Inotuzumab ozogamicin in adult acute lymphoblastic leukemia: Development, current status, and future directions.

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use.

Ruptured traumatic pseudoaneurysm of the middle cerebral artery following minor trauma treated with an MCA-MCA bypass: A case report.

Background: Traumatic middle cerebral artery (MCA) pseudoaneurysms following minor head trauma are rare. Case Description: We report a case of a 76-year-old man who presented with a traumatic acute subdural hematoma and subarachnoid hemorrhage (SAH) from a ruptured distal right MCA pseudoaneurysm treated with evacuation of the hematoma, resection of the pseudoaneurysm, and an MCA-to-MCA bypass. Conclusion: Although traumatic pseudoaneurysms of the distal intracranial vessels are rare, patients with traumatic SAH would benefit from vascular imaging. Treatment of pseudoaneurysms of distal intracranial vessels may be treated with vessel occlusion or trapping/excision of aneurysm with revascularization.

Impact of duration of dual anti-platelet therapy on risk of complications after stent-assisted coiling of unruptured aneurysms.

BACKGROUND: The optimal duration for dual antiplatelet therapy (DAPT) after stent-assisted coiling (SAC) of intracranial aneurysms is unclear. Longer-term therapy may reduce thrombotic complications but increase the risk of bleeding complications. METHODS: A retrospective review of prospectively maintained data at 12 institutions was conducted on patients with unruptured intracranial aneurysms who underwent SAC between January 1, 2016 and December 31, 2020, and were followed ≥6 months postprocedure. The type and duration of DAPT, stent(s) used, outcome, length of follow-up, complication rates, and incidence of significant in-stent stenosis (ISS) were collected. RESULTS: Of 556 patients reviewed, 450 met all inclusion criteria. Nine patients treated with DAPT <29 days after SAC and 11 treated for 43-89 days were excluded from the final analysis as none completed their prescribed duration of treatment. Eighty patients received short-term DAPT. There were no significant differences in the rate of thrombotic complications during predefined periods of risk in the short, medium, or long-term treatment groups (1/80, 1.3%; 2/188, 1.1%; and 0/162, 0%, respectively). Similarly, no differences were found in the rate of hemorrhagic complications during period of risk in any group (0/80, 0%; 3/188, 1.6%; and 1/162, 0.6%, respectively). Longer duration DAPT did not reduce ISS risk in any group. CONCLUSIONS: Continuing DAPT >42 days after SAC did not reduce the risk of thrombotic complications or in-stent stenosis, although the risk of additional hemorrhagic complications remained low. It may be reasonable to discontinue DAPT after 42 days following non-flow diverting SAC of unruptured intracranial aneurysms.

Trends and socioeconomic inequalities in the dental attendance of adult smokers in Scotland from 2009 to 2019, a repeated cross-sectional study.

BACKGROUND: Smoking continues to be the single largest cause of preventable disease and death and a major contributor to health inequalities. Dental professionals are well placed to offer behavioural support in combination with pharmacotherapy to increase smoking cessation rates across the population. We aimed to assess the trends and socioeconomic inequalities in the dental attendance of adult smokers in Scotland from 2009 to 2019 and examine the potential population reach of dental settings for smoking cessation interventions. METHODS: A secondary analysis was conducted of combined Scottish Health Surveys (SHeS) from 2009/11, 2013/15 and 2017/19. 'Recent' dental attendance (within the past two years) was the focus and descriptive analysis examined attendance of self-reported smokers compared to non-smokers and stratified by the area-based Scottish Index of Multiple Deprivation (SIMD) and individual socioeconomic measures (income, education, and occupation). Generalised linear models were used to model recent attendance in non-smokers relative to smokers adjusted by the socioeconomic measures, for each of the survey cohorts separately. Absolute differences and risk ratios were calculated with 95% Confidence Intervals (CI). RESULTS: Recent dental attendance was generally high and increased in both smokers (70-76%) and non-smokers (84-87%) from 2009/11 to 2017/19 and increased across all SIMD groups. After adjustment for sociodemographic variables, the adjusted Risk Difference (aRD) for recent attendance between non-smokers and smokers was 8.9% (95% CI 4.6%, 13.2%) by 2017/19. Within smokers, recent attendance was 7-9% lower in those living in the most deprived areas compared to those living in the least deprived areas over the three surveys. CONCLUSIONS: SHeS data from 2009 to 2019 demonstrated that a high and increasing proportion of smokers in the population attend the dentist, albeit slightly less frequently than non-smokers. There were large inequalities in the dental attendance of smokers, to a lesser extent in non-smokers, and these persisted over time. Dental settings provide a good potential opportunity to deliver population-level smoking cessation interventions, but smokers in the most deprived groups and older age groups may be harder to reach. Consideration should be given to ensure that these groups are given appropriate proportionate support to take up preventive interventions.

