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Abstract Humans naturally employ muscle coactivation to facilitate a broad range of movements, enhancing joint stability and movement accuracy. However, excessive muscle coactivation can become unfavorable or even detrimental. This phenomenon is often observed in industrial workers who endure repetitive or prolonged joint stress, particularly in areas such as the shoulders. Prolonged stress can result in soft tissue damage and the onset of work-related musculoskeletal disorders (MSDs). In recent years, there have been efforts to mitigate the emergence of work-related MSDs among industrial workers through the implementation of upper-limb occupational exoskeletons (OEs). While previous research has demonstrated their effectiveness in reducing shoulder muscle activation, particularly in static and overhead work activities, there has been a lack of studies examining the impact of upper-limb OEs on muscle coactivation during repetitive arm movements. To bridge this gap in knowledge, our study systematically assesses the influence of a passive exoskeleton’s anti-gravitational support on shoulder muscle coactivation during repetitive arm movements. Results show that peak and mean coactivation levels linearly decrease with the increase of the amount of anti-gravitational support provided by the upper-limb OE, reaching approximately 51% and 54%, respectively. Conversely, the percentage of the movement cycle corresponding to the coactivation peak appears unaffected by the level of assistance. This study marks the first instance in which a passive upper-limb OE has been shown to reduce shoulder muscle coactivations, potentially paving the way for a novel methodology in their evaluation.

Abstract Determining the genetic contributions to Parkinson’s disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study is part of the Global Parkinson’s Genetics Program, supported by the Aligning Science Across Parkinson’s initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population.

Abstract Mycoplasma hominis can be a part of human urogenital tract microbiome, and it is a frequent cause of urogenital infections. In rare cases, it can also cause extragenital infections, especially in immunocompromised patients. In this case series, we report two cases and provide a literature review of extragenital infections caused by M. hominis in patients with hypogammaglobulinemia. Patient 1 was a 61-year-old woman with diffuse large B-cell lymphoma who, after rituximab-containing chemotherapy and CAR-T therapy, developed M. hominis spondylodiscitis. Patient 2 was a 50-year-old woman with congenital hypogammaglobulinemia who developed disseminated M. hominis infection involving pleura, muscles, and right ankle. Antibiotic therapy with levofloxacin and doxycycline for 10 weeks in patient 1 and with levofloxacin alone for 6 weeks in patient 2 led to infection resolution. The literature review identified 14 additional cases reporting M. hominis extragenital infection in patients with hypogammaglobulinemia. M. hominis should also be suspected as an etiological agent of extragenital infection in patients with B-cell immunodeficiency with a clinical picture of persistent, standard-culture negative infection, particularly with arthritis or abscess formation. Even if M. hominis can grow on standard bacterial medium, in suspected cases molecular methods should be promptly used for correct diagnostic work-up and successful therapy.

Recent adverse childhood experiences (ACEs) scholarship emphasizes that differing ACEs affect the onset and course of psychopathology, and that sociopolitical context contributes to ACEs experienced by marginalized youth. Guided by the Immigration-Related Adverse Childhood Experiences Model, we explored the associations between different ACEs--immigration enforcement fear and perceived economic hardship--on posttraumatic stress disorder (PTSD) and depression among first and second-generation Latinx youth in immigrant families. Participants (n = 306) included students from 11 high schools in two states (58% female; 25% aged 17 or older). Fifty-three percent were first generation students and 80% were born in, or had a parent from, Mexico or Central America. We found that immigration enforcement fear predicted greater PTSD symptoms after accounting for other key covariates. Perceived economic hardship was associated with depression across all subscales. Findings highlight the need for a multidimensional approach to assess and understand how ACEs, including immigration enforcement fear, influence mental health for youth in Latinx immigrant families.

