Faster Progression Research Articles

Role of Ultrasonography in the Diagnosis of Acute Appendicitis

Introduction: Acute appendicitis is still prevalent as a major surgical emergency. Due to the fast progress of the ailment, surgery is often the most sensible approach to manage it. But any surgery comes with its fair share of risk. If the diagnosis of the disease can be made more accurate prior to surgery, the error rate of negative appendectomy can be greatly reduced. Aim of the study: The aim of the study was to evaluate the role of ultrasonography in the diagnosing acute appendicitis. Methods: This prospective cross-sectional study was conducted at the Institute of Nuclear Medicine & Allied Sciences (INMAS), Rangpur with Department of Surgery & Department of Pathology of Rangpur Medical College Hospital, Rangpur, Bangladesh. The study duration was 02 years, from 01January 2022 to 31 December 2023. A total of 100 cases were selected from those patients were come for ultrasound examination, send from the hospital with pain in the right lower quadrant of the abdomen for the purpose of this study. Result: Among the 100 participants of the study, histopathological diagnosis showed that 86% were acute appendicitis cases and 14% had normal appendicitis. Gender or age had no significant association with histopathological diagnosis, but male prevalence was observed in the study, with a high prevalence of young adults. The original site of pain was periumbilical pain shifted to the right iliac fossa for half the participants. Pain duration was between 18-24 hours for 36% of the cases. All participants presented with pain, fever, anorexia, and nausea had a high prevalence among participants. The sensitivity and specificity of high-resolution ultra-sonogram were 84.9% and 85.7% respectively. Conclusion: Appendicitis is a disease of the young, and can occur in participants of both genders. Histopathological diagnosis has no significant association with patient age or gender. Ultra-sonogram has high sensitivity and specificity ratio in diagnosing acute appendicitis and also h

Slowing the Progression of Chronic Kidney Disease in Patients with Type 2 Diabetes Using Four Pillars of Therapy: The Time to Act is Now.

Chronic kidney disease (CKD) is the most common co-morbidity in patients with type 2 diabetes (T2D) and its presence substantially amplifies the risk for premature death, adverse cardiovascular events, and faster progression of kidney injury to kidney failure. For nearly two decades, the pharmacological blockade of the renin-angiotensin-system (RAS) was the only pillar of therapy to afford cardiorenal protection in these patients. During the last 5 years, newer novel therapies have been added to our therapeutic armamentarium, offering promise for more effective management of diabetic kidney disease in the future. Large phase 3 clinical trials have demonstrated additive cardiorenal protective benefits of sodium-glucose co-transporter type 2 (SGLT-2) inhibitors, the non-steroidal mineralocorticoid-receptor-antagonist (MRA) finerenone, and glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide relative to placebo in patients with albuminuric CKD and T2D who are receiving standard-of-care treatment with a RAS-blocker. These therapies are likely much more effective when administered in a combined therapeutic algorithm, but the potential additive effects of combination therapy remain to be established in ongoing clinical trials. In this article, we assemble four pillars of therapy for the attenuation of residual cardiorenal risk in patients with CKD associated with T2D. We provide evidence from recent randomized trials and we discuss the concept of combined treatment for maximal cardiorenal protection in this high-risk patient population.

Parkinson’s disease is associated with clonal hematopoiesis with TET2 mutation

Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of mutated hematopoietic stem cells, is linked to immune alterations. Given the role of neuroinflammation and immune dysfunction in Parkinson’s disease (PD), we hypothesized a connection between CHIP and PD. We analyzed peripheral blood DNA from 341 PD, 92 isolated REM sleep behavior disorder (iRBD) patients, and 5003 controls using targeted sequencing of 24 genes associated with hematologic neoplasms. PD cases were classified by clinical progression mode: fast, slow, and typical. Using multivariable logistic regression models, CHIP prevalence was assessed against controls with a 1.0% variant allele fraction threshold. CHIP with TET2 mutations was more prevalent in PD than controls (aOR 1.75, 95% CI 1.11–2.77, p = 0.017), particularly in the fast motor progression subgroup (aOR 3.19, p = 0.004). No distinct associations were observed with iRBD. PD is linked to increased odds of CHIP with TET2 mutations, suggesting immune dysregulation in PD pathophysiology.