Immunogenicity of Abdala COVID-19 vaccine in Vietnamese people after primary and booster vaccinations: a prospective observational study in Vietnam.

OBJECTIVES: We studied the immunogenicity after primary and booster vaccinations of Abdala COVID-19 vaccine, a receptor binding domain protein subunit vaccine, in Vietnamese people by determining the level of neutralization and cross-neutralization activities against the ancestral SARS-CoV-2 and its variants, and SARS-CoV-1. METHODS: We performed a prospective observational study, enrolling adults aged 19-59 years in Dong Thap province, southern Vietnam, and collected blood samples from baseline until 4 weeks post booster dose. We measured anti-nucleocapsid, anti-spike and neutralizing antibodies against SARS-CoV-2, and assessed the cross-neutralization against 14 SARS-CoV-2 variants, and SARS-CoV-1. Complementary antibody data came from Vietnamese healthcare workers fully vaccinated with ChAdOx1-S. RESULTS: After primary vaccination, anti-spike antibody and neutralizing antibodies were detectable in 98.4% and 87% of 251 study participants, respectively, with neutralizing antibody titers similar to that induced by ChAdOx1-S vaccine. Antibody responses after a homologous (Abdala COVID-19) or heterologous (mRNA BNT162b2) booster could neutralize 14 SARS-CoV-2 variants (including Omicron), and SARS-CoV-1. CONCLUSIONS: Abdala COVID-19 vaccine is immunogenic in Vietnamese people. Enhanced antibody response after a booster dose could cross-neutralize 14 SARS-CoV-2 variants and SARS-CoV-1. Our results have added to the growing body of knowledge about the contribution of protein subunit vaccine platforms to pandemic control.

Internalized Shame Among Justice-Involved Women in Substance Use Disorder Treatment: Measurement Invariance and Changes During Treatment.

Shame is one of the leading barriers to successful recovery in substance use treatment settings. This secondary analysis study examined measurement invariance of the Internalized Shame Scale (ISS) and explored changes in shame during treatment. Participants (N=105) in the parent study were recruited from a nonprofit residential treatment center for justice-involved women and were randomized to receive mindfulness-based relapse prevention or relapse prevention treatment. A series of confirmatory factor analyses were used to assess measurement invariance in a one-factor measurement model of the ISS. Latent growth curve modeling was used to examine change in shame over time. Our findings support the assumption of measurement invariance across multiple time points and across treatment conditions, supporting comparisons of stigma scores across groups and over time. Although we observed significant reductions in shame from pre- to post-treatment, there were no differences across treatment conditions. Additional research is needed to determine how distinct treatment components relate to reductions in shame among individuals receiving treatment for a substance use disorder.

Autonomous stabilization with programmable stabilized state.

Reservoir engineering is a powerful technique to autonomously stabilize a quantum state. Traditional schemes involving multi-body states typically function for discrete entangled states. In this work, we enhance the stabilization capability to a continuous manifold of states with programmable stabilized state selection using multiple continuous tuning parameters. We experimentally achieve 84.6% and 82.5% stabilization fidelity for the odd and even-parity Bell states as two special points in the manifold. We also perform fast dissipative switching between these opposite parity states within 1.8 µs and 0.9 µs by sequentially applying different stabilization drives. Our result is a precursor for new reservoir engineering-based error correction schemes.

Piloting wastewater-based surveillance of norovirus in England.

Wastewater-based epidemiology (WBE) gained widespread use as a tool for supporting clinical disease surveillance during the COVID-19 pandemic. There is now significant interest in the continued development of WBE for other pathogens of clinical significance. In this study, approximately 3,200 samples of wastewater from across England, previously collected for quantification of SARS-CoV-2, were re-analysed for the quantification of norovirus genogroup I (GI) and II (GII). Overall, GI and GII were detected in 93% and 98% of samples respectively, and at least one of the genogroups was detected in 99% of samples. GI was found at significantly lower concentrations than GII, but the proportion of each genogroup varied over time, with GI becoming more prevalent than GII in some areas towards the end of the study period (May 2021 - March 2022). Using relative strength indices (RSI), it was possible to study the trends of each genogroup, and total norovirus over time. Increases in norovirus levels appeared to coincide with the removal of COVID-19 related lockdown restrictions within England. Local Moran's I analyses indicated several localised outbreaks of both GI and GII across England, notably the possible GI outbreak in the north of England in early 2022. Comparisons of national average norovirus concentrations in wastewater against concomitant norovirus reported case numbers showed a significant linear relationship. This highlights the potential for wastewater-based monitoring of norovirus as a valuable approach to support surveillance of norovirus in communities.

