Cyclophosphamide vs rituximab for eradicating inhibitors in acquired hemophilia A: A randomized trial in 108 patients.

BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by immunosuppression. International recommendations rely on registers and international expert panels. METHODS: CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5-2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events. RESULTS: Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL-1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03). CONCLUSION: Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive. FUNDING: French Ministry of Health. CLINICALTRIALS: gov number: NCT01808911.

Robust unfolding of MeV x-ray spectra from filter stack spectrometer data.

We present an inversion method capable of robustly unfolding MeV x-ray spectra from filter stack spectrometer (FSS) data without requiring an a priori specification of a spectral shape or arbitrary termination of the algorithm. Our inversion method is based upon the perturbative minimization (PM) algorithm, which has previously been shown to be capable of unfolding x-ray transmission data, albeit for a limited regime in which the x-ray mass attenuation coefficient of the filter material increases monotonically with x-ray energy. Our inversion method improves upon the PM algorithm through regular smoothing of the candidate spectrum and by adding stochasticity to the search. With these additions, the inversion method does not require a physics model for an initial guess, fitting, or user-selected termination of the search. Instead, the only assumption made by the inversion method is that the x-ray spectrum should be near a smooth curve. Testing with synthetic data shows that the inversion method can successfully recover the primary large-scale features of MeV x-ray spectra, including the number of x-rays in energy bins of several-MeV widths to within 10%. Fine-scale features, however, are more difficult to recover accurately. Examples of unfolding experimental FSS data obtained at the Texas Petawatt Laser Facility and the OMEGA EP laser facility are also presented.

Exploring National Trends and Organizational Predictors of Violence and Mistreatment From Patients and Visitors.

GOAL: Rising incidents of violence and mistreatment of healthcare workers by patients and visitors have been reported. U.S. healthcare workers are five times more likely to experience nonfatal workplace violence (WPV) than workers in any other profession. However, less is known about the national trends in the incidence of violence and mistreatment in healthcare. The specific organizational and individual-level factors that relate to stress arising from these occurrences specifically by patients and family members are also not fully understood. The goals of this study were to examine national trends of violence toward healthcare workers, understand which populations are most vulnerable to stress from violence and mistreatment, and explore organizational factors that are related to these occurrences. METHODS: Data were collected from three sources: (1) The Bureau of Labor Statistics Intentional Injury by Another Person data for the period 2011-2020, (2) data from a large national workers' compensation claim services provider for the period 2018-2022, and (3) results from a survey distributed at a large medical center in June and July 2022. Data were represented graphically and analyzed using multivariate regression and dominance analysis to identify specific predictors of WPV and mistreatment among healthcare workers. PRINCIPAL FINDINGS: Of the total surveyed sample, 23.7% of participants reported mistreatment from patients or visitors as a major stressor and 14.6% reported WPV from patients or visitors as a major stressor. Stress from mistreatment and WPV was most frequently reported by nurses, employees aged 18 to 24 years other than nurses, those who identified as White, and those who identified as female or a gender minority. The emergency room (ER) showed the highest percentages of stress from mistreatment (61.8%) and violence (55.9%) from patients or visitors. The top predictors of stress from WPV and mistreatment by patients or visitors among healthcare workers ranked high to low were working in the ER, working as a nurse, a lack of necessary supplies or equipment, patient or visitor attitudes or beliefs about COVID-19, and working in a hospital-based unit. PRACTICAL APPLICATIONS: In addition to protecting employees as a moral imperative, preventing WPV is critical for organizational performance. Employee productivity is estimated to decrease up to 50% in the 6 to 18 weeks following an incident of violence, while turnover can increase 30% to 40%. An effective WPV prevention plan and a proactive approach to supporting the physical and mental health conditions that may result from WPV can mitigate the potential costs and exposures from these incidents. Organizations must also set clear expectations of behavior with patients and visitors by refusing to tolerate violence and mistreatment of caregivers. The impact of WPV can remain present and active for up to 8 years following an incident. Policy-level interventions are also needed. Currently, there are no federal protections for healthcare workers related to violence, though some states have made it a felony to abuse healthcare workers.

The formation of ubiquitin rich condensates triggers recruitment of the ATG9A lipid transfer complex to initiate basal autophagy.

