Slow Progression Research Articles

A classification algorithm for prioritizing surgery in Pediatric patients with idiopathic scoliosis when Long Surgical delays are expected.

To identify the clinical phenotypes associated with the rate of progression while waiting for surgery and propose a classification scheme for identifying subgroups of patients to prioritize for surgery when long surgical delays are expected. We reviewed the clinical and radiographic data of a prospective cohort of patients scheduled for IS surgery from 2004 to 2020 with a minimum 1-year wait prior to surgery. Candidate predictors consisted of age, sex, Risser sign, menarchal status, angle of trunk rotation, scoliotic curve type, and main Cobb angle at baseline when scheduled for surgery. Univariate and Regression Tree analysis were performed to identify predictors associated with the annual curve progression rate in the main Cobb angle between baseline and surgery. There were 214 patients (178 females) aged 15 ± 2 years, with a Risser sign 3.4 ± 1.6 and a main Cobb angle 55°±10° at baseline. The average wait prior to surgery was 1.3 ± 0.4 years. Only the Risser sign, menarchal status and sex were significantly associated with the annual progression rate. We have identified 3 clinically and significantly different groups of patients presenting slow (3 ± 4°/yr if Risser sign 3 to 5), moderate (8 ± 4°/yr if female with Risser sign 0 to 2 and post-menarchal), and fast (15 ± 10°/yr if Risser sign 0 to 2 and premenarchal or male) progression rates. We present an evidence-based surgical prioritization algorithm for pediatric idiopathic scoliosis that can easily be implemented in clinical practice when long surgical delays are expected.

Exploring Angiogenesis and Artificial Intelligence in Alzheimer’s Disease: Implications for Early Detection and Therapeutic Strategies

Background: Alzheimer’s disease (AD) presents a significant global health challenge, affecting millions and imposing substantial socioeconomic burdens, with healthcare costs exceeding US$100 billion annually. The disease's complexity is underscored by its slow progression and the pivotal role of amyloid plaques in its pathology. Despite advancements in understanding AD, critical questions regarding the mechanisms of amyloid plaque development and their relationship with neuroinflammation and angiogenesis remain. Methods: This study employed advanced imaging techniques and artificial intelligence (AI) to investigate the interplay between amyloid beta (Aβ) accumulation, neuroinflammation, and angiogenesis in AD. Magnetic resonance imaging (MRI) facilitated detailed assessments of brain structure alterations, while machine learning models enhanced diagnostic accuracy by analyzing imaging data and identifying patterns linked to disease progression. Results: The findings revealed a significant association between Aβ deposition and increased angiogenesis, contributing to neurovascular dysfunction and exacerbating neuroinflammation. AI-driven analyses demonstrated improved diagnostic capabilities, detecting early changes in brain structure associated with mild cognitive impairment (MCI) and AD. Specifically, convolutional neural networks (CNNs) such as AlzheimerNet achieved remarkable accuracy in distinguishing AD from other neurodegenerative conditions. Conclusion: This research underscores the multifaceted nature of AD, highlighting the critical roles of amyloid plaques, neuroinflammation, and angiogenesis. The integration of AI and advanced imaging modalities offers promising avenues for early diagnosis and intervention, potentially transforming patient management strategies. Continued exploration of these pathways may yield effective therapeutic targets to mitigate the progression of AD and enhance patient outcomes.

Motor progression trajectories and risk of mild cognitive impairment in Parkinson's disease: A latent class trajectory model from PPMI cohort.

Rare studies have investigated the association between heterogeneity of motor progression and risk of early cognitive impairment in Parkinson's disease (PD). In this study, we aim to identify distinct trajectories of motor progression longitudinally and investigate their impact on predicting mild cognitive impairment (MCI). A 5-year cohort including 415 PD patients at baseline was collected from the Parkinson's Progression Markers Initiative. The severity of motor symptoms was evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III. The latent class trajectory model and nonlinear mixed-effects model were used to analyze and delineate the longitudinal changes in motor symptoms. Propensity score matching (PSM) was used to minimize the impact of potential confounders. Cox proportional hazard models were applied to calculate hazard ratios for MCI, and a Kaplan-Meier curve was generated using the occurrence of MCI during the follow-up as the time-to-event. Two latent trajectories were identified: a mild and remitting motor symptoms class (Class 1, 33.01%) and a severe and progressive motor symptom class (Class 2, 66.99%). Patients in Class 2 initially exhibited severe motor symptoms that worsened progressively despite receiving anti-PD medications. In comparison, patients in Class 1 exhibited milder symptoms that improved following drug therapy and a slower progression. During a 5-year follow-up, patients in Class 2 showed a higher risk of developing MCI compared to those in Class 1 before PSM (Log-Rank 28.58, p < 0.001) and after PSM (Log-Rank 8.20, p = 0.004). PD patients with severe and progressive motor symptoms are more likely to develop MCI than those with mild and stable motor symptoms.

VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.

Vacuolar Protein Sorting 35 (VPS35) is pivotal in the retromer complex, governing transmembrane protein trafficking within cells, and its dysfunction is implicated in neurodegenerative diseases. A missense mutation, Asp620Asn (D620N), specifically ties to familial late-onset Parkinson's, while reduced VPS35 levels are observed in Alzheimer's, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and tauopathies. VPS35's absence in certain neurons during development can initiate neurodegeneration, highlighting its necessity for neural health. Present therapeutic research mainly targets the clearance of harmful protein aggregates and symptom management. Innovative treatments focusing on VPS35 are under investigation, although fully understanding the mechanisms and optimal targeting strategies remain a challenge. This review offers a detailed account of VPS35's discovery, its role in neurodegenerative mechanisms - especially in Parkinson's and Alzheimer's - and its link to other disorders. It shines alight on recent insights into VPS35's function in development, disease, and as a therapeutic target. VPS35 is integral to cellular function and disease association, making it a significant candidate for developing therapies. Progress in modulating VPS35's activity may lead to breakthrough treatments that not only slow disease progression but may also act as biomarkers for neurodegeneration risk, marking a step forward in managing these complex conditions.

XOLARIS: A 24-Month, Prospective, Natural History Study of 201 Participants with Retinitis Pigmentosa GTPase Regulator-Associated X-Linked Retinitis Pigmentosa

ObjectiveTo improve the understanding of the natural disease progression of retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP). DesignA multicenter, prospective, observational natural history study over 24 months. ParticipantsMale participants aged ≥7 years with a pathogenic variant in the RPGR gene, a best-corrected visual acuity (BCVA) score of ≥34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and a mean 68-loci retinal sensitivity (assessed by microperimetry) of 0.1–20 decibels (dB). MethodsParticipants were divided into subgroups based on their BCVA score at baseline: 34–73 (lower BCVA) or ≥74 (higher BCVA) ETDRS letters. There were 7 visits over 24 months. Main Outcome MeasuresChange from baseline in BCVA, retinal sensitivity, low luminance visual acuity (LLVA), fixation stability, contrast sensitivity, visual field, anatomical measures, 25-item Visual Function Questionnaire (VFQ-25), intraocular pressure, and adverse events (AEs). ResultsOverall, 201 participants were included. The mean (standard deviation [SD]) age was 30.3 (11.9) years in the lower BCVA subgroup (n=170) and 27.7 (10.1) years in the higher BCVA subgroup (n=31). The study eye baseline mean (SD) BCVA scores were 59.4 (10.30) and 77.3 (3.95) in the lower and higher BCVA subgroups, respectively; the lower BCVA subgroup had lower retinal sensitivity in the study eye at baseline than the higher BCVA subgroup. Over 24 months, there were small observed changes in BCVA, retinal sensitivity, LLVA, fixation, contrast sensitivity, and fundus photography findings. There were observed mean (SD) changes at 24 months in the lower and higher BCVA subgroups of −1.01 (4.67) and 0.03 (5.83) dB-steradians in the volume of full-field hill of vision, −330.6 (869.51) and −122.7 (22.01) μm in distance from foveal center to the nearest border of preserved fundus autofluorescence, −104.3 (277.80) and −207.1 (171.01) μm in central ellipsoid width, and −2.8 (9.7) and −0.6 (7.6) in VFQ-25 composite score, respectively. There was 1 death from completed suicide. There were no ocular serious AEs, and most AEs were mild/moderate. ConclusionsThis study provides evidence of the slow natural progression of XLRP over 24 months in both subgroups and provides important functional, anatomical, and safety data.

