrin and g-C3N4/Ag material. g-C3N4/Ag material was synthesized by a green reductant of Cleistocalyx operculatus leaf extract. Electron scanning microscopy (SEM), X-ray diffraction (XRD), FT-IR spectroscopy, and UV-vis spectrometer were utilized to analyse the properties of the prepared materials. The prepared porphyrin@g-C3N4/Ag nanocomposite showed well integration of porphyrin nanostructures on the g-C3N4/Ag's surface, in which porphyrin nanofiber was of the diameter in nanoscales and the length of several micrometers, and Ag NPs had an average particle size of less than 20 nm. The photocatalytic behavior of the resultant nanocomposite was tested for the degradation of Rhodamine B dye, which exhibited a remarkable RhB photodegrading percentage. The possible mechanism for photocatalysis of the porphyrin@g-C3N4/Ag nanocomposite toward Rhodamine B dye was also proposed and discussed.

Search for Dark Matter Axions with CAST-CAPP.

The CAST-CAPP axion haloscope, operating at CERN inside the CAST dipole magnet, has searched for axions in the 19.74 µeV to 22.47 µeV mass range. The detection concept follows the Sikivie haloscope principle, where Dark Matter axions convert into photons within a resonator immersed in a magnetic field. The CAST-CAPP resonator is an array of four individual rectangular cavities inserted in a strong dipole magnet, phase-matched to maximize the detection sensitivity. Here we report on the data acquired for 4124 h from 2019 to 2021. Each cavity is equipped with a fast frequency tuning mechanism of 10 MHz/ min between 4.774 GHz and 5.434 GHz. In the present work, we exclude axion-photon couplings for virialized galactic axions down to gaγγ = 8 × 10-14 GeV-1 at the 90% confidence level. The here implemented phase-matching technique also allows for future large-scale upgrades.

Kinetic study on methylene blue removal from aqueous solution using UV/chlorine process and its combination with other advanced oxidation processes.

This study investigated the kinetic degradation of methylene blue (MB) by a UV/chlorine process and its combination with other advanced oxidation processes. The ∙OH and reactive chlorine species (RCS: Cl∙, ClO∙, etc.) were the primary reactive species, which accounted for 56.7% and 37.6% of MB degradation at pH 7, respectively. The second-order rate constant of Cl∙ towards MB was calculated to be 2.8 × 109 M-1 s-1. When the pH increased from 3 to 7, kMB by ∙OH increased from 0.15 to 0.21 min-1 before being reduced to 0.11 min-1 at pH 11. kMB by RCS continuously reduced from 0.16 to 0.13 min-1 when the pH was increased to 11. Humic acid (HA), Br-, and Cl- inhibited the degradation with kMB in the order: kMB (in HA) < kMB (in Br-) < kMB (in Cl-). HCO3- increased kMB from 0.37 to 0.48 min-1. The experimental and modeling methods fit well, indicating the effectiveness of using Kintecus® in predicting concentrations of free radicals in complex water matrices. TOC removal was achieved at 60% after 30 min in a control process and it was strongly inhibited by the presence of HA, with 22% removal achieved at 5 mgc L-1 HA. UV/chlorine/electrochemical oxidation (UV/chlorine/EO) significantly improves kMB from 0.37 to 0.94 min-1 at a high current (240 mA), while UV/chlorine/H2O2 decreased kMB at a low concentration of 0.01 mM H2O2 (kMB decreased by 6.1%). The results indicate that the energy cost for UV irradiation was the main cost in MB treatment in both UV/chlorine and UV/persulfate (UV/PS) processes, accounting for 91% and 84%, respectively.

Ni-Doped SnO2 as an Electron Transport Layer by a Low-Temperature Process in Planar Perovskite Solar Cells.

Perovskite solar cells (PSCs) based on a planar structure have recently become more attractive due to their simple manufacturing process and relatively low cost, while most perovskite solar cells employ highly porous TiO2 as an electron transport layer in mesoporous devices offering higher energy conversion efficiency (PCE). In planar structural devices, non-radiative recombination effects of the absorber layer and the electron transport layer cause potential loss and lower PCE. We created an efficient electron transport layer by combining low-temperature Ni-doped SnO2 with SDBS as a surfactant (denoted as Ni:SnO2). Doping Ni+ into low-temperature solution-processed SnO2 increased the power conversion efficiency of PSCs from 17.8 to 19.7%.

Can electrocoagulation technology be integrated with wastewater treatment systems to improve treatment efficiency?

