Exploring high-throughput synchrotron X-Ray powder diffraction for the structural analysis of pharmaceuticals.

Synchrotron radiation offers a host of advanced properties, surpassing conventional laboratory sources with its high brightness, tunable phonon energy, photon beam coherence for advanced X-ray imaging, and a structured time profile, ideal for capturing dynamic atomic and molecular processes. However, these benefits come at the cost of operational complexity and expenses. Three decades ago, synchrotron radiation facilities, while technically open to all scientists, primarily served a limited community. Despite substantial accessibility improvements over the past two decades, synchrotron measurements still do not qualify as routine analyses. The intrinsic complexity of synchrotron science means experiments are pursued only when no alternatives suffice. In recent years, strides have been made in technology transfer offices, intermediate synchrotron-based analytical service companies, and the development of high-throughput synchrotron systems at various facilities, reshaping the perception of synchrotron science. This article investigates the practical application of synchrotron X-Ray Powder Diffraction (s-XRPD) techniques in pharmaceutical analysis. By utilizing concrete examples, we demonstrate how high-throughput systems have the potential to revolutionize s-XRPD applications in the pharmaceutical industry, rapidly generating XRPD patterns of comparable or superior quality to those obtained in state-of-the-art laboratory XRPD, all in less than 5 s. Additional cases featuring well-established pharmaceutical active ingredients (API) and excipients substantiate the concept of high throughput in pharmaceuticals, affirming data quality through structural refinements aligned with literature-derived unit cell parameters. Synchrotron data need not always be state-of-the-art to compete with lab-XRPD data. The key lies in ensuring user-friendliness, reproducibility, accessibility, cost-effectiveness, and the streamlined efforts associated with synchrotron instrumentation to remain highly competitive with their laboratory counterparts.

[Bacterial and fungal co-infection: an association of criminals to look for]. / Co-infection bactérienne et fongique : une association de malfaiteurs à chercher.

INTRODUCTION: Mucorales are fungi that cause opportunistic infections. Its incidence increases. CASE REPORT: We report case of a 68-year-old woman with myelodysplastic syndrome responsible for prolonged neutropenia, hospitalized for pneumonia and sinusitis caused by Pseudomonas aeruginosa. But, despite antibiotic therapy, the patient's health deteriorated with discovery of systemic emboli on CT-scan and died. Sinus biopsies performed before her death diagnosed invasive fungal infection (Mucorales). CONCLUSION: Mucorales co-infections are rare but have already been described. Any invasive fungal infection should be searched on the event of any clinical suspicion: ground (neutropenia), lack of response to well-conducted antibiotic therapy, rapidly unfavorable outcome. The presence of other microbiological documentation do not must stop the search of invasive fungal infection, because it could have short-term life-threatening impact.

[Voiding dysfunction after TVT: A 20-year experience TVT-placement under local anesthesia and sedation]. / Troubles mictionnelles après pose de TVT : 20 ans d'expérience de pose sous diazanalgésie et anesthésie locale.

BACKGROUND: Trans-vaginal tape has become the gold standard for the cure of urinary stress incontinence, but post-operative voiding dysfunction is frequently reported. The purpose of this study is to assess the incidence of voiding dysfunction, dysuria, chronic urinary retention, and necessity of reoperation after retropubic TVT placement under local anaesthesia and sedation. MATERIAL AND METHOD: We perform a retrospective study of a cohort of patient treated with the placement of a retropubic TVT under local anaesthesia and sedation between 1999 and 2019 for a SUI. Post-operative voiding dysfunction and necessity of reoperation were reviewed to access the principal aim of this study. RESULTS: Three hundred and two patients who met the eligibility criteria were included in the study. At 3 months, the dysuria rate and chronic urinary retention rate was 4.3% and 1%. At 12 months it was 2.6% and 0.3% respectively. The 12-month sling section rate was 1% and long-term self-catherization rate was 0.3%. The objective cure rate was 93% and subjective cure was 92%. CONCLUSION: TVT placement under local anaesthesia and sedation resulted in few voiding dysfunctions at medium/long-term, necessity of re-operation for refractory obstructive disorder and well functional results. Even if these results support more frequent use of this type of anaesthesia, it would be interesting to be able to follow them in a prospective study to conclude. LEVEL OF EVIDENCE: 4.

An x-ray penumbral imager for measurements of electron-temperature profiles in inertial confinement fusion implosions at OMEGA.