Abstract Aims Several mechanisms have been identified in the aetiopathogenesis of heart failure with preserved ejection fraction (HFpEF). Among these, coronary microvascular dysfunction (CMD) may play a key pathophysiological role. We performed a systematic review and meta‐analysis to investigate the prevalence, echocardiographic correlates, and prognostic implications of CMD in patients with HFpEF. Methods and results A systematic search for articles up to 1 May 2023 was performed. The primary aim was to assess the prevalence of CMD. Secondary aims were to compare key echocardiographic parameters (E/e′ ratio, left atrial volume index [LAVi], and left ventricular mass index [LVMi]), clinical outcomes [death and hospitalization for heart failure (HF)], and prevalence of atrial fibrillation (AF) between patients with and without CMD. Meta‐regressions according to baseline patient characteristics and study features were performed to explore potential heterogeneity sources. We identified 14 observational studies, enrolling 1138 patients with HFpEF. The overall prevalence of CMD was 58%. Compared with patients without CMD, patients with HFpEF and CMD had larger LAVi [mean difference (MD) 3.85 confidence interval (CI) 1.19–6.5, P

Bony hemangiomas are benign vascular lesions with an expansive growth; usually they tend to obliterate the entire bony cavity. They are typical lesion of the spinal bones, but they can rarely arise within other bones of the neurocranium. Diabetic microangiopathy is a condition characterized by the development of aberrant vessel tangles anastomosed to each other due to dysregulated neoangiogenesis. We report the case of a 56-year-old woman, suffering from type 2 diabetes mellitus, admitted to the neurology department due to a reported worsening of paresthesias and dysesthesias of the upper and lower limbs. She performed a contrast-enhanced brain CT scan that showed the presence, at the level of the right mastoid process, of an hypervascular angioma. A subsequent MRI study of the brain and spine showed the presence of multiple bone angiomas, at the level of the right frontal theca and C7, Th3, and Th7 vertebral bodies. Due to the absence of further symptoms and clinical and radiological signs of intracranial compression, the patient did not perform surgery. A radiological follow-up was advised. Although possible pathophysiological correlations between diabetes and vertebral hemangiomas are mentioned in literature, vascular lesions of this type involving vertebrae and skull base simultaneously can be discovered in a patient with chronic diabetic disease. As long as these lesions remain asymptomatic, surgical treatment is not indicated, and the patient is followed over time with radiological follow-up.

Abstract Introduction People with Parkinson’s Disease (PD) show abnormal gait patterns compromising their independence and quality of life. Among all gait alterations due to PD, reduced step length, increased cadence, and decreased ground-reaction force during the loading response and push-off phases are the most common. Wearable biofeedback technologies offer the possibility to provide correlated single or multi-modal stimuli associated with specific gait events or gait performance, hence promoting subjects’ awareness of their gait disturbances. Moreover, the portability and applicability in clinical and home settings for gait rehabilitation increase the efficiency in the management of PD. The Wearable Vibrotactile Bidirectional Interface (BI) is a biofeedback device designed to extract gait features in real-time and deliver a customized vibrotactile stimulus at the waist of PD subjects synchronously with specific gait phases. The aims of this study were to measure the effect of the BI on gait parameters usually compromised by the typical bradykinetic gait and to assess its usability and safety in clinical practice. Methods In this case series, seven subjects (age: 70.4 ± 8.1 years; H&Y: 2.7 ± 0.3) used the BI and performed a test on a 10-meter walkway (10mWT) and a two-minute walk test (2MWT) as pre-training (Pre-trn) and post-training (Post-trn) assessments. Gait tests were executed in random order with (Bf) and without (No-Bf) the activation of the biofeedback stimulus. All subjects performed three training sessions of 40 min to familiarize themselves with the BI during walking activities. A descriptive analysis of gait parameters (i.e., gait speed, step length, cadence, walking distance, double-support phase) was carried out. The 2-sided Wilcoxon sign-test was used to assess differences between Bf and No-Bf assessments (p

The black hole sign (BHS) is a rare radiological sign seen in the hyperacute phase of bleeding. It manifests within a hemorrhage in early hours, with limited studies exploring clot formation and evolution over a short duration. Despite various hypothesized mechanisms, the precise lifetime and dynamics of black hole sign development remain unclear. We describe the rare finding of a black hole sign within a deep brain hemorrhage, initially observed in the lateral portion of the clot during the first CT scan. Remarkably, in a subsequent CT scan, just 1 hour later, the BHS migrated towards the inner edge. Notably, while the hemorrhage size remained largely unchanged within this short timeframe, hyperacute bleeding led to increased perihematomal edema and sulci flattening. Histopathological features of the “evolving clot” are initially characterized by heightened cellularity. This increased cell density renders the hematoma less resistant to compressive forces, such as heightened endocranial pressure, offering a plausible explanation for the crushing and displacement of the BHS. Our study sheds light on the unique radiological progression of BHS within a deep brain ICH, emphasizing its association with dynamic clot formation and the consequential impact on surrounding structures.