Genetic parameters of feeding behaviour traits in ducks bred for foie gras production.

The mule duck accounts for over 90% of French foie gras production, a sector where feed represents two-thirds of production costs. This study focuses on analysing the feeding behaviours of the mule duck and its parental populations (Pekin and Muscovy) using automated feeders. To assess feed efficiency, feed conversion ratio and residual feed intake were analysed, along with six traits derived at the daily and meal levels. Genetic parameters were estimated separately in purebred populations, as well as with a joint crossbred model that estimated the parental contributions to the hybrid crossbred performances. In relation to higher feed intakes and much-reduced feeding times (P < 0.001), the feeding rate in the Pekin population was twice as high as in the Muscovy population (19 g/min vs 9 g/min), while the mule duck exhibited a large heterosis for this trait (29 g/min). Feeding traits exhibited moderate (0.38 ± 0.11) to high (0.65 ± 0.11) heritabilities. Similar correlation patterns were observed between feeding traits in the two parental populations. In the Pekin line, the feed conversion ratio did not significantly correlate with feeding traits except for daily feed intake. However, in the Muscovy population, it was negatively correlated with the number of meals (-0.51 ± 0.21) and positively with meal feed intake and meal duration (+0.79 ± 0.17 and + 0.71 ± 0.26, respectively). The contributions of the two parental species to the hybrid's performance differed, with the Pekin contributing more to feeding and meat traits compared to the Muscovy. They were similar only for liver weight. Additionally, unfavourable correlations between meat traits and liver traits were estimated in both pathways. Genetic relationships between feeding traits and slaughter traits varied by parental origin, suggesting different strategies for improving hybrid performance in the two parental species. However, in both pathways, genetic correlations between feed conversion ratio and meat traits (breast muscle and thigh weights) were favourable (<-0.42 ± 0.18), whereas they were unfavourable (>0.41 ± 0.20) for fatty liver weight. Altogether, improving liver traits and feed efficiency in the hybrid through selection in the parental populations could be enhanced by considering feeding traits recorded with electronic feeders, provided that adverse correlations are properly accounted for in a multitrait index.

Small Animal Models to Study Herpes Simplex Virus Infections.

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two of the most prevalent human viruses worldwide. They are known to cause a variety of diseases including genital herpes, meningitis, encephalitis, cold sores and herpes stromal keratitis. The seropositive rate for HSV-1 is around 90%, whereas for HSV-2 it remains around 20-25% for the general adult population. The infections caused by these viruses remain difficult to study because a large proportion of infected individuals are asymptomatic. Furthermore, given the neurotropic characteristics of the virus, studies aimed at understanding the complex pathogenesis in humans is difficult. As a result, animal models have been developed to understand several characteristics of HSV biology, pathogenesis, disease and host responses to infection. These models are also commonly used as the first evaluation of new drugs and vaccines. There are several well-established animal models to study infection with HSV, including mice, guinea pigs and rabbits. Variables within the animal models depend on the species of animal, route of infection, viral strain, dosage, etc. This review aims at summarizing the most commonly used animal models to study HSV pathogenesis and therapies.

Scaling up noncommunicable disease care in a resource-limited context: lessons learned and implications for policy.