Autophagy is an essential cellular recycling process that maintains protein and organelle homeostasis. ATG9A vesicle recruitment is a critical early step in autophagy to initiate autophagosome biogenesis. The mechanisms of ATG9A vesicle recruitment are best understood in the context of starvation-induced non-selective autophagy, whereas less is known about the signals driving ATG9A vesicle recruitment to autophagy initiation sites in the absence of nutrient stress. Here we demonstrate that loss of ATG9A or the lipid transfer protein ATG2 leads to the accumulation of phosphorylated p62 aggregates in the context of basal autophagy. Furthermore, we show that p62 degradation requires the lipid scramblase activity of ATG9A. Lastly, we present evidence that poly-ubiquitin is an essential signal that recruits ATG9A and mediates autophagy foci assembly in nutrient replete cells. Together, our data support a ubiquitin-driven model of ATG9A recruitment and autophagosome formation during basal autophagy.

[Inflammatory syndrome of unknown origin and PET/CT: Economic and iatrogenic impacts of false positive]. / Syndrome inflammatoire inexpliqué et TEP/CT : impacts économiques et iatrogènes des faux positifs.

INTRODUCTION: PET/CT is regularly used to investigate inflammatory syndrome of unknown origin (IUO), but hypermetabolisms found are not always consistent with the final diagnosis. The objective of the study was to assess the cost attributed to the diagnostic work-up for these false positives. MATERIALS AND METHODS: We conducted an ancillary study on a previous retrospective cohort from the internal medicine department at Amiens university hospital in patients who had a PET/CT scan between October 2004 and April 2017. Patients were included if PET/CT had been prescribed to investigate IUO. Among the 763 PET/CT performed, 144 met the inclusion criteria and a false-positive rate of 17.4% (n=25) was reported. RESULTS: Among these 25 patients, 21 underwent further investigations. The most frequently found hypermetabolic territories were digestive (n=12, mean SUVmax 8 [±4.33]) and osteoarticular (n=11, mean SUVmax 4.33 [±1.15]). The total cost of the 13 prescribed consultations was €390, the total cost of the 40 additional tests was €4,476 (mainly digestive endoscopies and radiological tests) and the total cost of medical transport was €572. The total cost of the 35 days of hospitalization specifically required to investigate these false positives was €22,952. In 23.8% (n=5), these investigations led to the incidental discovery of tumor lesions. CONCLUSION: The economic impact of false-positive PET/CT results does not appear to be negligible and merits a genuine prospective medico-economic study.

Systematic review and network meta-analysis of restorative therapy and adhesive strategies in root caries lesions.

AIM: This systematic review and network meta-analysis (NMA) aimed to establish a clinically relevant hierarchy of the different adhesive and/or restorative approaches to restore cavitated root caries lesions through the synthesis of available evidence. MATERIALS AND METHODS: A systematic search was conducted in Medline/Web of Science/Embase/ Cochrane Library/Scopus/grey literature. RCTs investigating ≥2 restorative strategies (restorative /adhesive materials) for root caries lesions in adult patients were included. Risk of bias within studies was assessed (Cochrane_RoB-2) and the primary outcome was survival rate of restorations at different follow-up times (6-/12-/24-months). Network meta-analyses were conducted using a random effects model stratified by follow-up times. I2-statistics assessed the ratio of true to total variance in the observed effects. All available combinations of adhesives (1-SE: one-step self-etch; 2-3ER: two-/three-step etch-and-rinse) and restorative materials (conventional composite (CC) as well as conventional and resin-modified glass ionomer cements (GIC, RMGIC)) were included. Risk of bias across studies and confidence in NMA (CINeMA) were assessed. RESULTS: 547 studies were identified and nine were eligible for the NMA. In total, 1263 root caries lesions have been restored in 473 patients in the included clinical trials. Patients involved were either healthy (n = 6 trials), living in nursing homes (n = 1 trial) or received head-and-neck radiotherapy (n = 2 trials). There was statistically weak evidence to favour either of material/material combination regarding the survival rate. A tendency for higher survival rate (24-months) was observed for 2-3ER/CC (OR24mths 2.65; 95%CI=1.45/4.84) as well as RMGIC (OR24mths 2.05; 95%CI=1.17/3.61) compared to GIC. These findings were though not statistically significant and confidence of the NMA was low. CONCLUSION: An evidence-based choice of restorative strategy for managing cavitated root caries lesions is currently impossible. There is a clear need for more standardised, well-designed RCTs evaluating the retention rate of root caries restoration approaches.