Hot-spot shape and electron temperature (Te) are key performance metrics used to assess the efficiency of converting shell kinetic energy into hot-spot thermal energy in inertial confinement fusion implosions. X-ray penumbral imaging offers a means to diagnose hot-spot shape and Te, where the latter can be used as a surrogate measure of the ion temperature (Ti) in sufficiently equilibrated hot spots. We have implemented a new x-ray penumbral imager on OMEGA. We demonstrate minimal line-of-sight variations in the inferred Te for a set of implosions. Furthermore, we demonstrate spatially resolved Te measurements with an average uncertainty of 10% with 6 µm spatial resolution.

Disorder-Free Localization in an Interacting 2D Lattice Gauge Theory.

Disorder-free localization has been recently introduced as a mechanism for ergodicity breaking in low-dimensional homogeneous lattice gauge theories caused by local constraints imposed by gauge invariance. We show that also genuinely interacting systems in two spatial dimensions can become nonergodic as a consequence of this mechanism. This result is all the more surprising since the conventional many-body localization is conjectured to be unstable in two dimensions; hence the gauge invariance represents an alternative robust localization mechanism surviving in higher dimensions in the presence of interactions. Specifically, we demonstrate nonergodic behavior in the quantum link model by obtaining a bound on the localization-delocalization transition through a classical correlated percolation problem implying a fragmentation of Hilbert space on the nonergodic side of the transition. We study the quantum dynamics in this system by introducing the method of "variational classical networks," an efficient and perturbatively controlled representation of the wave function in terms of a network of classical spins akin to artificial neural networks. We identify a distinguishing dynamical signature by studying the propagation of line defects, yielding different light cone structures in the localized and ergodic phases, respectively. The methods we introduce in this work can be applied to any lattice gauge theory with finite-dimensional local Hilbert spaces irrespective of spatial dimensionality.

High-resolution x-ray radiography with Fresnel zone plates on the University of Rochester's OMEGA Laser Systems.

Experiments performed at the Laboratory for Laser Energetics with a continuous-wave (cw) x-ray source and on the OMEGA and OMEGA EP Laser Systems [Boehly et al., Opt. Commun. 133, 495 (1997) and Waxer et al., Opt. Photonics News 16, 30 (2005)] have utilized a Fresnel zone plate (FZP) to obtain x-ray images with a spatial resolution as small as ∼1.5 µm. Such FZP images were obtained with a charge-coupled device or a framing camera at energies ranging from 4.5 keV to 6.7 keV using x-ray line emission from both the cw source and high-intensity, laser-beam-illuminated metal foils. In all cases, the resolution test results are determined from patterns and grids backlit by these sources. The resolutions obtained are shown to be due to a combination of the spectral content of the x-ray sources and detector resolution limited by the magnification of the images (14× to 22×). High-speed framing cameras were used to obtain FZP images with frame times as short as ∼30 ps. Double-shell implosions on OMEGA were backlit by laser-irradiated Fe foils, thus obtaining a framing-camera-limited, FZP-image resolution of ∼3 µm-4 µm.

[Diffusion prophylactic axillary irradiation in breast cancer - Literature review]. / Irradiation axillaire prophylactique « de diffusion ¼ dans le cancer du sein ­ revue de la littérature.

PURPOSE: In breast cancer, radiotherapy is an essential component of the treatment. However, indications of irradiation of the internal mammary chain and axillary area are debatables. Axillary recurrence in patients with invasive breast carcinoma remains an issue. Currently, the substitution of axillary lymph node dissection by sentinel node biopsy leads to revisit the role of axillary irradiation. Breast irradiation including level I, II and III might decrease the risk of axillary recurrence. MATERIAL AND METHODS: A literature search was performed in PubMed and the Cochrane library to identify articles publishing data regarding dose-volume analysis of axillary levels in breast irradiation aiming to determine the potential therapeutic implications. RESULTS: Eleven articles were retained. A total of 375 treatment plans were analyzed. The results concerning the irradiation technique, initial dose prescribed to breast, delineated volumes and dose received at axillary levels were heterogeneous. The average dose delivered to axilla levels I-III with 3D-conformal radiotherapy using standard fields were between 24Gy and 43.5Gy, 3Gy and 32.5Gy and between 1.0Gy and 20.5Gy respectively. The average doses delivered to axilla levels I-III with 3D-conformal radiotherapy using high tangential fields were between 38Gy and 49.7Gy, 11Gy and 47.1Gy and 5Gy 38.7Gy, 32.1Gy and 5Gy (result available for only one study) respectively. Finally, the average doses delivered to axilla levels I-III with intensity modulated radiation therapy were between 14.5Gy and 42.6Gy, 3.4Gy and 35Gy and between 1.2Gy and 25.5Gy respectively. CONCLUSIONS: Incidental axillary dose seems insufficient to be therapeutic regardless of the irradiation technique. There are meaningful differences between intensity modulated radiation therapy and 3D-conformal radiotherapy.

