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•Patients with MCL experiencing late relapse benefit from BTK-inhibitors over chemoimmunotherapies.•Overall, chemoimmunotherapies as second-line treatment are discouraged in the era of chimeric antigen receptor T-cell therapies.

Background: Parkinson’s disease (PD) is a complex neurodegenerative disorder impacting everyday function and quality of life. Rehabilitation plays a crucial role in improving symptoms, function, and quality of life and reducing disability, particularly given the lack of disease-modifying agents and limitations of medications and surgical therapies. However, rehabilitative care is under-recognized and under-utilized in PD and often only utilized in later disease stages, despite research and guidelines demonstrating its positive effects. Currently, there is a lack of consensus regarding fundamental topics related to rehabilitative services in PD.Objective: The goal of the international Parkinson’s Foundation Rehabilitation Medicine Task Force was to develop a consensus statement regarding the incorporation of rehabilitation in PD care.Methods: The Task Force, comprised of international multidisciplinary experts in PD and rehabilitation and people directly affected by PD, met virtually to discuss topics such as rehabilitative services, existing therapy guidelines and rehabilitation literature in PD, and gaps and needs. A systematic, interactive, and iterative process was used to develop consensus-based statements on core components of PD rehabilitation and discipline-specific interventions.Results: The expert-based consensus statement outlines key tenets of rehabilitative care including its multidisciplinary approach and discipline-specific guidance for occupational therapy, physical therapy, speech language pathology/therapy, and psychology/neuropsychology across all PD stages.Conclusions: Rehabilitative interventions should be an essential component in the comprehensive treatment of PD, from diagnosis to advanced disease. Greater education and awareness of the benefits of rehabilitative services for people with PD and their care partners, and further evidence-based and scientific study are encouraged.

Parkinson’s disease (PD) is a complex neurodegenerative disorder impacting everyday function and quality of life. Rehabilitation plays a crucial role in improving symptoms, function, and quality of life and reducing disability, particularly given the lack of disease-modifying agents and limitations of medications and surgical therapies. However, rehabilitative care is under-recognized and under-utilized in PD and often only utilized in later disease stages, despite research and guidelines demonstrating its positive effects. Currently, there is a lack of consensus regarding fundamental topics related to rehabilitative services in PD. The goal of the international Parkinson’s Foundation Rehabilitation Medicine Task Force was to develop a consensus statement regarding the incorporation of rehabilitation in PD care. The Task Force, comprised of international multidisciplinary experts in PD and rehabilitation and people directly affected by PD, met virtually to discuss topics such as rehabilitative services, existing therapy guidelines and rehabilitation literature in PD, and gaps and needs. A systematic, interactive, and iterative process was used to develop consensus-based statements on core components of PD rehabilitation and discipline-specific interventions. The expert-based consensus statement outlines key tenets of rehabilitative care including its multidisciplinary approach and discipline-specific guidance for occupational therapy, physical therapy, speech language pathology/therapy, and psychology/neuropsychology across all PD stages. Rehabilitative interventions should be an essential component in the comprehensive treatment of PD, from diagnosis to advanced disease. Greater education and awareness of the benefits of rehabilitative services for people with PD and their care partners, and further evidence-based and scientific study are encouraged.

The amethyst and agate geodes from the Los Catalanes Gemmological District in Uruguay represent one of the main deposits of its kind worldwide. The geometry of the deposit is horizontal, with an irregular distribution of amethyst geodes within the upper level of the basalt lava flows and shows strong variations in their abundance, as well as quality, geometry, and shape. Reliable exploration guides are scarce, and the limited knowledge of the geological parameters controlling its occurrence makes exploration unpredictable, leading to inaccurate reserve estimation. Based on cutting-edge methods including nucleation-assisted microthermometry of one-phase fluid inclusions and determination of triple oxygen isotope in silicates and carbonates, as well as analysis of geode-hosted water and groundwater, we estimate the crystallisation temperatures in the range between 15 and 60 °C. These low temperatures point to amethyst crystallisation after the emplacement of the complete basalt pile. The mineralising fluid shows isotopic signatures consistent with meteoric water and very low salinities from pure water up to rarely over 3 wt% NaCl-eq., likely sourced from the groundwater hosted in the aquifers in the basaltic sequence and underlying units. Based on the insights provided by the new data, we propose the combination of open- and closed-system crystallisation inside pre-existing cavities due to the episodic infiltration of meteoric water in a rather stable geological context.

Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n= 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n= 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p= 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p= 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p= 0.0336. Twelve months progression-free survival was 62% (95% CI: 51–75) in PMBCL versus 48% (95% CI: 41–57) in other LBCL, p= 0.0386. Twelve months overall survival was 86% (95% CI: 78–95) in PMBCL versus 71% (95% CI: 64–79) in other LBCL, p= 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n= 20) or placebo (n= 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n= 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET–CT) was not met (P= 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P= 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666.

•R-COMP is a curative option for older patients with DLBCL and intermediate- to high-risk EPI, even in the presence of a baseline cardiopathy.•R-CHOP is confirmed as the standard therapy for patients at low risk based on the EPI.

The Hayabusa2 spacecraft explored asteroid Ryugu and brought its surface materials to Earth. Ryugu samples resemble Ivuna-type (CI) chondrites—the most chemically primitive meteorites—and contain secondary phyllosilicates and carbonates, which are indicative of aqueous alteration. Understanding the conditions (such as temperature, redox state and fluid composition) during aqueous alteration is crucial to elucidating how Ryugu evolved to its present state, but little is known about the temporal changes in these conditions. Here we show that calcium carbonate (calcite) grains in Ryugu and Ivuna samples have variable 18O/16O and 13C/12C ratios that are, respectively, 24–46‰ and 65–108‰ greater than terrestrial standard values, whereas those of calcium–magnesium carbonate (dolomite) grains are much more homogeneous, ranging within 31–36‰ for oxygen and 67–75‰ for carbon. We infer that the calcite precipitated first over a wide range of temperatures and oxygen partial pressures, and that the proportion of gaseous CO2/CO/CH4molecules changed temporally. By contrast, the dolomite formed later in a more oxygen-rich and thus CO2-dominated environment when the system was approaching equilibrium. The characteristic isotopic compositions of secondary carbonates in Ryugu and Ivuna are not observed for other hydrous meteorites, suggesting a unique evolutionary pathway for their parent asteroid(s).

In some cases of infants with apparently isolated single-suture synostosis, an underlying variant can be found. We aimed to determine the molecular substratum in isolated sagittal and metopic craniosynostosis. To this end, we included all infants who presented isolated midline synostosis (sagittal or metopic) and had undergone surgery at the craniosynostosis national reference center of Lyon University Hospital. All infants were examined by a multidisciplinary team including neurosurgeons, clinical geneticists and neuropsychologist. Among 101 infants tested, 13 carried a total of 13 variants; that is, 12.9% of the infants carried a variant in genes known to be involved in craniosynostosis. Seven infants carried SMAD6variants, 2 in FGFR2, 1 in TWIST1, one in FREM1, one in ALX4and one in TCF12. All variants were detected at the heterozygous level in genes associated with autosomal dominant craniosynostosis. Also, neurodevelopmental testing showed especially delayed acquisition of language in children with than without variants in SMAD6. In conclusion, a high percentage of young children with isolated midline craniosynostosis, especially in isolated trigonocephaly, carried SMAD6variants. The interpretation of the pathogenicity of the genes must take into account incomplete penetrance, usually observed in craniosynostosis. Our results highlight the interest of molecular analysis in the context of isolated sagittal and/or metopic craniosynostosis to enhance an understanding of the pathophysiology of midline craniosynostosis.