Cyclin-dependent kinase 4 drives cystic kidney disease in the absence of mTORC1 signaling activity

Progression of cystic kidney disease has been linked to activation of the mTORC1 signaling pathway. Yet the utility of mTORC1 inhibitors to treat patients with polycystic kidney disease remains controversial despite promising preclinical data. To define the cell intrinsic role of mTORC1 for cyst development, the mTORC1 subunit gene Raptor was selectively inactivated in kidney tubular cells lacking cilia due to simultaneous deletion of the kinesin family member gene Kif3A. In contrast to a rapid onset of cyst formation and kidney failure in mice with defective ciliogenesis, both kidney function, cyst formation discerned by magnetic resonance imaging and overall survival were strikingly improved in mice additionally lacking Raptor. However, these mice eventually succumbed to cystic kidney disease despite mTORC1 inactivation. In-depth transcriptome analysis revealed the rapid activation of other growth-promoting signaling pathways, overriding the effects of mTORC1 deletion and identified cyclin-dependent kinase (CDK) 4 as an alternate driver of cyst growth. Additional inhibition of CDK4-dependent signaling by the CDK4/6 inhibitor Palbociclib markedly slowed disease progression in mice and human organoid models of polycystic kidney disease and potentiated the effects of mTORC1 deletion/inhibition. Our findings indicate that cystic kidneys rapidly adopt bypass mechanisms typically observed in drug resistant cancers. Thus, future clinical trials need to consider combinatorial or sequential therapies to improve therapeutic efficacy in patients with cystic kidney disease.

Novel cathepsin C inhibitor, BI 1291583, intended for treatment of bronchiectasis: Phase I characterization in healthy volunteers.

Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil-derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single-rising-dose study (NCT03414008) and two multiple-rising-dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug-drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug-related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra-proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose-dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co-administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).

Effects of chronic treatment with metformin on brain glucose hypometabolism and central insulin actions in transgenic mice with tauopathy

Brain glucose hypometabolism and insulin alterations are common features of many neurological diseases. Herein we sought to corroborate the brain glucose hypometabolism that develops with ageing in 12-months old Tau-VLW transgenic mice, a model of tauopathy, as well as to determine whether this model showed signs of altered peripheral glucose metabolism. Our results demonstrated that 12-old months Tau mice exhibited brain glucose hypometabolism as well as basal hyperglycemia, impaired glucose tolerance, hyperinsulinemia, and signs of insulin resistance. Then, we further studied the effect of chronic metformin treatment (9 months) in Tau-VLW mice from 9 to 18 months of age. Longitudinal PET neuroimaging studies revealed that chronic metformin altered the temporal profile in the progression of brain glucose hypometabolism associated with ageing. Besides, metformin altered the content and/or phosphorylation of key components of the insulin signal transduction pathway in the frontal cortex leading to significant changes in the content of the active forms. Thus, metformin increased the expression of pAKT-Y474 while reducing pmTOR-S2448 and pGSK3β. These changes might be related, at least partially, to a slow progression of ageing, neurological damage, and cognitive decline. Metformin also improved the peripheral glucose tolerance and the ability of the Tau-VLW mice to maintain their body weight through ageing. Altogether our study shows that the tau-VLW mice could be a useful model to study the potential interrelationship between tauopathy and central and peripheral glucose metabolism alterations. More importantly our results suggest that chronic metformin treatment may have direct beneficial central effects by post-transcriptional modulation of key components of the insulin signal transduction pathway.

THE ROLE OF EMERGING TECHNOLOGIES OF STUDENTS' ACADEMIC ACHIEVEMENT AT POLITEKNIK SEBERANG PERAI (PSP)