Halide Adsorption Enhances Electrochemical Hydrogenolysis of 5-Hydroxymethylfurfural by Suppressing Hydrogenation.

Reductive upgrading of 5-hydroxymethylfurfural (HMF), a biomass-derived platform molecule, to 2,5-dimethylfuran (DMF), a biofuel with an energy density 40% greater than that of ethanol, involves hydrogenolysis of both the aldehyde (C═O) and the alcohol (C-OH) groups of HMF. It is known that when hydrogenation of the aldehyde occurs to form 2,5-bis(hydroxymethyl)furan (BHMF), BHMF cannot be further reduced to DMF. Thus, aldehyde hydrogenation must be suppressed to increase the selectivity for DMF production. Previously, it was shown that on a Cu electrode hydrogenolysis occurs mainly through proton-coupled electron transfer (PCET), where a proton from the solution and an electron from the electrode are transferred to the organic species. In contrast, hydrogenation occurs not only through PCET but also through hydrogen atom transfer (HAT), where a surface-adsorbed hydrogen atom (H*) is transferred to the organic species. This study shows that halide adsorption on Cu can effectively suppress HAT by decreasing the steady-state H* coverage on Cu during HMF reduction. As HAT enables only aldehyde hydrogenation, a striking suppression of BHMF is observed, thereby enhancing DMF production. We discuss how the identity and concentration of the halide, along with the reduction conditions (i.e., potential and pH), affect halide adsorption on Cu and identify when optimal halide coverages are achieved to maximize DMF selectivity. Our experimental results are presented alongside computational results that elucidate how halide adsorption affects the adsorption energy of hydrogen and the steady-state H* coverage on Cu, which provide an atomic-level understanding of all experimentally observed effects.

Healthcare utilization and unmet needs of patients with antisynthetase syndrome: An international patient survey.

Antisynthease syndrome (ASSD) is a rare, complex and understudied autoimmune disease. Internet-based studies can overcome barriers of traditional on-site research and are therefore very appealing for rare diseases. The aim of this study was to investigate patient-reported symptoms, diagnostic delay, symptoms, medical care, health status, working status, disease knowledge and willingness to participate in research of ASSD patients by conducting an international web-based survey. The multilingual questionnaire was created by an international group of rheumatologists and patients and distributed online. 236 participants from 22 countries completed the survey. 184/236 (78.0%) were female, mean age (SD) was 49.6 years (11.3) and most common antisynthetase antibody was Jo-1 (169/236, 71.6%). 79/236 (33.5%) reported to work full-time. Median diagnostic delay was one year. The most common symptom at disease onset was fatigue 159/236 (67.4%), followed by myalgia 130/236 (55.1%). The complete triad of myositis, arthritis and lung involvement verified by a clinician was present in 42/236 (17.8%) at disease onset and in 88/236 (37.3%) during the disease course. 36/236 (15.3%) reported to have been diagnosed with fibromyalgia and 40/236 (16.3%) with depression. The most reported immunosuppressive treatments were oral corticosteroids 179/236 (75.9%), followed by rituximab 85/236 (36.0%). 73/236 (30.9%) had received physiotherapy treatment. 71/236 (30.1%) reported to know useful online information sources related to ASSD. 223/236 (94.5%) were willing to share health data for research purposes once a year. Our results reiterate that internet-based research is invaluable for cooperating with patients to foster knowledge in rare diseases.

Adult breast, lung, pancreatic, upper and lower gastrointestinal cancer patients with hospitalized venous thromboembolism in the national French hospital discharge database.