Side-effect management of chimeric antigen receptor (CAR) T-cell therapy.

Chimeric antigen receptor (CAR) T cells directed against the B-cell marker CD19 are currently changing the landscape for treatment of patients with refractory and/or relapsed B-cell malignancies. Due to the nature of CAR T cells as living drugs, they display a unique toxicity profile. As CAR T-cell therapy is extending towards other diseases and being more broadly employed in hematology and oncology, optimal management strategies of side-effects associated with CAR T-cell therapy are of high relevance. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias constitute challenges in the treatment of patients with CAR T cells. This review summarizes the current understanding of CAR T-cell toxicity and its management.

Synthesis and characterization of crystalline niobium and tantalum carbonyl complexes at room temperature.

A variety of homoleptic transition metal carbonyl complexes are known as bulk compounds for group 7-12 metals. These metals typically feature a maximum of 6 CO ligands to form complexes with 18 valence electrons. In contrast, group 3-5 metals, with fewer valence electrons, have been shown to form highly coordinated heptacarbonyl and octacarbonyl complexes-although they were only identified by gas-phase mass spectrometry and/or matrix isolation spectroscopy work. Now we have prepared heptacarbonyl cations of niobium and tantalum as crystalline salts that are stable at room temperature. The [M(CO)7]+ (M = Nb or Ta) complexes were formed by the oxidation of [M(CO)6]- with 2Ag+[Al(ORF)4]- (RF, C(CF3)3) under a CO atmosphere; their experimental characterization was supported by density functional theory calculations. Other unusual carbonyl compounds were also synthesized: two isostructural salts that contained the 84-valence-electron cluster cation [Ag6{Nb(CO)6}4]2+, the piano-stool complexes [(1,2-F2C6H4)M(CO)4]+ and two polymorphs of neutral Ta2(CO)12 with a long, unsupported Ta-Ta bond.

IgG antibody response against Plasmodium falciparum aminopeptidase 1 antigen in Gabonese children living in Makokou and Franceville.

The search for novel chemical classes of anti-malarial compounds to cope with the current state of chemoresistance of malaria parasites has led to the identification of Plasmodium falciparum aminopeptidase 1 (PfA-M1) as a new therapeutic target. PfA-M1, known to be involved in the hemoglobin digestion cascade which helps to provide most of the amino acids necessary to the parasite's metabolism, is currently considered as a promising target for anti-malarial chemotherapy. However, its immunogenic properties have not yet been tested in the Gabonese population. In Gabon, the prevalence of malaria remains three times higher in semi-urban areas (60·12%) than in urban areas (17·06%). We show that malaria-specific PfA-M1 antibodies are present in children and increase with the level of infection. Children living in semi-urban areas have higher anti-PfA-M1 antibody titers (0·14 ± 0·02 AU) than those living in urban areas (0·08 ± 0·02 AU, P = 0·03), and their antibody titers increase with age (P < 0·0001). Moreover, anti-PfA-M1 antibody titers decrease in children with hyperparasitemia (0·027 ± 0·055 AU) but they remain high in children with low parasite density (0·21 ± 0·034 AU, P = 0·034). In conclusion, our results suggest that malaria-specific PfA-M1 antibodies may play an important role in the immune response of the host against P. falciparum in Gabonese children. Further studies on the role of PfA-M1 during anemia are needed.

Comparing the range of musculoskeletal therapies applied by physical therapists with postgraduate qualifications in manual therapy in patients with non-specific neck pain with international guidelines and recommendations: An observational study.