Considerable amounts of domestic and industrial wastewater that should be treated before reuse are discharged into the environment annually. Electrocoagulation is an electrochemical technology in which electrical current is conducted through electrodes, it is mainly used to remove several types of wastewater pollutants, such as dyes, toxic materials, oil content, chemical oxygen demand, and salinity, individually or in combination with other processes. Electrocoagulation technology used in hybrid systems along with other technologies for wastewater treatment are reviewed in this work, and the articles reviewed herein were published from 2018 to 2021. Electrocoagulation is widely employed in integrated systems with other electrochemical technologies or conventional methods for effective removal of different pollutants with less cost and sometimes over shorter durations of operation. It has also been observed that the hybrid effects besides increasing the removal efficiency can overcome the disadvantages of using electrocoagulation alone, such as less sludge formation, high cost of operation and increased life of the used electrodes, and stable flux of water with longer periods of operation. More than 20 types of other technologies have been combined efficiently with electrocoagulation.

Green synthesis of a photocatalyst Ag/TiO2 nanocomposite using Cleistocalyx operculatus leaf extract for degradation of organic dyes.

Green synthesis has emerged as a sustainable approach for the fabrication of nanomaterials in the last few decades. Leaf extracts have been considered low-cost and highly efficient reactants for the synthesis of nanoparticles. In this study, an aqueous extract of Cleistocalyx operculatus leaves was employed as a reductant to synthesize Ag/TiO2 nanocomposites. The morphology, structure, and interface interaction of the Ag/TiO2 nanocomposites were investigated by (i) X-ray diffraction (XRD) to determine the crystallinity, (ii) scanning electron microscopy (SEM) to determine the morphologies, (iii) energy dispersive X-ray spectroscopy (EDX) to determine the elemental composition and distribution, and (iv) diffuse reflectance spectroscopy (DRS) to understand the optical properties. The results showed that Ag nanoparticles (AgNPs) with particle sizes of 20-40 nm homogeneously covered the surface of the TiO2 nanoparticles. The green-synthesized Ag/TiO2 nanocomposite also exhibited an excellent photodegradation ability for Rhodamine B with a removal percentage up to 91.4% after 180 min of photocatalytic reaction.

Being small for gestational age is not an independent risk factor for mortality in neonates with congenital diaphragmatic hernia: a multicenter study.

BACKGROUND: Congenital diaphragmatic hernia (CDH) accounts for 8% of all major congenital anomalies. Neonates who are small for gestational age (SGA) generally have a poorer prognosis. We sought to identify risk factors and variables associated with outcomes in neonates with CDH who are SGA in comparison to neonates who are appropriate for gestational age (AGA). METHODS: We used the multicenter Diaphragmatic Hernia Research & Exploration Advancing Molecular Science (DHREAMS) study to include neonates enrolled from 2005 to 2019. Chi-squared or Fisher's exact tests were used to compare categorical variables and t tests or Wilcoxon rank sum for continuous variables. Cox model analyzed time to event outcomes and logistic regression analyzed binary outcomes. RESULTS: 589 neonates were examined. Ninety were SGA (15.3%). SGA patients were more likely to be female (p = 0.003), have a left sided CDH (p = 0.05), have additional congenital anomalies and be diagnosed with a genetic syndrome (p < 0.001). On initial single-variable analysis, SGA correlated with higher frequency of death prior to discharge (p < 0.001) and supplemental oxygen requirement at 28 days (p = 0.005). Twice as many SGA patients died before repair (12.2% vs 6.4%, p = 0.04). Using unadjusted Cox model, the risk of death prior to discharge among SGA patients was 1.57 times the risk for AGA patients (p = 0.029). There was no correlation between SGA and need for ECMO, pulmonary hypertensive medication at discharge or oxygen at discharge. After adjusting for confounding variables, SGA no longer correlated with mortality prior to discharge or incidence of unrepaired defects but remained significant for oxygen requirement at 28 days (p = 0.03). CONCLUSION: Infants with CDH who are SGA have worse survival and poorer lung function than AGA infants. However, the outcome of SGA neonates is impacted by other factors including gestational age, genetic syndromes, and particularly congenital anomalies that contribute heavily to their poorer prognosis.

Novel pure α-, ß-, and mixed-phase α/ß-Bi2O3 photocatalysts for enhanced organic dye degradation under both visible light and solar irradiation.