Background: Conventional treatment options for end-stage heart failure (ESHF) in children include heart transplantation (HT) and ventricular assist devices (VADs), both with significant drawbacks in the pediatric population. Pulmonary artery banding (PAB) has been effectively used as bridge to transplant or recovery in pediatric ESHF. We herein describe the early and mid-term clinical outcomes from a multicenter international experience. Methods: This is a multicenter retrospective study including children admitted for ESHF caused by dilated cardiomyopathy and treated with PAB. The primary outcome was the freedom from death/VAD/HT. Results: Thirty-one patients (median age 210 days [131-357]) with ESHF underwent PAB in 5 centers. Pediatric Interagency Registry for Mechanically Assisted Circulatory Support (PEDIMACS) score was I to III in 90%; 15 patients were intubated preoperatively. Preoperative left ventricular (LV) ejection fraction was

Focused parathyroidectomy is the preferred surgical method for treating primary hyperparathyroidism (pHPT) sustained by the pre-operatively well-localized parathyroid adenoma. We aimed to compare the effectiveness, safety, and short-term clinical outcome of minimally invasive video-assisted parathyroidectomy (MIVAP) in locoregional anaesthesia (LA) vs. general anaesthesia (GA) by means of propensity score matching (PSM) analysis. Retrospective research of patients who underwent MIVAP between January 2014 and December 2022 was carried out. Patients were divided into two groups based on the anaesthesiologic procedure (LA vs. GA). Overall, 553 patients underwent MIVAP. After PSM, 115 patients in the LA group and 230 patients in the GA group were included. MIVAP under LA was associated with shorter median operative time (16 vs. 35 min, p < 0.001), shorter median operative room occupation time (44 vs. 73 min, p < 0.001), and lesser median post-operative visual analogue scale pain, with comparable post-operative hospital stay and complication rate. MIVAP under LA is a safe and feasible procedure with significant advantages over GA in terms of post-operative pain and operative room occupation time. This last step can finally result in more efficient utilisation of the operative room and the health care system’s resources.

Abstract Artificial Intelligence has the potential to reshape the landscape of clinical trials through innovative applications, with a notable advancement being the emergence of synthetic patient generation. This process involves simulating cohorts of virtual patients that can either replace or supplement real individuals within trial settings. By leveraging synthetic patients, it becomes possible to eliminate the need for obtaining patient consent and creating control groups that mimic patients in active treatment arms. This method not only streamlines trial processes, reducing time and costs but also fortifies the protection of sensitive participant data. Furthermore, integrating synthetic patients amplifies trial efficiency by expanding the sample size. These straightforward and cost‐effective methods also enable the development of personalized subject‐specific models, enabling predictions of patient responses to interventions. Synthetic data holds great promise for generating real‐world evidence in clinical trials while upholding rigorous confidentiality standards throughout the process. Therefore, this study aims to demonstrate the applicability and performance of these methods in the context of onco‐hematological research, breaking through the theoretical and practical barriers associated with the implementation of artificial intelligence in medical trials.

Abstract Aims Chimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy. Methods Patients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers. Results Incidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01). Conclusions There is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised. Graphical Abstract

A highly specific AXL-receptor targeted family of non-immunoglobulin, single domain protein binders (Pronectins™) have been isolated from three (3) synthetic libraries that employ the human scaffold of the 14th domain of Fibronectin III (14FN3) and evolutionary CDRs diversity of over 25 billion loop sequences. The three libraries, each containing diversity in two loops, were designed to expand upon a human database of more than 6000 natural scaffold sequences and approximately 3000 human loop sequences. We used a bioinformatic-based approach to maximize "human" amino acid loop diversity and minimize or prevent altogether CDR immunogenicity created by the use of mutagenesis processes to generate diversity. A combination of phage display and yeast display was used to isolate 59 AXL receptor targeted Pronectins with KD ranging between 2 and 100 nM. FACS analysis with tumor cells over-expressing AXL and the use of an AXL knock-out cell line allowed us to identify Pronectin candidates with exquisite specificity for AXL receptor. Based upon several in vitro cell-based tests, we selected the best candidate, AXL54, to further characterize its in vitro cancer cells killing activity. Finally, AXL54 was used to produce the first bi-specific T cell engager protein (AXL54 [Pronectin]-linker-scFV CD3), a "new in class" protein for further testing of its anti-tumor activity in vitro and in vivo.