Can we really distinguish 'responders' from 'non-responders' to myopia control interventions?

It is common to hear talk of 'responders' and 'non-responders' with respect to myopia control interventions. We consider the reality of distinguishing these sub-groups using data from the first year of the Low-concentration Atropine for Myopia Progression (LAMP) study. The first year of the LAMP study was a robustly designed, placebo-controlled trial of three different low concentrations of atropine using a large sample size (N > 100 randomised to each group). The authors subsequently published mean axial elongation and myopia progression rates by age group. We used these data to calculate efficacy in terms of both absolute reduction in myopic progression and absolute reduction in axial elongation for each of the different atropine concentrations at each age group. We then compared these efficacy data to the overall progression for each of the two progression metrics. Plotting efficacy as a function of overall myopia progression and axial elongation for each of the different atropine concentrations demonstrates the invariant nature of efficacy, in terms of clinically meaningful reduction in progression, despite a substantial range of underlying overall progression. That is, faster progressors-the so-called non-responders-achieved similar reduction in axial elongation and myopia progression as the slower progressors-the so-called responders-within the various atropine treatment groups. The use of the terms, responders and non-responders, during myopia progression interventions is not supported by evidence. Those designated as such may simply be slower or faster progressors, who, on average achieve the same benefit from treatment.

Neuropsychiatric symptoms and lifelong mental activities in cerebral amyloid angiopathy – a cross-sectional study

BackgroundWhile several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted.MethodsWe prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer’s Disease (AD) Assessment Scale’s (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS.ResultsPatients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94–5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19–0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05–1.39) and 0.63 units (95% CI 0.19–1.08) more severe NPS. NPS number (MMSE mean difference − 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26–2.56) and severity (MMSE − 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57–1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect − 0.08, 95% CI -0.22 to -0.002).DiscussionThis study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA.

Hyperprogressive disease in patients with advanced cancer treated with immune checkpoint inhibitors.

Hyperprogressive disease (HPD) is a new phenomenon developing in the era of immune checkpoint inhibitor (ICI) therapy. HPD is characterized by an unexpected and fast progression in tumor volume and poor survival. There is no standardized definition for HPD and clinicopathological variables associated with HPD are unclear. Herein, we assessed incidence, treatment outcomes and factors predictive of HPD in patients treated with ICIs. We retrospectively analyzed patients with advanced cancer treated with ICI at one academic center between 2014 and 2021. We used the Lo Russo's adopted criteria combined with clinical and radiologic parameters for the definition of HPD. All patients who underwent their first tumor evaluation according to RECIST1.1 were included. Of 155 patients, 147 were eligible for analysis. The median age was 61 and 83% were male. The cancer types were; lung 67.3%, bladder 12.9%, gastric 9.5%, 5, colon 5.4% and renal cell carcinoma 4.8%. 59.9% of patients were treatment-naive and others had one or more lines of chemotherapy. 19 (12.9%) patients had HPD. In patients who had HPD, progression-free survival (PFS) was significantly shorter (1.5 vs 9.8months, (HR 9.56; 95% CI (5.51-16.57), p < 0.001). The median overall survival (OS) was also shorter for HPD patients than non-HPD (3.0 vs 23.1months, respectively, HR 12.03, 95% CI (6.64-21.81), p < 0.001). Gastric cancer, larger sum of target lesion diameters at baseline, liver metastases, higher LDH level and higher neutrophil-lymphocyte ratio (NLR) were significantly associated with HPD. Our findings demonstrated that HPD was a rapid phenomenon with significantly poor survival rates. Several clinicopathological factors and tumor characteristics might indicate HPD.

A Comparative Review of Tocosomes, Liposomes, and Nanoliposomes as Potent and Novel Nanonutraceutical Delivery Systems for Health and Biomedical Applications.