BACKGROUND: Venous thromboembolism (VTE) and cancer are strongly associated. In France, evidence on patients with pancreatic, upper GI [gastrointestinal], lower GI, lung, or breast cancer-associated VTE and their hospital management is limited. The aims of this study were to provide data on the number of hospitalized VTE events among cancer patients, the patients' characteristics, and their hospital management to estimate the burden of disease and the hospital burden of cancer-related VTE and to provide guidance on research. METHODS: This longitudinal, observational, and retrospective study was based on the comprehensive hospital discharge database (PMSI). Adult patients (≥ 18 years old) hospitalized with a cancer of interest in 2016 and hospitalized (within 2 years with VTE (captured a as a principal, related, or significant associated diagnosis) were included in the study. RESULTS: We identified 340,946 cancer patients, of which 7.2% (24,433 patients) were hospitalized with VTE. The proportions of hospitalized VTE were 14.6% (3,237) for patients with pancreatic cancer, 11.2% (8,339) for lung cancer, 9.9% (2,232) for upper GI cancer, 6.7% (7,011) for lower GI cancer, and 3.1% (3,614) for breast cancer. Around two thirds of cancer patients with a hospitalized VTE had active cancer (with metastases and/or receiving chemotherapy during the six months prior to the index date): from 62% of patients with pancreatic cancer to 72% with breast cancer. Around a third of patients were admitted to the hospital through the emergency room, up to 3% of patients stayed in an intensive care unit. The average length of stay ranged from 10 (breast cancer) to 15 days (upper GI cancer). Nine (lower GI cancer) to 18% (pancreatic cancer) of patients died during the VTE hospital stay. CONCLUSIONS: The burden of cancer-associated VTE is substantial, both in terms of the number of patients affected and in the hospital use. These findings offer guidance on future research on VTE prophylaxis in a very high-risk population, particularly in patients with active cancer.

A step closer to continuous buffer preparation from solids: Predicting powder compaction and how to prevent it.

The preparation of buffer solutions used in the biopharmaceutical industry is typically performed manually by the addition of one or multiple buffering reagents to water. Recently, the adaptation of powder feeders for continuous solid feeding was demonstrated for continuous buffer preparation. However, the intrinsic characteristics of powders can change the stability of the process, due to the hygroscopic nature of some substances and humidity-induced caking and compaction behavior, but there is no simple and easy methodology available for predicting this behavior for buffer species. To predict which buffering reagents are suitable without special precautions and investigate their behavior, force displacement measurements were conducted with a customized rheometer over 18 h. While most of the eight investigated buffering reagents indicated uniform compaction, especially sodium acetate and dipotassium hydrogen phosphate (K2HPO4) showed a significant increase in yield stress after 2 h. Experiments conducted with a 3D printed miniaturized screw conveyor confirmed the increased yield stress measurements by visible compaction and failure of the feeding. By taking additional precautions and adjusting the design of the hopper, we demonstrated a highly linear profile of all buffering reagents over a duration of 12 and 24 h. We showed that force displacement measurements accurately predict the behavior of buffer components in continuous feeding devices for continuous buffer preparation and are a valuable tool to identify buffer components that need special precautions. Stable, precise feeding of all tested buffer components was demonstrated, highlighting the importance of identifying buffers that need a specialized setup with a rapid methodology.

Green room temperature synthesis of silver-gold alloy nanoparticles.

Metallic alloy nanoparticles (NPs) exhibit interesting optical, electrical and catalytic properties, dependent on their size, shape and composition. In particular, silver-gold alloy NPs are widely applied as model systems to better understand the syntheses and formation (kinetics) of alloy NPs, as the two elements are fully miscible. Our study targets product design via environmentally friendly synthesis conditions. We use dextran as the reducing and stabilizing agent for the synthesis of homogeneous silver-gold alloy NPs at room temperature. Our approach is a one-pot, low temperature, reaction-controlled, green and scalable synthesis route of well-controlled composition and narrow particle size distribution. The composition over a broad range of molar gold contents is confirmed by scanning transmission electron microscopy-energy-dispersive X-ray spectroscopy (STEM-EDX) measurements and auxiliary inductively coupled plasma-optical emission spectroscopy measurements (ICP-OES). The distributions of the resulting particles in size and composition are obtained from multi-wavelength analytical ultracentrifugation using the optical back coupling method and further confirmed by high-pressure liquid chromatography. Finally, we provide insight into the reaction kinetics during the synthesis, discuss the reaction mechanism and demonstrate possibilities for scale-up by a factor of more than 250 by increasing the reactor volume and NP concentration.

Impact of a suspension drop onto a hot substrate: diminution of splash and prevention of film boiling.