BackgroundBased on findings from other contexts, informed by intergroup contact theory, that more contact is associated with less stigma, we hypothesized that community members with greater exposure to cases of Ebola virus disease (EVD) were less likely to report EVD-related stigma towards EVD survivors. We assessed personal stigmatizing attitudes towards Ebola survivors, which reflects personal fear and judgement, as well as perceived stigma towards EVD survivors, which reflects an individual's perception of the attitudes of the community towards a stigmatized group.MethodsFrom September 2016 to July 2017, we conducted a cross-sectional, community-based study of EVD-related stigma among individuals who did not contract Ebola in four EVD-affected rural communities of Kono District, Sierra Leone. We identified individuals from all quarantined households and obtained a random sample of those who were unexposed. Exposed individuals either lived in a quarantined household or were reported to have been in contact with an EVD case. Our explanatory variable was proximity to an EVD case during the outbreak. Our primary outcome was stigma towards EVD survivors, measured by a 6-item adapted HIV-related stigma index validated in Zambia and South Africa, with 1 item reflecting personal stigmatizing attitudes and 5 items reflecting perceived community stigma. The 6-item EVD stigma index had good internal consistency (Cronbach's alpha=0.82). We used modified Poisson and negative binomial regression models, adjusting for potential confounders, to estimate the association between exposure proximity and EVD stigma.ResultsWe interviewed 538 participants aged 12 to 85 years. Most (57%) had been quarantined. Over one-third (39%) reported personal stigmatizing attitudes or perceived community stigma; the most frequently endorsed item was fear and judgment towards EVD survivors. Having contact with someone with EVD was significantly associated with a lower likelihood of perceived community stigma (prevalence ratio [PR], 0.26; 95% CI, 0.13-0.54) and personal stigmatizing attitudes (PR, 0.44; 95% CI, 0.29-0.65). In contrast, being quarantined was significantly associated with a higher likelihood of perceived community stigma (PR, 3.9; 95% CI, 1.5-10.1).ConclusionsIn this cross-sectional study, we found evidence of an inverse relationship between EVD-related stigma and contact with an EVD case. This finding substantiates intergroup contact theory and may form the basis for anti-stigma interventions.

Divertor components for ITER and even beyond will be subjected to cyclic steady state heat loads with a duration of several minutes to hours, repeatedly occurring slow transients during reattachment or ramp-up and down, as well as heat loads during ELMs applying a combination of low cycle fatigue and creep as well as high cycle fatigue via thermal shock loads. While for the qualification of components the duration of the fatigue cycles up to now has been kept small, i.e., close to the required time to reach thermal saturation which is 10 s for typical divertor components, creep in these components has not yet been assessed.In this study divertor tungsten monoblock mock-up manufactured via hot radial pressing in the ITER-like geometry consisting of 4 monoblocks and quality checked via ultrasonic testing are exposed to high heat flux loads in the electron beam facility JUDITH 2 using a high temperature cooling circuit with controlled water chemistry. Thereby, cyclic loads up to 1000 cycles with a duration of 10 to 600 s and a power density of 20 MW/m2 were applied, representing strike point loading conditions in DEMO during strike point sweeping scenarios. Each of the tungsten monoblocks is loaded individually providing the possibility to study different scenarios on one single mock-up. The aim is to assess the performance and degradation of performance due to the applied loads, which is supported by characterization via metallography, profilometry, SEM and hardness testing after the high heat flux tests.