Contemporary nutraceutical and biomedical sectors are witnessing fast progress in efficient product development due to the advancements in nanoscience and encapsulation technology. Nutraceuticals are generally defined as food substances, or a section thereof, that provide us with health benefits such as disease prevention and therapy. Nutraceutical and biomedical compounds as well as food supplements are a natural approach for attaining therapeutic outcomes with negligible or ideally no adverse effects. Nonetheless, these materials are susceptible to deterioration due to exposure to heat, oxygen, moisture, light, and unfavorable pH values. Tocosomes, or bilayered lyotropic vesicles, are an ideal encapsulation protocol for the food and nutraceutical industries. Biocompatibility, high entrapment capacity, storage stability, improved bioavailability, site specific delivery, and sustained-release characteristics are among the advantages of this nanocarrier. Similar to liposomal carriers and nanoliposomes, tocosomes are able to encapsulate hydrophilic and hydrophobic compounds separately or simultaneously, offering synergistic bioactive delivery. This manuscript describes different aspects of tocosome in parallel to liposome and nanoliposome technologies pertaining to nutraceutical and nanonutraceutical applications. Different properties of these nanocarriers, such as their physicochemical characteristics, preparation approaches, targeting mechanisms, and their applications in the biomedical and nutraceutical industries, are also covered.

Subclinical Atherosclerosis Progression in Low-Risk, Middle-Aged Adults: Carotid Leads Femoral in IMT Increase but Not in Plaque Formation.

Clinical data, risk factors, carotid/femoral intima-media thickness (IMT), and plaque presence were analyzed. Cardiovascular risk factors and scores increased significantly at follow-up. Both carotid and femoral mean IMT increased (p < 0.001). While plaque prevalence rose and was similar in both arteries (carotid: 4.8% to 17.9%, femoral: 3.6% to 17.7%, p < 0.001 for both), the progression of plaque burden was greater in femorals. Notably, the carotid mean IMT demonstrated a faster yearly progression rate compared to the mean femoral IMT. The prevalence of pathological nomogram-based mean IMT right or left was higher in the carotids (52.9% to 78.8%, p < 0.001) compared to femorals (23.2% to 44.7%, p < 0.001), with a significant increase at the end of follow-up in both territories. This study demonstrates significant subclinical atherosclerosis progression in low-risk, middle-aged adults over 5 years. Carotid arteries showed a faster progression rate of mean IMT and a higher prevalence of pathological nomogram-based mean IMT compared to the femoral arteries. However, plaque burden was similar in both territories, with greater progression in femorals. Identifying carotid and femoral atherosclerosis burden may be a valuable tool for risk stratification in this population.

Framingham Stroke Risk Profile Score and White Matter Disease Progression.

To evaluate the relationship between Framingham Stroke Risk Profile (FSRP) score and rate of white matter hyperintensity (WMH) progression and cognition. Consecutive patients enrolled in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry (2011-2020) with 2 brain-MRI scans at least 1 year apart were included. The primary outcome was annual change in WMH volume (cm 3 /year) stratified as fast versus slow (above vs. below median). Cognition was assessed using a Mini-Mental State Exam (MMSE, 0-30). FSRP score (0 to 8) was calculated by summing the presence of age 65 years or older, smoking, systolic blood pressure greater than 130 mmHg, diabetes, coronary disease, atrial fibrillation, left ventricular hypertrophy, and antihypertensive medication use. Linear and logistic regression analyses were performed to examine the association between FSRP and WMH progression, and cognition. In all, 207 patients were included, with a mean age of 60±16 y and 54.6% female. FSRP scores risk distribution was: 31.9% scored 0 to 1, 36.7% scored 2 to 3, and 31.4% scored ≥4. The baseline WMH volume was 9.6 cm 3 (IQR: 3.3-28.4 cm 3 ), and the annual rate of WMH progression was 0.9 cm3/year (IQR: 0.1 to 3.1 cm 3 /year). A higher FSRP score was associated with fast WMH progression (odds ratio, 1.45; 95% CI: 1.22-1.72; P<0.001) and a lower MMSE score (23.6 vs. 27.1; P<0.001). There was a dose-dependent relationship between higher FSRP score and fast WMH progression (odds ratios, 2.20, 4.64, 7.86, 8.03 for FSRP scores 1, 2, 3, and ≥4, respectively; trend P <0.001). This study demonstrated an association between higher FSRP scores and accelerated WMH progression, as well as lower cognition.