BACKGROUND: Although primary care models for the care of common non-communicable diseases (NCD) have been developed in sub-Saharan Africa, few have described an integrated, decentralized approach at the community level. We report the results of a four-year, Ethiopian project to expand this model of NCD care to 15 primary hospitals and 45 health centres encompassing a wide geographical spread and serving a population of approximately 7.5 million people. METHODS: Following baseline assessment of the 60 sites, 30 master trainers were used to cascade train a total of 621 health workers in the diagnosis, management and health education of the major common NCDs identified in a scoping review (hypertension, diabetes, chronic respiratory disease and epilepsy). Pre- and post-training assessments and regular mentoring visits were carried out to assess progress and remedy supply or equipment and medicines shortages and establish reporting systems. The project was accompanied by a series of community engagement activities to raise awareness and improve health seeking behaviour. RESULTS: A total of 643,296 people were screened for hypertension and diabetes leading to a new diagnosis in 24,313 who were started on treatment. Significant numbers of new cases of respiratory disease (3,986) and epilepsy (1,925) were also started on treatment. Mortality rates were low except among patients with hypertension in the rural health centres where 311 (10.2%) died during the project. Loss to follow up (LTFU), defined as failure to attend clinic for > 6 months despite reminders, was low in the hospitals but represented a significant problem in the urban and rural health centres with up to 20 to 30% of patients with hypertension or diabetes absenting from treatment by the end of the project. Estimates of the population disease burden enrolled within the project, however, were disappointing; asthma (0.49%), hypertension (1.7%), epilepsy (3.3%) and diabetes (3.4%). CONCLUSION: This project demonstrates the feasibility of scaling up integrated NCD services in a variety of locations, with fairly modest costs and a methodology that is replicable and sustainable. However, the relatively small gain in the detection and treatment of common NCDs highlights the huge challenge in making NCD services available to all.

Tetrameric, active PKM2 inhibits IP3 receptors, potentially requiring GRP75 as an additional interaction partner.

Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme interacting with the inositol 1,4,5-trisphosphate receptor (IP3R). This interaction suppresses IP3R-mediated cytosolic [Ca2+] rises. As PKM2 exists in monomeric, dimeric and tetrameric forms displaying different properties including catalytic activity, we investigated the molecular determinants of PKM2 enabling its interaction with IP3Rs. Treatment of HeLa cells with TEPP-46, a compound stabilizing the tetrameric form of PKM2, increased both its catalytic activity and the suppression of IP3R-mediated Ca2+ signals. Consistently, in PKM2 knock-out HeLa cells, PKM2C424L, a tetrameric, highly active PKM2 mutant, but not inactive PKM2K270M or the less active PKM2K305Q, suppressed IP3R-mediated Ca2+ release. Surprisingly, however, in vitro assays did not reveal a direct interaction between purified PKM2 and either the purified Fragment 5 of IP3R1 (a.a. 1932-2216) or the therein located D5SD peptide (a.a. 2078-2098 of IP3R1), the presumed interaction sites of PKM2 on the IP3R. Moreover, on-nucleus patch clamp of heterologously expressed IP3R1 in DT40 cells devoid of endogenous IP3Rs did not reveal any functional effect of purified wild-type PKM2, mutant PKM2 or PKM1 proteins. These results indicate that an additional factor mediates the regulation of the IP3R by PKM2 in cellulo. Immunoprecipitation of GRP75 using HeLa cell lysates co-precipitated IP3R1, IP3R3 and PKM2. Moreover, the D5SD peptide not only disrupted PKM2:IP3R, but also PKM2:GRP75 and GRP75:IP3R interactions. Our data therefore support a model in which catalytically active, tetrameric PKM2 suppresses Ca2+ signaling via the IP3R through a multiprotein complex involving GRP75.

Factors affecting the non-publication of clinical trials of prevalent urological cancer.

OBJECTIVES: Clinical trials (CTs) are critical in understanding and managing cancer. However, despite being completed, CT results are often unpublished, compromising the ability to glean useful information from them. This study aimed to evaluate factors influencing the non-publication of urological oncology clinical trials. METHODOLOGY: We conducted a comprehensive search of ClinicalTrials.gov to identify CTs focused on urological cancers completed between 2000 and 2020. We used the National Clinical Trial (NCT) identifier number to check whether the trial was published. RESULTS: 9,145 oncology CTs were conducted between 2000 and 2020, of which 8.39% (n = 767) focused on urological cancers, and 47.2% (n = 362) of these trials remained unpublished. Univariable analysis revealed that trials with a sample size of less than 50 and phase 4 were significantly associated with non-publication p < 0.001. In contrast, trials involving triple masking, a higher number of agents, and those conducted in High-Income Countries were associated with a higher likelihood of publication p < 0.05. Multivariable analysis demonstrated that trials enrolling more than 50 patients and employing three or more agents, along with triple and quadruple masking, had higher odds of being published (OR = 1.62; 95%CI (1.22-2.16), 1.89; 95%CI (1.10-3.27), 3.04; 95%CI (1.44-6.44), 5.62; 95%CI (1.72-18.37), and 5.41; 95%CI (1.76-16.67), p < 0.05, respectively). However, trials conducted in low-middle-income Countries had lower odds of publication (OR = 0.26; 95%CI (0.08-0.87), p = 0.02). CONCLUSION: We found that almost one-half (47.2%) of all completed urologic oncology clinical trials are not published in a PubMed-indexed journal. This non-publication rate represents a significant loss of scientific knowledge and progress. We identified several key variables including sample size.