Background: Bone metastatic involvement represents a leading cause of death in patients with advanced breast cancer (BC). At present, it is not clear whether the bone metastatic load might impact Overall Survival (OS) in patients with bone metastatic BC at diagnosis. For this purpose, we used the Bone Scan Index (BSI), which is a reproducible and quantitative expression of tumor load observed at bone scintigraphy. Objective: The aim of this study was to associate BSI with OS in bone metastatic BC patients. Methods: In this retrospective study, we enrolled BC patients with bone metastases at the scintigraphic bone scan performed for staging purposes. The BSI was calculated through the DASciS software, and statistical analysis was carried out. Other clinical variables relevant to OS analysis were taken into account. Results: Of a total of 94 patients, 32% died. In most cases, the histotype was ductal infiltrating carcinoma. The median OS from diagnosis was 72 months (CI 95%: 62-NA). The univariate analysis with COX regression showed that only hormone therapy significantly correlates with OS (HR 0.417, CI 95%: 0.174-0.997, p < 0.049). As concerning BSI, the statistical analysis showed that it does not predict OS in BC patients (HR 0.960, 95% CI: 0.416-2.216, p < 0.924). Conclusion: Although the BSI significantly predicts OS in prostate cancer and in other tumors, we observed that the metastatic load of bone disease has not a key role in prognostic stratification in our population.

•The microscope’s magnification abilities have long been essential in neurosurgery, allowing interventions otherwise impossible. However, its ergonomic challenges prompt the exploration of alternatives like the exoscope, which offers similar magnification with better ergonomics.•The visual field provided by the exoscope is larger compared to the microscope, specifically measuring 54.10 cm2for the microscope and 81.18 cm2for the exoscope at 30 cm with 2.7× zoom.•We found no differences in image sharpness at any zoom level between the microscope and the exoscope.•In terms of ergonomics, the exoscope is superior to the microscope. Using spine UpSurgeOn®models, we observed that to view the most lateral angles of the field of vision with the microscope, the upper body needs to be inclined approximately 20 degrees relative to the neutral axis. In contrast, with the exoscope, it is possible to maintain the upper body straight at 0 degrees relative to the neutral axis.•Selective Dorsal Rhizotomy represents a surgical domain where the exoscope proves particularly relevant: allowing exclusive tilting of the camera and enabling the maintenance of an upright posture with a direct gaze towards the anterior screen, proves to be the best choice in terms of ergonomics, as well as the breadth of the visual field, allowing access to even the least accessible angles. Easier interaction with operating room staff is another advantage of the exoscope over the microscope.

GitHub provides developers with a practical way to distribute source code and collaboratively work on common projects. To enhance account security and privacy, GitHub allows its users to manage access permissions, review audit logs, and enable two-factor authentication. However, despite the endless effort, the platform still faces various issues related to the privacy of its users. This paper presents an empirical study delving into the GitHub ecosystem. Our focus is on investigating the utilization of privacy settings on the platform and identifying various types of sensitive information disclosed by users. Leveraging a dataset comprising 6,132 developers, we report and analyze their activities by means of comments on pull requests. Our findings indicate an active engagement by users with the available privacy settings on GitHub. Notably, we observe the disclosure of different forms of private information within pull request comments. This observation has prompted our exploration into sensitivity detection using a large language model and BERT, to pave the way for a personalized privacy assistant. Our work provides insights into the utilization of existing privacy protection tools, such as privacy settings, along with their inherent limitations. Essentially, we aim to advance research in this field by providing both the motivation for creating such privacy protection tools and a proposed methodology for personalizing them.

IMPORTANCE: The Global Burden of Disease study conducted between 1990 and 2016, based on a global study of 195 countries and territories, identified Parkinson disease (PD) as the fastest growing neurological disorder when measured using death and disability. Most people affected by PD live in low- and middle-income countries (LMICs) and experience large inequalities in access to neurological care and essential medicines. This Special Communication describes 6 actions steps that are urgently needed to address global disparities in PD. OBSERVATIONS: The adoption by the 73rd World Health Assembly (WHA) of resolution 73.10 to develop an intersectoral global action plan on epilepsy and other neurological disorders in consultation with member states was the stimulus to coordinate efforts and leverage momentum to advance the agenda of neurological conditions, such as PD. In April 2021, the Brain Health Unit at the World Health Organization convened a multidisciplinary, sex-balanced, international consultation workshop, which identified 6 workable avenues for action within the domains of disease burden; advocacy and awareness; prevention and risk reduction; diagnosis, treatment, and care; caregiver support; and research. CONCLUSIONS AND RELEVANCE: The dramatic increase of PD cases in many world regions and the potential costs of PD-associated treatment will need to be addressed to prevent possible health service strain. Across the board, governments, multilateral agencies, donors, public health organizations, and health care professionals constitute potential stakeholders who are urged to make this a priority.

Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1(feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the full-length isoform encoded by the FLVCR1gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1ain mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

Software development activity has reached a high degree of complexity, guided by the heterogeneity of the components, data sources, and tasks. The proliferation of open-source software (OSS) repositories has stressed the need to reuse available software artifacts efficiently. To this aim, it is necessary to explore approaches to mine data from software repositories and leverage it to produce helpful recommendations. We designed and implemented FOCUS as a novel approach to provide developers with API calls and source code while they are programming. The system works on the basis of a context-aware collaborative filtering technique to extract API usages from OSS projects. In this work, we show the suitability of FOCUS for Android programming by evaluating it on a dataset of 2,600 mobile apps. The empirical evaluation results show that our approach outperforms two state-of-the-art API recommenders, UP-Miner and PAM, in terms of prediction accuracy. We also point out that there is no significant relationship between the categories for apps defined in Google Play and their API usages. Finally, we show that participants of a user study positively perceive the API and source code recommended by FOCUS as relevant to the current development context.

Trigonocephaly is a craniosynostosis characterized by a premature fusion of the metopic suture associating a characteristic triangular head shape, with a frontal medial crest and hypotelorism. Various techniques have been described for its surgical treatment which is usually performed during the first year of life. However, there might be cases with a late referral, after the age of one year. One of the technical issues with a fronto-orbital advancement surgery in a child over one year of age is that there is a significant risk of persistent residual bone defects. This article describes a surgical technique of crenellated fronto-orbital advancement for correcting trigonocephaly in children over one year of age, allowing to reduce residual bone defects.

Patients with Parkinson’s disease (PD) are at higher risk of vaccine-preventable respiratory infections. However, advanced, homebound individuals may have less access to vaccinations. In light of COVID-19, understanding barriers to vaccination in PD may inform strategies to increase vaccine uptake. To identify influenza and pneumococcal vaccination rates, including barriers and facilitators to vaccination, among homebound and ambulatory individuals with PD and related disorders. Cross-sectional US-based study among individuals with PD, aged > 65 years, stratified as homebound or ambulatory. Participants completed semi-structured interviews on vaccination rates and barriers, and healthcare utilization. Among 143 participants, 9.8% had missed all influenza vaccinations in the past 5 years, and 32.2% lacked any pneumococcal vaccination, with no between-group differences. Homebound participants (n = 41) reported difficulty traveling to clinic (p < 0.01) as a vaccination barrier, and despite similar outpatient visit frequencies, had more frequent emergency department visits (31.7% vs. 9.8%, p < 0.01) and hospitalizations (14.6% vs. 2.9%, p = 0.03). Vaccine hesitancy was reported in 35% of participants, vaccine refusal in 19%, and 13.3% reported unvaccinated household members, with no between-group differences. Nearly 13% thought providers recommended againstvaccines for PD patients, and 31.5% were unsure of vaccine recommendations in PD. Among a sample of homebound and ambulatory people with PD, many lack age-appropriate immunizations despite ample healthcare utilization. Many participants were unsure whether healthcare providers recommend vaccinations for people with PD. In light of COVID-19, neurologist reinforcement that vaccinations are indicated, safe, and recommended may be beneficial.

ABSTRACTAlthough psychosis and psychoanalysis have been closely linked since the earliest Freudian theories, the psychoanalytic treatment of psychotic states still presents major difficulties. The establishment of a therapeutic situation allowing the deployment of psychic work is still uncertain. The resumption of the work of S. Freud and DW. Winnicott associated with the development of the theorization of a metapsychology of the process of symbolization by the French school (Green, Roussillon) allows a revival of the reflection on the stakes of the establishment of the therapeutic situation. This theorization of representative processes makes it possible to consider the psychotherapeutic approach to psychoses from the angle of a “psychopathology of the psychic apparatus” and thus to model the psychic dynamics involved in psychotic problems which initially appear in a chaotic form. The apparent failure of the psychic processes, in their linking and transforming activity with which the psychotic states are confronted, can then be thought of as the seat of a particular psychic work that can provide essential support to the therapeutic work. Two cases studies illustrate these processes.