Role of L-carnitine in Cardiovascular Health: Literature Review.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Secondary preventive measures, like anti-platelet medications, B-blockers, and angiotensin-converting enzyme (ACE) inhibitors, have been found to dramatically lower the risk of cardiovascular disease. However, prolonged usage of these drugs has been linked to multiple adverse impacts. Hence, finding more efficient treatments, especially dietary strategies for long-term use in daily life, is advantageous for primary prevention and treatment. L-carnitine, a naturally occurring amino acid derivative normally synthesized in the liver and kidney, is believed to have a considerable influence on cardiovascular health. L-carnitine can enhance both contractile performance and structural integrity of the cardiac muscle by maintaining efficient energy production and reducing oxidative stress. This literature review aims to address several pressing questions regarding the role of L-carnitine in cardiovascular health: what are the physiological functions of L-carnitine, particularly in relation to cardiovascular health; how effective and safe is L-carnitine supplementation in the management of various cardiovascular diseases, primarily ischemic heart disease, heart failure, and peripheral vascular disease; what are the underlying mechanisms through which L-carnitine exerts its cardioprotective effects; what controversies exist in the current research; and finally, what should be the future directions? Through this comprehensive analysis, the review aims to enrich our understanding of L-carnitine's role in cardiovascular health, providing a robust foundation for future academic and clinical endeavors. PubMed, Embase, and Google Scholar have been used to search the following keywords: L-carnitine, cardiovascular health, mitochondrial function, and L-carnitine side effects. Then, using the existing search engine formats, some keyword combinations were used to find the related articles included and every possibility, including using every first keyword combination with another keyword, using every keyword in every place at each given box, etc. Around 308 articles were reviewed using this process, including systemic reviews, meta-analysis studies, randomized controlled trials, and literature review articles. Inthe end, after leaving the pure articles related to the topic as 35 articles, which are attached below with direct citation, the majority of them were very fresh articles, as recent as 2010, and back words, except just one paper related to the impact of L-carnitine post-myocardial infarction, as its data provided us with a positive and promising impact of L-carnitine in this field. L‑carnitine seems to have a pivotal role in cardiovascular health due to its energy metabolism, anti-oxidative stress, and endothelial role. The safety and effectiveness of L-carnitine administration remain an issue for scientific investigation. One of the major concerns is that the intestinal metabolism of L-carnitine generates trimethylamine-N-oxide (TMAO), a compound that has been linked with faster atherosclerosis progression.

Neuropsychiatric symptoms: Risk factor or disease marker? A study of structural imaging biomarkers of Alzheimer's disease and incident cognitive decline.

Neuropsychiatric symptoms (NPS) are risk factors for Alzheimer's disease (AD) but can also manifest secondary to AD pathology. Mild behavioral impairment (MBI) refers to later-life emergent and persistent NPS that may mark early-stage AD. To distinguish MBI from NPS that are transient or which represent psychiatric conditions (non-MBI NPS), we investigated the effect of applying MBI criteria on NPS associations with AD structural imaging biomarkers and incident cognitive decline. Data for participants (n = 1273) with normal cognition (NC) or mild cognitive impairment (MCI) in the National Alzheimer's Coordinating Center Uniform Data Set were analyzed. NPS status (MBI, non-MBI NPS) was derived from the Neuropsychiatric Inventory Questionnaire and psychiatric history. Normalized measures of bilateral hippocampal (HPC) and entorhinal cortex (EC) volume, and AD meta-region of interest (ROI) mean cortical thickness were acquired from T1-weighted magnetic resonance imaging scans. Multivariable linear and Cox regressions examined NPS associations with imaging biomarkers and incident cognitive decline, respectively. MBI was associated with lower volume and cortical thickness in all ROIs in both NC and MCI, except for EC volume in NC. Non-MBI NPS were only associated with lower HPC volume in NC. Although both of the NPS groups showed higher hazards for MCI/dementia than No NPS, MBI participants showed more rapid decline. Although both types of NPS were linked to HPC atrophy, only NPS that emerged and persisted in later-life, consistent with MBI criteria, were related to AD neurodegenerative patterns beyond the HPC. Moreover, MBI predicted faster progression to dementia than non-MBI NPS.