The aim of this study is to compare Dutch usual care musculoskeletal therapy in patients with non-specific neck pain with recommendations from international clinical practice guidelines. Physical therapy is diverse, as it may consist of exercise, massage, advice, and other modalities. Physical therapists with post graduate qualifications in manual therapy (MT) may additionally apply spinal thrust manipulation or non-thrust mobilization techniques to treat neck pain. It is important that, in the absence of a Dutch clinical guideline for the treatment of patients with neck pain, musculoskeletal therapists use the available recommendations from international clinical practice guidelines when treating patients with neck pain. One updated clinical practice guideline was identified (Blanpied, 2017), a report from the Task Force on Neck Pain (Guzman et al., 2008) and the IFOMPT International Framework for Examination of the Cervical Region for potential of Cervical Arterial Dysfunction prior to Orthopaedic Manual Therapy Intervention (Rushton et al., 2014). At baseline 1193 patients are included and data with regard to pain, disability, fear avoidance, expectations and applied treatment modalities are gathered. Outcome is measured using the Global Perceived Effect questionnaire. Results show that patients with acute neck pain are treated significantly more often with manipulation compared to patients with sub-acute or chronic neck pain (p < .000) and younger patients are treated with manipulation more often than older patients (p < .000). In the presence of comorbidity, the preference of spinal manipulation seems to diminish, in favour of mobilization and exercise. Almost every patient receives multimodal therapy (94.3%) and spinal manipulation and mobilization are rarely used as a stand-alone treatment (4.5% and 0.8%). Dutch musculoskeletal therapists choose treatment strategies that correspond with recommendations from international guidelines.

[VOTE versus ACLTE: comparison of two snoring noise classifications using machine learning methods]. / VOTE versus ACLTE: Vergleich zweier Schnarchgeräuschklassifikationen mit Methoden des maschinellen Lernens.

BACKGROUND: Acoustic snoring sound analysis is a noninvasive method for diagnosis of the mechanical mechanisms causing snoring that can be performed during natural sleep. The objective of this work is development and evaluation of classification schemes for snoring sounds that can provide meaningful diagnostic support. MATERIALS AND METHODS: Based on two annotated snoring noise databases with different classifications (s-VOTE with four classes versus ACLTE with five classes), identically structured machine classification systems were trained. The feature extractor openSMILE was used in combination with a linear support vector machine for classification. RESULTS: With an unweighted average recall (UAR) of 55.4% for the s­VOTE model and 49.1% for the ACLTE, the results are at a similar level. In both models, the best differentiation is achieved for epiglottic snoring, while velar and oropharyngeal snoring are more often confused. CONCLUSION: Automated acoustic methods can help diagnose sleep-disordered breathing. A reason for the restricted recognition performance is the limited size of the training datasets.

Stromal coexpression of uPA/PAI-1 protein predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer.

BACKGROUND: To evaluate whether uPA/PAI-1 protein in hormone receptor-positive (HR+) breast tumor can predict prognosis in early breast cancer (BC). METHODS: 606 women with HR + BC who had ≥5 years of endocrine therapy and in whom tumor tissue was available were included in this analysis. Stromal uPA/PAI-1 protein expression was evaluated by immunohistochemistry and correlated with distant recurrence-free survival (DRFS) and overall survival (OS). RESULTS: Stromal uPA was detected in 292/538 tumors (54.3%) while 269/505 samples (53.3%) exhibited stromal PAI-1. Co-expression of both proteins was found in 163/437 (37.3%) samples. Stromal uPA/PAI-1 co-expression was not associated with tumor size, age, nodal status, grading, or receptor status. Tumor stroma with both uPA and PAI-1 protein expression were more likely to have a shorter DRFS (HR: 1.87; 95%CI 1.18-2.96; p = 0.007) and OS (HR: 1.29; 95%CI 0.93-1.80; p = 0.129) than women without uPA/PAI-1 co-expression. After a median follow-up of 10 years, women with uPA/PAI-1-positive tumors experienced a significantly shorter DRFS (86.5% vs 72.4%; p < 0.001) and OS (70.4% vs 58.9%; p = 0.020) compared to women with uPA/PAI-1 negative tumors. CONCLUSION: Stromal co-expression of uPA and PAI-1 in breast cancer predicts poor DRFS and OS in postmenopausal women with HR + early-stage BC who receive endocrine therapy.

Cherenkov detector analysis for implosions with multiple nuclear reactions.

Nuclear reactions that produce γ rays occur in inertial fusion implosions and are commonly measured with Cherenkov detectors. Typically a detector is primarily sensitive to a single reaction, but in some implosions, multiple fusion reactions can occur and are combined in the data. We discuss an analysis technique using multiple thresholded detectors to reproduce the individual burn histories from reactions like DT and HT fusion, which is applicable to separated-reactant mix experiments. Requirements for this technique and resulting analysis uncertainties are quantified using synthetic data.

Diffusion-dominated mixing in moderate convergence implosions.

High-Z material mixed into the fuel degrades inertial fusion implosions and can prevent ignition. Mix is often assumed to be dominated by hydrodynamic instabilities, but we report Omega data, using shells with ∼150nm deuterated layers to gain unprecedented resolution, which give strong evidence that the dominant mix mechanism is diffusion for these moderate temperature (≲6 keV) and convergence (∼12) implosions. Small-scale instability-driven or turbulent mix is negligible.