Fit patients with mantle cell lymphoma aged 18–65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.

Patients with mantle cell lymphoma (MCL) that fail induction treatment represent a difficult-to-treat population, where no standard therapy exists. We evaluated outcomes in patients with first relapsed-refractory (r/r) MCL after upfront high dose cytarabine including standard regimens. Overall survival (OS-2) and progression-free survival (PFS-2) were estimated from the time of salvage therapy. The previously described threshold of 24 months was used to define patients as early- or late-progressors (POD). Overall, 261 r/r MCL patients were included. Second-line regimens consisted of rituximab-bendamustine (R-B, 21%), R-B and cytarabine (R-BAC, 29%), ibrutinib (19%), and others (31%). The four groups were balanced in terms of clinicopathological features. Adjusting for age and early/late-POD, patients treated with R-BAC had significantly higher complete remission (63%) than comparators. Overall, Ibrutinib and R-BAC were associated with improved median PFS-2 [24 and 25 months, respectively], compared to R-B (13) or others (7). In patients with early-POD (n= 127), ibrutinib was associated with inferior risk of death than comparators (HR 2.41 for R-B, 2.17 for others, 2.78 for R-BAC). In patients with late-POD (n= 134), no significant differences were observed between ibrutinib and bendamustine-based treatments. Ibrutinib was associated with improved outcome in early-POD patients.

Gaucher disease (GD) is a rare disorder characterized by defective function of β-glucocerebrosidase, which leads to progressive accumulation of its substrate in various organs, particularly the mononuclear phagocyte system. Hepatosplenomegaly and cytopenia represent the disease's most common features, but patients with GD also show hyperinflammation, hypergammaglobulinemia, and immune dysregulation involving B, T, and natural killer cells. As clinical phenotype can be underhand, symptoms can overlap with autoimmune lymphoproliferative syndrome (ALPS) or other ALPS-like disorders.

L’approche psychopathologique et clinique des processus psychiques en jeu dans la phase d’éveil de coma permet une exploration singulière des processus de subjectivation. Cette approche relativement récente est liée à la présence de psychologues cliniciens dans les services de réanimation. Cependant, cette « clinique » de l’éveil plonge ses racines dans les pratiques psychiatriques du début du 20e siècle avec la pratique des « comas thérapeutiques » tels que les comas dits « insuliniques » où le moment de l’éveil était pensé comme un « événement thérapeutique » permettant un réaménagement psychique. Nous proposons de penser ces processus psychiques engagés dans l’éveil de coma comme mobilisant le registre de la symbolisation primaire articulant éprouvés et échanges intersubjectifs au sein d’une relation comportant une part de dépendance aux réactions de l’environnement. D’une part, l’étude des propos des patients lors de l’éveil de coma nous permet de définir plusieurs fonctions aux productions dites « délirantes » : une fonction protectrice, une fonction transitionnelle, une fonction organisatrice, une fonction d’appropriation/évacuation. D’autre part, l’incapacité à éprouver une sensation tolérable de douleur permet un premier ré-ancrage dans le corps. Alors que l’impossibilité de ressentir la douleur suscite l’investissement de productions hallucinatoires. Cette étude se conclut sur la nécessité de recourir à une écoute clinique des propos prononcés lors de phases d’éveil de coma.

The aim of this study was to identify quantitative tools to classify the severity of trigonocephaly to guide surgical management and predict outcome.

Surgical treatment of craniosynostosis in children may generate secondary cranial vault defects by incomplete ossification process. The incidence of cranial defects after craniosynostosis surgery is poorly reported in the literature with a variable incidence of 0.5% to 18.2%. To better understand the impact and management of the cranial defects after craniosynostosis surgery, we selected and reviewed al cranioplasties that met this criterion between 2002 and 2019.