P051 ASSOCIATION OF BASELINE PLASMA ALDOSTERONE CONCENTRATION WITH ARTERIAL STIFFNESS PROGRESSION IN HYPERTENSIVE PATIENTS

Objective: Limited studies have examined the relationship between plasma aldosterone concentration (PAC) and arterial stiffness progression. The objective of this study was to investigate the longitudinal association between baseline PAC and arterial stiffness progression in hypertensive patients. Methods: A total of 1138 hypertensive patients were enrolled in the study. PAC was measured using standard techniques while in a sitting position. Arterial stiffness was quantified using brachial-ankle pulse wave velocity (baPWV), an indicator of arterial stiffness that is non-invasive in nature. Progression of baPWV was assessed using the baPWV change rate(the absolute difference between baseline and follow-up baPWV, divided by the follow-up time in years. Multivariate linear regression models were employed to idenitify the associations between baseline PAC and the baPWV change rate. Additionally, multivariable restricted cubic splines were utilized to investigate the dose-response relationship between baseline PAC and baPWV change rate. Results: Multivariate linear regression analyses revealed that an increase of one unit in PAC at baseline was associated with a 1.96 cm/s/year increase [95% confidence interval (CI), 0.99, 2.92] in baPWV change rate. Furthermore, RCS demonstrated a significant dose-response relationship between baseline PAC and the baPWV change rate. Conclusion: This study found that higher levels of PAC were associated with a faster progression of arterial stiffness. These findings should be confirmed by further investigations.

Investigations on the machinability performance of Al2O3/TiCN CVD coated carbide tools in sustainable high-speed hard-turning of AISI 4340 alloy steel

Abstract This study investigates the effectiveness of CVD coated carbide inserts in turning hardened AISI 4340 steel at high-machining speed V=300,350m/min under sustainable dry cutting environment. Experiments were executed in accordance to Taguchi L4 orthogonal array and crucial machinability aspects tool life, tool wear progression and mechanism, cutting force, and surface roughness were evaluated in detail. The results of this study revealed that Al2O3/TiCN coating successfully inhibited the faster progression of tool wear at low cutting speed (300m/min), feed rate (0.05mm/rev) and depth of cut (0.1mm), thus delivering the highest tool life of 19.25 min and lowest cutting force of 76.8 N. However, better surface finish of 0.305µm was obtained at high cutting speed (350m/min), low feed rate (0.05mm/rev), and high depth of cut (0.1mm). Nevertheless, at high cutting speed (350 m/min) and feed rate (0.1 mm/rev), involvement of intense thermal-mechanical effects suppressed the effectiveness of coating and tool completed its useful life at 9.24 min. Severe flaking on the cutting edge was observed at high machining parameters. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) analysis revealed that adhesion, oxidation, and small scale chipping and abrasion were the primary wear mechanisms attributing in competing the tool life criteria (Vb=300µm) in all cutting conditions. Furthermore, it was established that the cutting force and surface roughness increased with increasing tool flank wear due to coating delamination, material adhesion and tool chipping. This research emphasizes the significant potential of adopting Al2O3/TiCN coated carbide inserts for high-speed industrial hard-turning of AISI 4340 steel.

THE ROLE OF AI IN HEALTHCARE INDUSTRY

This article analyses the present condition of technological applications based on artificial intelligence (AI) and their influence on the healthcare sector. This work conducted a comprehensive literature research and examined certain real-world instances of AI implementations in the healthcare sector. Undoubtedly, the fast progress of artificial intelligence (AI) and associated technologies will enable healthcare providers to provide fresh value for their patients and enhance the effectiveness of their internal operations. However, successful deployment of AI will always pose distinct problems and the adoption of specific approaches to revolutionize the whole care service and operations in order to fully utilize the advantages of future technology. The analysis is derived on an examination of several academic sources, encompassing research from ScienceDirect, MDPI, Elsevier, and the Journal of Consortium. These sources address studies and data published from recent years till 2024.