Education is crucial for global progress, constantly evolving with emerging technologies that impact teaching and learning. This essay explores how new technologies influence academic success, specifically examining elevated failure rates at Politeknik Seberang Perai (PSP) in Malaysia. Factors like insufficient information, slow progress, and inadequate time management are linked to these failurerates. The study investigates the influence of new technologies on academic achievement at PSP using an ex post facto research strategy and quantitative methods to collect data from 200 respondents across various departments. The research identifies the types of technologies used by students and evaluates their impact on academic performance. Chi-Square analysis and Spearman correlation coefficient are utilized to test hypotheses. Findings reveal that modern technology, particularly cell phones, is widely accessible to students, with notable discrepancies in access across departments. A weak correlation exists between the frequency of technology use and academic achievement, with a statistically significant association only found in obtaining material online. The study contributes to the literature on the use of new technologies for academic purposes within PSP. Results emphasize the necessity of educating students on effective technology use to enhance academic outcomes. It highlights that simply having access to new technologies does not guarantee academic success; it depends on how students integrate these tools into their learning processes. Recommendations include teaching students efficient technology utilization and recognizing that academic improvement is not assured solely by usingtechnology. The study underscores the importance of strategic technology integration in education to foster academic achievement.

Forecasting of COVID-19 Cases Under Different Precaution Strategies in Turkey

The coronavirus disease started at the end of 2019 and affected all the countries in the world. In Turkey, the vaccination process started at the beginning of 2021 but performed in slow progress. Thus, the Turkish Government tried to implement precautions to control this virus's spread. In this study, we evaluated and compared five different forecasting models, ARIMA, Prophet, NARNN, Stacked LSTM, and Bidirectional LSTM, in order to show the effect of these precaution strategies on virus spread using a real-world data set. According to the test results, ARIMA and Prophet were found to be the most accurate models for small data sets that are split regarding precautions. Moreover, test results showed that when data size grows, LSTM model performance increases. However, these models' performance decreased when we fed these models by using the entire data set without splitting.

No association between markers of systemic inflammation and endothelial dysfunction with Alzheimer's disease progression: a longitudinal study.

Systemic inflammation and endothelial dysfunction are potentially modifiable factors implicated in Alzheimer's disease (AD), which offer potential therapeutic targets to slow disease progression. We investigated the relationship between baseline circulating levels of inflammatory (TNF-α, IL-1ß) and endothelial cell markers (VCAM-1, ICAM-1, E-selectin) and 18-month cognitive decline (ADAS-cog12) in 266 mild-to-moderate AD patients from the NILVAD study. We employed individual growth models to examine associations, potential mediation, and interaction effects while adjusting for confounders. The average increase in ADAS-cog12 scores over all patients was 8.1 points in 18months. No significant association was found between the markers and the rate of cognitive decline. Mediation analysis revealed no mediating role for endothelial cell markers, and interaction effects were not observed. Our results do not support the role of systemic inflammation or endothelial dysfunction in progression in persons with AD.

Health Quality 5.0: What Does Co-Creation Have to Do With It?

In this latest article in Leslee Thompson's Health Quality 5.0 series, she discusses the slow progress of patient engagement in healthcare over the past two decades, emphasizing the need for co-creation where patients and providers collaborate equally. It explores the challenges of overcoming traditional power dynamics and integrating patient knowledge into healthcare systems. Highlighting examples from around the world, the article identifies five success factors for global impact and stresses the importance of a holistic, inclusive approach to healthcare transformation. Co-creation is presented as essential for building resilient, high-performing health systems centred on patients' needs and experiences.

Machine Learning-Based Stroke Patient Rehabilitation Stage Classification Using Kinect Data

Everyone aspires to live a healthy life, but many will inevitably experience some form of disease, illness, or accident that results in disability at some point. Rehabilitation plays a crucial role in helping individuals recover from these disabilities and return to their daily activities. Traditional rehabilitation methods are often expensive, are inefficient, and lead to slow progress for patients. However, in this era of technology, various sensor-based automatic rehabilitation is also possible. A Kinect sensor is a skeletal tracking device that captures human motions and gestures. It can provide feedback to the users, allowing them to better understand their progress and adjust their movements accordingly. In this study, stroke-based rehabilitation is presented along with the Toronto Rehab Stroke Pose Dataset (TRSP). Pre-processing of the raw dataset was performed using various features, and several state-of-the-art classifiers were applied to evaluate the data provided by the Kinect sensor. Among the various classifiers, eXtreme Gradient Boosing (XGB) attained the maximum accuracy of 92% for the TRSP dataset. Furthermore, hyperparameters of the XGB have been optimized using a metaheuristic gray wolf optimizer for better performance.

A Critical Review of Noninvasive Brain Stimulation Technologies in Alzheimer's Dementia and Primary Progressive Aphasia.

Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer's disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer's Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters.

Exploring circular RNAs as biomarkers for Parkinson's disease and their expression changes after aerobic exercise rehabilitation.

Circular RNAs (circRNAs) are circularized single-stranded ribonucleic acids that interacts with DNA, RNA, and proteins to play critical roles in cell biology. CircRNAs regulate microRNA content, gene expression, and may code for specific peptides. Indeed, circRNAs are differentially expressed in neurodegenerative disorders like Parkinson's disease (PD), playing a potential role in the mechanisms of brain pathology. The RNA molecules with aberrant expression in the brain can cross the blood-brain barrier and reach the bloodstream, which enable their use as non-invasive PD disease biomarker. Promising targets with valuable discriminatory ability in combined circRNA signatures include MAPK9_circ_0001566, SLAIN1_circ_0000497, SLAIN2_circ_0126525, PSEN1_circ_0003848, circ_0004381, and circ_0017204. On the other hand, regular exercises are effective therapy for mitigating PD symptoms, promoting neuroprotective effects with epigenetic modulation. Aerobic exercises slow symptom progression in PD by improving motor control, ameliorating higher functions, and enhancing brain activity and neuropathology. These improvements are accompanied by changes circRNA expression, including hsa_circ_0001535 (circFAM13B) and hsa_circ_0000437 (circCORO1C). The sensitivity of current methods for detecting circulating circRNAs is considered a limitation. While amplification kits already exist for low-abundant microRNAs, similar kits are needed for circRNAs. Alternatively, the use of digital PCR can help overcome this constraint. The current review examines the potential use of circRNAs as non-invasive biomarkers of PD and to assess the effects of rehabilitation. Although circRNAs hold promise as targets for PD diagnosis and therapeutics, further validation is needed before their clinical implementation.

Real-World Clinical Profile and Safety of Nintedanib in Systemic Sclerosis-Associated Interstitial Lung Disease: A Subgroup Analysis of Interstitial Lung Disease Data From an Interstitial Lung Disease (ILD) Specialty Clinic in India.

Systemic sclerosis (SSc) is a multisystem autoimmune disorder characterized by dysregulated innate and adaptive immunity. Interstitial lung disease (ILD) is a common and serious complication of SSc, often leading to significant morbidity and mortality. Consistent demographic characteristics that aid in the early diagnosis of ILD in SSc are lacking. This study aims to identify clinical and demographic parameters associated with ILD in SSc patients and assess the safety and tolerability of nintedanibwith other immunosuppressants. This study is a subgroup analysis of data from the ILD clinic at All India Institute of Medical Sciences Raipur, collected between January 2022 and January 2024. We assessed the clinical and demographic profiles, high-resolution computed tomography thorax patterns, autoantibody profiles, lung function, and treatments used in the patients. We enrolled 57 patients with SSc-associated ILD. The mean age of the participants was 39.0 ± 11.1 years, with 53 (92.9%) being women. The mean body mass index was 20.4 ± 4.32 kg/m². Dyspnea was the most common symptom, followed by skin tightening and cough. Antinuclear antibody tests were positive in 92.9% of patients, and anti-Scl-70 antibodies were positive in 57.9%. Rheumatoid arthritis-SSc overlap was observed in 15.8% of patients. The mean predicted forced vital capacity was 46.5 ± 19.9%, the mean predicted total lung capacity was 64.5 ± 20.4%, and the mean predicted diffusing capacity for carbon monoxide was 46.2 ± 15.7%. The mean six-minute walk distance was 360.3 ± 81.2 meters, and the mean King's Brief Interstitial Lung Disease score was 63.9 ± 10.7. Common radiological abnormalities included ground-glass opacities in 57.8%, traction bronchiectasis in 43.8%, and honeycombing in 28.07%. The predominant ILD pattern was nonspecific interstitial pneumonia. Patients received a combination of prednisolone (5 mg/day) with mycophenolate mofetil (63.2%), hydroxychloroquine (17.5%), cyclophosphamide (12.3%), and methotrexate (7.02%). Nintedanib, the only antifibrotic used, was administered to 17 (29.8%) patients. ILD is relatively common in SSc, particularly in patients with diffuse cutaneous SSc and those with anti-topoisomerase antibodies. Female patients comprised the predominant population in this study. Patients tolerated mycophenolate mofetil and cyclophosphamide well. Nintedanib was the only antifibrotic used, and all patients tolerated the combination of antifibrotics and immunosuppressants well. Early diagnosis is crucial to slow disease progression and preserve lung function. Our results highlight the need for vigilant screening in high-risk groups and suggest that MMF, cyclophosphamide, and nintedanib can be safely incorporated into treatment regimens, offering a potential strategy to improve patient outcomes.