In the present study, the effect of graphite lubricant additives on the dynamics of a single drop impact onto a heated surface has been investigated in the nucleate boiling and thermal atomization regimes. In the nucleate boiling regime the drop impact is accompanied by the nucleation and expansion of multiple vapor bubbles. The drop residence time at the substrate is determined by the time of its mass loss due to splash and evaporation. At higher temperatures, above the Leidenfrost point, impact may lead to drop rebound. In this experimental and theoretical study the effect of additives on the outcome of drop impact, in particular, the addition of solid graphite particles, is investigated. The residence time of the drop has been measured for various initial drop temperatures and suspension concentrations. The addition of the particles leads to some increase of the residence time, while its dependence on the substrate temperature follows the scaling relation obtained in the theory. Moreover, the presence of the particles in the drop leads to suppression of splash and a significant increase of the drop rebound temperature, which is often associated with the Leidenfrost point. These effects are caused by the properties of the deposited layer, and pinning of the contact line of the entire drop and of each vapor bubble, preventing bubble coalescence and drop rebound. The phenomena are also explained by a significant increase of the liquid viscosity caused by the evaporation of the bulk liquid at high wall temperatures.

Development and Implementation of Atomically Anisotropic First-Principles Force Fields: A Benzene Case Study.

π-interactions are an important motif in chemical and biochemical systems. However, due to their anisotropic electron densities and complex balance of intermolecular interactions, aromatic molecules represent an ongoing challenge for accurate and transferable force field development. Historically, ab initio force fields for aromatics have not exhibited good accuracy with respect to bulk properties or have only been used to study gas-phase dimers. Using benzene as a proof of concept, herein we show how our own ab initio MASTIFF force field incorporates an atomically anisotropic description of intermolecular interactions to yield an accurate and robust model for aromatic interactions irrespective of phase. Compared to existing models, the MASTIFF benzene force field not only is accurate for liquid phase properties but also offers transferability to the gas and solid phases. Additionally, we introduce a computationally efficient OpenMM plugin which enables customizable anisotropic intermolecular functional forms and which can be generically used in any MD simulation where a model for nonspherical atomic features is required. Overall, our results demonstrate the importance of atomic-level anisotropy in enabling next-generation ab initio force field development.

[Platypnea-orthodeoxia syndrome secondary to pneumonia: Two cases]. / Syndrome platypnée-orthodéoxie secondaire à une pneumopathie : à propos de deux cas.

INTRODUCTION: The platypnea-orthodeoxia syndrome is a rare situation characterized by the appearance of dyspnea and/or hypoxemia during the transition to orthostatism. OBSERVATIONS: We report the case of two patients, who presented with a platypnea-orthodeoxia syndrome following pneumocystis pneumonia and COVID-19, revealing an intracardiac communication with a right-left shunt on contrast ultrasound. CONCLUSION: This syndrome can be detected easily at the bedside with positional maneuvers and the shunt demonstrated by a hyperoxia test. Non-reversible situations may require correction of the anatomical anomaly by transcatheter intervention or surgery.

Total atrial conduction time provides novel information in prediction for stroke in patients with sinus rhythm.

The total atrial conduction time (TACT) measured by echocardiography predicts the risk of atrial fibrillation (AF). This study aimed to investigate whether adding the TACT to the revised Framingham stroke risk profile (rFSRP) improves the efficacy of predicting stroke incidence in patients without prior stroke or known AF. The TACT was measured in 376 consecutive patients > 18 years (58.5 ± 16.3 years; 46% male) receiving echocardiography without any prior history of stroke or AF. The primary endpoint was the occurrence of ischemic stroke, and the secondary endpoint was any documentation of AF during the 2 years of follow-up. During the follow-up period, ischemic strokes occurred in 10 patients (2.65%), and AF in 22 patients (5.85%). The TACT was significantly longer in those who later had a stroke compared with those who did not (169.4 vs. 142.7 ms, p < 0.001). Both rFSRP and TACT predicted the risk for stroke incidence. The univariate model showed that the TACT was a predictor of ischemic stroke incidence (p < 0.001; hazard ratio of 1.94 for every 10 ms; 95% confidence interval, 1.49-2.54). The addition of TACT to rFSRP significantly improved the area under the receiver operating characteristic curve (0.79 vs. 0.85, p = 0.001). Stroke risk prediction was significantly improved by the addition of TACT to rFSRP. The utility of the TACT should be further investigated in large-scale randomized clinical trials.

[Cognition and driving ability in chronic pain syndrome]. / Kognition und Kraftfahreignung bei chronischem Schmerzsyndrom.

Cognitive impairments in patients with chronic pain are increasingly attracting interest in scientific research. The consequences of these cognitive impairments on coping with pain, everyday life and the driving ability are rarely included in clinical practice although half of all patients are affected. This article summarizes the current research situation and discusses possibilities of the integration in clinical and therapeutic care.