The Analysis of Influential Factors on the Delay of Dredging Work at Rebaq Rinding River Line in Kutai Kertanegara Regency, Indonesia

Along with fast progress of industrial world, particularly in the building construction project which also increasing rapidly, the difficulty level in managing and implementing construction projects also rising where the higher the difficulty the longer the time required to complete the project. A delay in work implementation is evident from the work package of Dredging Work Project for Rebaq Rinding River at Muara Muntai District of Kutai Kertanegara Regency. Thus, this research was performed to determine factors that influence project delays. The selected data analysis method was a factor analysis and multiple linear regression analysis from the questionnaire answers that distributed to 45 respondents ranging from the service users, contractors, and consultants involved in the Dredging Work Project in Rebaq Rinding River at Muara Muntai District of Kutai Kertanegara Regency which experienced delays. According to the result of this research, factor that has significant influence to project delays is factor of Work Implementation Method with value of tcount = 3.162 &gt; from ttable = 2.028, and based on T test, it was found that the most dominant factor is the factor of Work Implementation Method with ß value = 0.646. The strategy used in dealing with project delays are: prior to the beginning of work implementation, implementation schedule must be prepared in accordance with the rational work stages and the work stages implementation must follow the planned method.

Temporalities of oxytocin for labour augmentation: a mixed-methods study of time factors shaping labour practices in a busy maternity unit in Tanzania

BackgroundHigh rates of labour augmentation with oxytocin have been found in some low- and lower-middle-income countries, causing potential perinatal harm. It is critical to understand the reasons for this overuse. Aim was to explore factors that shape practices around using oxytocin for labour augmentation in a high-volume labour ward in Dar es Salaam, Tanzania.MethodsMixed-methods data collection was conducted from March 2021 to February 2022, including structured observations of 234 births, 220 h of unstructured labour ward observations and 13 individual in-depth interviews with birth attendants. Thematic network analysis and descriptive statistics were used to analyse data. We used a time-lens to understand practices of oxytocin for labour augmentation in time-pressured labour wards.ResultsBirth attendants constantly had to prioritise certain care practices over others in response to time pressure. This led to overuse of oxytocin for augmentation to ensure faster labour progression and decongestion of the, often overburdened, ward. Simultaneously, birth attendants had little time to monitor foetal and maternal condition. Surprisingly, while oxytocin was used in 146 out of 234 (62.4%) structured labour observations, only 9/234 (4.2%) women had active labour lasting more than 12 h. Correspondingly, 21/48 (43.8%) women who were augmented with oxytocin in the first stage of labour had uncomplicated labour progression at the start of augmentation. While the partograph was often not used for decision-making, timing of starting oxytocin often correlated with natural cycles of ward-rounds and shift-turnovers instead of individual women’s labour progression. This resulted in co-existence of ‘too early’ and ‘too late’ use of oxytocin. Liberal use of oxytocin for labour augmentation was facilitated by an underlying fear of prolonged labour and low alertness of oxytocin-related risks.ConclusionsTime scarcity in the labour ward often made birth attendants deviate from clinical guidelines for labour augmentation with oxytocin. Efforts to navigate time pressure resulted in too many women with uncomplicated labour progression receiving oxytocin with little monitoring of labour. Fear of prolonged labour and low alertness to oxytocin-mediated risks were crucial drivers. These findings call for research into safety and benefits of oxytocin in low-resource settings and interventions to address congestion in labour wards to prevent using oxytocin as a time-management tool.

Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis

BackgroundPositive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. Study design and settingsA randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial’s last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. ResultsMean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL − RNS60 group; 3.3 years in low NfL − placebo group; 1.9 years in high NfL − RNS60 group; 1.8 years in high NfL − placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 − RNS60 group; 2.3 years in low MCP-1 − placebo group; 2.8 years in high MCP-1 − RNS60 group; 2.6 years in high MCP-1 − placebo group) levels at baseline. Conclusions and relevanceIn this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug’s effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. Trial registrationStudy preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.

Tracking the pre-clinical progression of transthyretin amyloid cardiomyopathy using artificial intelligence-enabled electrocardiography and echocardiography.