Improved efficacy of pembrolizumab combined with soluble EphB4-albumin in HPV-negative EphrinB2 positive head neck squamous cell carcinoma.

OBJECTIVE: Patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need. METHODS: This is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome. RESULTS: Twenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities. DISCUSSION: The combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

Neural correlates of motor imagery and execution in real-world dynamic behavior: evidence for similarities and differences.

A large body of evidence shows that motor imagery and action execution behaviors result from overlapping neural substrates, even in the absence of overt movement during motor imagery. To date it is unclear how neural activations in motor imagery and execution compare for naturalistic whole-body movements, such as walking. Neuroimaging studies have not directly compared imagery and execution during dynamic walking movements. Here we recorded brain activation with mobile EEG during walking compared to during imagery of walking, with mental counting as a control condition. We asked 24 healthy participants to either walk six steps on a path, imagine taking six steps, or mentally count from one to six. We found beta and alpha power modulation during motor imagery resembling action execution patterns; a correspondence not found performing the control task of mental counting. Neural overlap occurred early in the execution and imagery walking actions, suggesting activation of shared action representations. Remarkably, a distinctive walking-related beta rebound occurred both during action execution and imagery at the end of the action suggesting that, like actual walking, motor imagery involves resetting or inhibition of motor processes. However, we also found that motor imagery elicits a distinct pattern of more distributed beta activity, especially at the beginning of the task. These results indicate that motor imagery and execution of naturalistic walking involve shared motor-cognitive activations, but that motor imagery requires additional cortical resources.

Investigating the Brain Mechanisms of Externally Cued Sit-to-Stand Movement in Parkinson's Disease.

BACKGROUND: One of the more challenging daily-life actions for Parkinson's disease patients is starting to stand from a sitting position. Parkinson's disease patients are known to have difficulty with self-initiated movements and benefit from external cues. However, the brain processes underlying external cueing as an aid remain unknown. The advent of mobile electroencephalography (EEG) now enables the investigation of these processes in dynamic sit-to-stand movements. OBJECTIVE: To identify cortical correlates of the mechanisms underlying auditory cued sit-to-stand movement in Parkinson's disease. METHODS: Twenty-two Parkinson's disease patients and 24 healthy age-matched participants performed self-initiated and externally cued sit-to-stand movements while cortical activity was recorded through 32-channel mobile EEG. RESULTS: Overall impaired integration of sensory and motor information can be seen in the Parkinson's disease patients exhibiting less modulation in the θ band during movement compared to healthy age-matched controls. How Parkinson's disease patients use external cueing of sit-to-stand movements can be seen in larger high ß power over sensorimotor brain areas compared to healthy controls, signaling sensory integration supporting the maintenance of motor output. This appears to require changes in cognitive processing to update the motor plan, reflected in frontal θ power increases in Parkinson's disease patients when cued. CONCLUSION: These findings provide the first neural evidence for why and how cueing improves motor function in sit-to-stand movement in Parkinson's disease. The Parkinson's disease patients' neural correlates indicate that cueing induces greater activation of motor cortical areas supporting the maintenance of a more stable motor output, but involves the use of cognitive resources to update the motor plan. © 2024 International Parkinson and Movement Disorder Society.

Tissue Engineered 3D Constructs for Volumetric Muscle Loss.

Severe injuries to skeletal muscles, including cases of volumetric muscle loss (VML), are linked to substantial tissue damage, resulting in functional impairment and lasting disability. While skeletal muscle can regenerate following minor damage, extensive tissue loss in VML disrupts the natural regenerative capacity of the affected muscle tissue. Existing clinical approaches for VML, such as soft-tissue reconstruction and advanced bracing methods, need to be revised to restore tissue function and are associated with limitations in tissue availability and donor-site complications. Advancements in tissue engineering (TE), particularly in scaffold design and the delivery of cells and growth factors, show promising potential for regenerating damaged skeletal muscle tissue and restoring function. This article provides a brief overview of the pathophysiology of VML and critiques the shortcomings of current treatments. The subsequent section focuses on the criteria for designing TE scaffolds, offering insights into various natural and synthetic biomaterials and cell types for effectively regenerating skeletal muscle. We also review multiple TE strategies involving both acellular and cellular scaffolds to encourage the development and maturation of muscle tissue and facilitate integration, vascularization, and innervation. Finally, the article explores technical challenges hindering successful translation into clinical applications.