Intra- and inter-tooth variation in strontium isotope ratios from prehistoric seals by laser ablation multi-collector inductively coupled plasma mass spectrometry.

RATIONALE: Strontium isotope ratios (87 Sr/86 Sr) in modern-day marine environments are considered to be homogeneous (~0.7092). However, in the Baltic Sea, the Sr ratios are controlled by mixing seawater and continental drainage from major rivers discharging into the Baltic. This pilot study explores if variations in Sr can be detected in marine mammals from archaeological sites in the Baltic Sea. METHODS: 87 Sr/86 Sr ratios were measured in tooth enamel from three seal species by laser ablation multi-collector inductively coupled plasma mass spectrometry (LA-MC-ICP-MS). The method enables micro-sampling of solid materials. This is the first time that the method has been applied to marine samples from archaeological collections. RESULTS: The analyses showed inter-tooth 87 Sr/86 Sr variation suggesting that different ratios can be detected in different regions of the Baltic Sea. Furthermore, the intra-tooth variation suggests possible different geographic origin or seasonal movement of seals within different regions in the Baltic Sea through their lifetime. CONCLUSIONS: The method was successfully applied to archaeological marine samples showing that: (1) the 87 Sr/86 Sr ratio in marine environments is not uniform, (2) 87 Sr/86 Sr differences might reflect differences in ecology and life history of different seal species, and (3) archaeological mobility studies based on 87 Sr/86 Sr ratios in humans should therefore be evaluated together with diet reconstruction.

Three-dimensional kinematics of the cervical spine using an electromagnetic tracking device. Differences between healthy subjects and subjects with non-specific neck pain and the effect of age.

BACKGROUND: A cross-sectional observational study of three-dimensional cervical kinematics in 35 non-specific neck pain patients and 100 asymptomatic controls. To compare qualitative and quantitative aspects of cervical kinematics between healthy subjects and subjects with non-specific neck pain and to determine the effect of age on cervical kinematics in healthy subjects. METHODS: Three-dimensional kinematics of active lateral bending and flexion-extension of 35 patients and 100 controls were registered by means of an electromagnetic tracking system. The means of several kinematic parameters were compared using t-tests. In addition, we assessed the age-dependency of the three-dimensional kinematic parameters by stratifying the 100 control subjects in 6 age categories. FINDINGS: Comparison of the patient group with the control group reveals no statistically significant differences in qualitative and quantitative parameters. Analysis of the effect of age showed that the range of motion decreases significantly (p < 0.01) with increasing age. In lateral bending, the ratio between axial rotation and lateral bending increases significantly (p < 0.01) among older subjects. Differences in acceleration, jerk and polynomial fit are seen between the age categories, but are not significant. INTERPRETATION: This study demonstrates no significant differences in kinematic parameters between healthy subjects and subjects with non-specific neck pain. Healthy subjects in higher age categories demonstrate higher ratios of coupled movements and lower ranges of motion. Future research should focus on classifying patients with non-specific neck pain in order to gain a better insight on possible subgroup specific differences in kinematics. More studies on this subject are warranted. LEVEL OF EVIDENCE: 4.

Primary T cells for mRNA-mediated immunotoxin delivery.

Immune cells become increasingly attractive as delivery system for immunotoxins in cancer therapy to reduce the intrinsic toxicity and severe side effects of chimeric protein toxins. In this study, we investigated the potential of human primary T cells to deliver a secreted immunotoxin through transient messenger RNA (mRNA) transfection. The chimeric protein toxin was directed toward the neovasculature of cancer cells by fusing a truncated version of Pseudomonas exotoxin A (PE38) to human vascular endothelial growth factor (VEGF) and to the single chain variable fragment (scFv) of anti-Her2/neu. Protocols for the transient transfection of human embryonic kidney cells (HEK293) as well as activated primary human T cells were established. Transient transfection with mRNA coding for the immunotoxins e23-PE38, VEGF-PE38 and its attenuated variant VEGF-PE38D yielded efficient expression and secretion. Mass spectrometry analysis endorsed that a fraction of VEGF-PE38D was properly translocated into the endoplasmic reticulum. Furthermore, cytotoxic activity of immunotoxin secreting T cells toward cancer cells was confirmed in co-culture with ovarian adenocarcinoma cells in the presence of a bispecific antibody (bsAb), highlighting the potential of primary T cells for mRNA-mediated immunotoxin delivery.