Combining the pure α- and ß-phases of bismuth oxide enhances its photocatalytic activity under both visible and solar irradiation. α-Bi2O3, ß-Bi2O3, and α/ß-Bi2O3 were synthesized by a solvothermal calcination method. The structural, optical, and morphological properties of the as-synthesized catalysts were analyzed using XRD, UV-DRS, XPS, SEM, TEM, and PL. The bandgaps of α/ß-Bi2O3, α-Bi2O3, and ß-Bi2O3 were calculated to be 2.59, 2.73, and 2.34 eV, respectively. The photocatalytic activities of the catalysts under visible and solar irradiation were examined by the degradation of carcinogenic reactive blue 198 and reactive black 5 dyes. The kinetic plots of the degradation reactions followed pseudo-first-order kinetics. α/ß-Bi2O3 exhibited higher photocatalytic activity (∼99%) than α-Bi2O3 and ß-Bi2O3 under visible and solar irradiation. The TOC and COD results confirmed the maximum degradation ability of α/ß-Bi2O3, and the decolorization percentage remained above 90%, even after five cycles under visible irradiation. The photocatalytic dye degradation mechanism employed by α/ß-Bi2O3 was proposed based on active species trapping experiments.

Generation patterns and consumer behavior of single-use plastic towards plastic-free university campuses.

This study was conducted to estimate the generation of single-use plastics (SUPs) and elucidate consumer behavior towards a plastic-free university. The results show that the consumption rate of plastic bottles was the highest at 1.39 g per student per day (g.s-1.d-1), followed by plastic cups (0.20 g s-1.d-1), and plastic bags (0.14 g s-1.d-1). Approximately 94.41% of students were highly aware of the negative impacts of SUPs. More than four-fifths of the students (82.32%) assumed that they were responsible for the SUP pollution issue, whereas 59.52% considered SUP reduction (or lack thereof) by individuals, governments, and producers/businesses be important factors. Approximately 19.03% of the students supported implementing a high fine, one-tenth agreed for a total ban on SUPs, while nearly one-fifth believed reducing SUP consumption was unnecessary. Strategies for plastic-free universities was initiated by establishing the goal of "plastic-free university" and implementing integrated actions including a ban (plastic cups and bags) awareness-raising, and suitable alternatives.

The efficiency of potential food waste-degrading bacteria under harsh conditions.

AIMS: Investigate the impact of highly adapted bacterial strains and their ability in waste degradation under a wide range of temperatures. METHODS AND RESULTS: Bacteria isolated from soil and food waste were grown in various media under fluctuated temperatures. After screening for organic compound degradation, the seven strongest bacterial strains have been selected for further experiments. Their enzyme activities were expressed in terms of the size of the hydrolysis zone in a wide temperature range of 2·5-70°C. The enzyme production assay was carried out for each protease, cellulase and amylase. The waste degradation was determined with a maximum 80% decrease in the volume of food waste in 21 days compared to the control in lab scale with enriched bacterial cultures and soil bacteria as additives at room temperature around 18-20°C. CONCLUSION: These seven bacteria are promising candidates for food waste biodegradation in composting especially in the winter without heating expense for maintaining ambient temperature. SIGNIFICANCE AND IMPACT OF THE STUDY: It is necessary to coax the uncultured bacteria from the various environments into the laboratory for investigating their valuable functions. Herein, using enrichment culture of consortium and additive of soil has illustrated the significant mean in food waste degradation.

Host Genetic Associations with Salivary Microbiome in Oral Cancer.

Despite the growing recognition of a host genetic effect on shaping gut microbiota composition, the genetic determinants of oral microbiota remain largely unexplored, especially in the context of oral diseases. Here, we performed a microbiome genome-wide association study in 2 independent cohorts of patients with oral squamous cell carcinoma (OSCC, n = 144 and 67) and an additional group of noncancer individuals (n = 104). Besides oral bacterial dysbiosis and signatures observed in OSCC, associations of 3 loci with the abundance of genus-level taxa and 4 loci with ß diversity measures were detected (q < 0.05) at the discovery stage. The most significant hit (rs10906082 with the genus Lachnoanaerobaculum, P = 3.55 × 10-9 at discovery stage) was replicated in a second OSCC cohort. Moreover, the other 2 taxonomical associations, rs10973953 with the genus Kingella (P = 1.38 × 10-9) and rs4721629 with the genus Parvimonas (P = 3.53 × 10-8), were suggestive in the meta-analysis combining 2 OSCC cohorts. Further pathway analysis revealed that these loci were enriched for genes in regulation of oncogenic and angiogenic responses, implicating a genetic anchor to the oral microbiome in estimation of casual relationships with OSCC. Our findings delineate the role of host genotypes in influencing the structure of oral microbial communities.