Diagnosing transthyretin amyloid cardiomyopathy (ATTR-CM) requires advanced imaging, precluding large-scale testing for pre-clinical disease. We examined the application of artificial intelligence (AI) to echocardiography (TTE) and electrocardiography (ECG) as a scalable strategy to quantify pre-clinical trends in ATTR-CM. Across age/sex-matched case-control datasets in the Yale-New Haven Health System (YNHHS) we trained deep learning models to identify ATTR-CM-specific signatures on TTE videos and ECG images (area under the curve of 0.93 and 0.91, respectively). We deployed these across all studies of individuals referred for cardiac nuclear amyloid imaging in an independent population at YNHHS and an external population from the Houston Methodist Hospitals (HMH) to define longitudinal trends in AI-defined probabilities for ATTR-CM using age/sex-adjusted linear mixed models, and describe discrimination metrics during the early pre-clinical stage. Among 984 participants referred for cardiac nuclear amyloid imaging at YNHHS (median age 74 years, 44.3% female) and 806 at HMH (69 years, 34.5% female), 112 (11.4%) and 174 (21.6%) tested positive for ATTR-CM, respectively. Across both cohorts and modalities, AI-defined ATTR-CM probabilities derived from 7,423 TTEs and 32,205 ECGs showed significantly faster progression rates in the years before clinical diagnosis in cases versus controls (p time × group interaction ≤0.004). In the one-to-three-year window before cardiac nuclear amyloid imaging sensitivity/specificity metrics were estimated at 86.2%/44.2% [YNHHS] vs 65.7%/65.5% [HMH] for AI-Echo, and 89.8%/40.6% [YNHHS] vs 88.5%/35.1% [HMH] for AI-ECG. We demonstrate that AI tools for echocardiographic videos and ECG images can enable scalable identification of pre-clinical ATTR-CM, flagging individuals who may benefit from risk-modifying therapies.

Targeting Neurological Aspects of Mucopolysaccharidosis Type II: Enzyme Replacement Therapy and Beyond.

Mucopolysaccharidosis type II (MPS II) is a rare, pediatric, neurometabolic disorder due to the lack of activity of the lysosomal hydrolase iduronate 2-sulfatase (IDS), normally degrading heparansulfate and dermatansulfate within cell lysosomes. The deficit of activity is caused by mutations affecting the IDS gene, leading to the pathological accumulation of both glycosaminoglycans in the lysosomal compartment and in the extracellular matrix of most body districts. Although a continuum of clinical phenotypes is described, two main forms are commonly recognized-attenuated and severe-the latter being characterized by an earlier and faster clinical progression and by a progressive impairment of central nervous system (CNS) functions. However, attenuated forms havealso been recently described as presenting some neurological involvement, although less deep, such as deficits of attention and hearing loss. The main treatment for the disease is represented by enzyme replacement therapy (ERT), applied in several countries since 2006, which, albeit showing partial efficacy on some peripheral organs, exhibited a very poor efficacy on bones and heart, and a total inefficacy on CNS impairment, due to the inability of the recombinant enzyme to cross the blood-brain barrier (BBB). Together with ERT, whose design enhancements, performed in the last few years, allowed a possible brain penetration of the drug through the BBB, other therapeutic approaches aimed at targeting CNS involvement in MPS II were proposed and evaluated in the last decades, such as intrathecal ERT, intracerebroventricular ERT, ex vivo gene therapy, or adeno-associated viral vector (AAV) gene therapy. The aim of this review is to summarize the main clinical aspects of MPS II in addition to current therapeutic options, with particular emphasis on the neurological ones and on the main CNS-targeted therapeutic approaches explored through the years.

Analyzing changes in EU social inclusion using the global Malmquist productivity index

AbstractIn this paper, we use the global and the biennial Malmquist productivity indices for the Inverted Benefit‐of‐the‐Doubt model to analyze changes in EU social inclusion using data for the period 2011–2020. Our empirical results indicate that relatively more progress took place in EU social inclusion during the period 2015–2020, compared to the period 2011–2015. In addition, in the period 2011–2015, these improvements were possible mainly through the effect of efficiency change, while in the period 2015–2020, the main source of progress was the effect of the best‐practice change. In addition, we found that the “older” Member States achieved slightly faster progress rates, compared to the “new” Member States in the period 2011–2015, while the opposite was true for the period 2015–2020.