Genome wide association study of clinical duration and age at onset of sporadic CJD.

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.

Review on the impacts of indoor vector control on domiciliary pests: good intentions challenged by harsh realities.

Arthropod vectored diseases have been a major impediment to societal advancements globally. Strategies to mitigate transmission of these diseases include preventative care (e.g. vaccination), primary treatment and most notably, the suppression of vectors in both indoor and outdoor spaces. The outcomes of indoor vector control (IVC) strategies, such as long-lasting insecticide-treated nets (LLINs) and indoor residual sprays (IRSs), are heavily influenced by individual and community-level perceptions and acceptance. These perceptions, and therefore product acceptance, are largely influenced by the successful suppression of non-target nuisance pests such as bed bugs and cockroaches. Adoption and consistent use of LLINs and IRS is responsible for immense reductions in the prevalence and incidence of malaria. However, recent observations suggest that failed control of indoor pests, leading to product distrust and abandonment, may threaten vector control programme success and further derail already slowed progress towards malaria elimination. We review the evidence of the relationship between IVC and nuisance pests and discuss the dearth of research on this relationship. We make the case that the ancillary control of indoor nuisance and public health pests needs to be considered in the development and implementation of new technologies for malaria elimination.

Hepatic Epithelioid Hemangioendothelioma: A Case Report of an Extremely Rare Tumor

Epithelioid hemangioendothelioma is a very rare vascular tumour, with fewer than 500 cases described worldwide. Diagnosis is often multifocal or at an advanced stage with non-specific symptoms. Pathological examination by biopsy is crucial to confirm the diagnosis. The liver is the most frequent site of predilection, followed by the lungs and bones. The etiology of hepatic epithelioid hemangioendothelioma is poorly understood and is not linked to chronic liver disease, with a heterogeneous and unpredictable course depending on the individual. Given the rarity of this cancer, there are no established treatment standards for this type of tumor of intermediate malignancy. Surgical resection is performed in the case of unifocal disease, and orthotopic liver transplantation remains an option in the case of multifocal and/or unresectable disease, with high survival rates and disease free survival (DFS). Transcatheter arterial chemoembolization (TACE) and chemotherapy/radiotherapy regimens are other treatment possibilities. However, surveillance may be proposed for asymptomatic patients with a slow progression. We report the case of a patient followed for a multifocal EHE with pulmonary metastases, discovered following pain in the right hypochondrium. Morphological and immunohistochemical examination confirmed the diagnosis of hepatic epithelioid hemangioendothelioma. Given the moderate symptoms, surveillance was recommended for our patient with a good clinical course and radiological stability for 3 years.

A Novel Strategy for Glioblastoma Treatment by Natural Bioactive Molecules Showed a Highly Effective Anti-Cancer Potential.

Glioblastoma (GBM) is a severe form of brain tumor that has a high fatality rate. It grows aggressively and most of the time results in resistance to traditional treatments like chemo- and radiotherapy and surgery. Biodiversity, beyond representing a big resource for human well-being, provides several natural compounds that have shown great potential as anticancer drugs. Many of them are being extensively researched and significantly slow GBM progression by reducing the proliferation rate, migration, and inflammation and also by modulating oxidative stress. Here, the use of some natural compounds, such as Allium lusitanicum, Succisa pratensis, and Dianthus superbus, was explored to tackle GBM; they showed their impact on cell number reduction, which was partially given by cell cycle quiescence. Furthermore, a reduced cell migration ability was reported, accomplished by morphological cytoskeleton changes, which even highlighted a mesenchymal-epithelial transition. Furthermore, metabolic studies showed an induced cell oxidative stress modulation and a massive metabolic rearrangement. Therefore, a new therapeutic option was suggested to overcome the limitations of conventional treatments and thereby improve patient outcomes.