Background: Chin-on-chest deformity is a rare and severely disabling condition characterized by kyphotic deformity in the cervicothoracic spine. To treat this deformity, various osteotomy techniques were described. Methods: A comprehensive literature search of biomedical databases including MEDLINE (via PubMed), Scopus (via Elsevier), Embase (via Elsevier), and Cochrane Library in English from 1/1/1990 to 3/31/2022 was conducted using a combination of text and Medical Subject Headings (MeSH). Results: The final analysis included 16 studies. All the studies were assigned a level of evidence of four. Except for two articles, all of the articles were non-comparative studies. A total of 288 patients were included in this review. Of the 288 patients, 107 underwent posterior column extension osteotomy (PCEO), 108 underwent pedicle subtraction osteotomy (PSO), and 33 underwent vertebral column resection osteotomy (VCRO). The most common osteotomy level in fifteen of the studies was C7/T1. The studies included in this review described several techniques for cervical sagittal balance correction. The range of preoperative and postoperative visual analogue scale (VAS) scores was 5.5–8.6 to 1.7–4.91, respectively. The range of preoperative and postoperative neck disability index (NDI) was 34.2–65.4 to 22.1–51.3, respectively. The most common complications were upper extremity paresthesia and hand numbness through the C8 dermatome distribution. Conclusions: Corrective osteotomies provide satisfactory results in patients with chin-on-chest deformity; however, the quality of the included studies limits the evidence.

The final steps of the O2 cascade during exercise depend on the product of the microvascular-to-intramyocyte PO2${P}_{{{\rm{O}}}_{\rm{2}}}$ difference and muscle O2 diffusing capacity ( DmO2$D{{\rm{m}}}_{{{\rm{O}}}_2}$ ). Non-invasive methods to determine DmO2$D{{\rm{m}}}_{{{\rm{O}}}_2}$ in humans are currently unavailable. Muscle oxygen uptake (m V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ) recovery rate constant (k), measured by near-infrared spectroscopy (NIRS) using intermittent arterial occlusions, is associated with muscle oxidative capacity in vivo. We reasoned that k would be limited by DmO2$D{{\rm{m}}}_{{{\rm{O}}}_2}$ when muscle oxygenation is low (kLOW ), and hypothesized that: (i) k in well oxygenated muscle (kHIGH ) is associated with maximal O2 flux in fibre bundles; and (ii) ∆k (kHIGH  - kLOW ) is associated with capillary density (CD). Vastus lateralis k was measured in 12 participants using NIRS after moderate exercise. The timing and duration of arterial occlusions were manipulated to maintain tissue saturation index within a 10% range either below (LOW) or above (HIGH) half-maximal desaturation, assessed during sustained arterial occlusion. Maximal O2 flux in phosphorylating state was 37.7 ± 10.6 pmol s-1  mg-1 (∼5.8 ml min-1  100 g-1 ). CD ranged 348 to 586 mm-2 . kHIGH was greater than kLOW (3.15 ± 0.45 vs. 1.56 ± 0.79 min-1 , P < 0.001). Maximal O2 flux was correlated with kHIGH (r = 0.80, P = 0.002) but not kLOW (r = -0.10, P = 0.755). Δk ranged -0.26 to -2.55 min-1 , and correlated with CD (r = -0.68, P = 0.015). m V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ k reflects muscle oxidative capacity only in well oxygenated muscle. ∆k, the difference in k between well and poorly oxygenated muscle, was associated with CD, a mediator of DmO2$D{{\rm{m}}}_{{{\rm{O}}}_2}$ . Assessment of muscle k and ∆k using NIRS provides a non-invasive window on muscle oxidative and O2 diffusing capacity. KEY POINTS: We determined post-exercise recovery kinetics of quadriceps muscle oxygen uptake (m V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ) measured by near-infrared spectroscopy (NIRS) in humans under conditions of both non-limiting (HIGH) and limiting (LOW) O2 availability, for comparison with biopsy variables. The m V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ recovery rate constant in HIGH O2 availability was hypothesized to reflect muscle oxidative capacity (kHIGH ) and the difference in k between HIGH and LOW O2 availability (∆k) was hypothesized to reflect muscle O2 diffusing capacity. kHIGH was correlated with phosphorylating oxidative capacity of permeabilized muscle fibre bundles (r = 0.80). ∆k was negatively correlated with capillary density (r = -0.68) of biopsy samples. NIRS provides non-invasive means of assessing both muscle oxidative and oxygen diffusing capacity in vivo.