Natural Outcome Research Articles

Rainmaking: Observed with social systems theory

AbstractThis article examines contemporary efforts to control climate change through the lens of social systems theory, particularly by drawing comparisons to rain dances and shamanic rituals. It argues that modern climate control strategies bear functional similarities to archaic rituals aimed at influencing weather patterns, despite the absence of direct causality. Using Niklas Luhmann's concepts of autopoietic systems and functional equivalence, the article demonstrates that both historical and contemporary approaches to climate influence rely on blame‐shifting mechanisms and the social production of scapegoats, with failure often attributed not to the rituals or solutions themselves but to noncompliance or impurity among participants. The originality of this article lies in its application of social systems theory to link contemporary climate control strategies with ancient rituals, positioning them as functionally equivalent social phenomena. By drawing comparisons between shamanistic practices, corporate consulting, and global climate governance, the article provides a unique lens for understanding that the primary function of modern climate efforts may be to regulate social behaviour rather than achieving concrete natural environmental outcomes.

N-terminal prohormone of brain natriuretic peptide predicts recurrent cardiovascular events in patients with acute coronary syndrome both in the acute and post-discharge setting: a TRACER substudy

Abstract Background N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is a circulating peptide released by the heart in response to increased wall tension and stretching, for example, occurring during myocardial and/or atrial dysfunction. NT-proBNP is a diagnostic and prognostic marker in patients with heart failure but might also have prognostic utility in the acute phase of patients with acute coronary syndrome (ACS) and at one month after ACS. Purpose To assess the prognostic value of NT-proBNP over time in patients with ACS both in the acute setting and when re-assessed after one month. Methods The TRACER study randomized 12,944 patients with non-ST-segment elevation ACS (NSTE-ACS) to treatment with vorapaxar vs. placebo. Plasma samples for biomarker analyses were obtained at randomization (median 21 hours after hospital admission) in 6,800 patients and at an outpatient visit after one month in 5,313 patients. NT-proBNP was analysed using the Elecsys electrochemiluminescence immunoassays method. The primary composite endpoint in this substudy was the one-year risk of cardiovascular (CV) mortality, myocardial infarction, or ischaemic stroke. Associations between continuous natural log-transformed NT-proBNP levels and outcomes were assessed using Cox regression models accounting for study treatment and established risk factors. Results The median concentration of NT-proBNP during hospitalization for ACS and after one month was 496 ng/L and 264 ng/L, respectively. Higher age, female sex, a history of heart failure, and lower body mass index were independently associated with higher levels of NT-proBNP among patients in the acute setting, with renal disease also being an important factor after one month. The composite outcome of CV mortality, MI, or ischaemic stroke occurred in 901 patients (incidence rate 10.1 per 100 person-years) included at baseline and in 381 patients (incidence rate 5.4 per 100 person-years) included at one month. Higher circulating levels of NT-proBNP were independently associated with a higher risk of the composite endpoint at baseline (adjusted hazard ratio with 95% confidence interval comparing the third vs. the first sample quartile: 1.25 [1.03 – 1.51]) and at one month (1.56 [1.15 – 2.11]) (Figure 1 and 2). Incorporating NT-proBNP at baseline into a model with other established risk factors increased the concordance index of the multivariable model from 0.656 to 0.660 (p < 0.001), and after one month, from 0.711 to 0.733 (p < 0.001). These findings remained consistent across the various components of the composite endpoint. Conclusions In patients with ACS, the level of NT-proBNP is an indicator of increased risk of CV outcomes both in the acute setting and, even more pronounced, one month after the index ACS. Measuring NT-proBNP provided incremental prognostic information beyond established risk factors, both in the acute and post-discharge settings.Fig 1.NT-proBNP quartile groupsFig 2.NT-proBNP and CV outcome

Natural course and effect of tafamidis treatment in real-life octogenarians with wild-type transthyretin cardiac amyloidosis: an international multi-centre analysis

Abstract Background and aims In real-life, wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is increasingly diagnosed in elderly patients above 80 years old. Nevertheless, specific data on natural course and outcome under tafamidis treatment in octogenarians are particularly scarce. We aimed to study tafamidis impact on mortality and its determinants in real-life ATTRwt-CM octogenarians. Methods International multi-centric cohort study of 710 consecutive ATTRwt-CM patients, stratified between octogenarians and non-octogenarians at diagnose and tafamidis naive or treatment. Mean follow-up was 2.2±1.8 years to all-cause mortality endpoint. Results The cohort consisted of 58.3% octogenarians (median 84 years, 74.2% male). Before tafamidis availability, natural course in octogenarians (148/257) versus non-octogenarians (109/257) was poor with 41% three-year and 70% five-year mortality versus 19% and 42%, respectively (p<0.001). Since tafamidis availability, 70.1% (253/361) octogenarians were initiated on tafamidis, less than 83.7% (231/276) non-octogenarians (p<0.001). Tafamidis discontinuation was similar (octogenarians 11.4%, non-octogenarians 7.9%, p=0.260). Overall tafamidis treated octogenarians had better survival than untreated octogenarians (p<0.001) and untreated non-octogenarians (p=0.026), with 23% three-year and 51% five-year mortality. Tafamidis treatment related to lower mortality in octogenarians (HR 0.37, 95%CI 0.20-0.67, p=0.001), after correcting for age, NAC stage and NYHA class, the other independent predictors. Propensity-score matching for those variables in 218 subjects confirmed tafamidis mortality benefit in octogenarians (p<0.001). Octogenarians had poorer survival under tafamidis, when initiated at ≥90 years old (p<0.001), NAC stage ≥3 (p=0.001) or NYHA class ≥3 (p=0.055). Conclusions Tafamidis treatment in real-life octogenarians independently improves survival, with better effect of early initiation at lower disease stage and age.Structured graphical abstractDistributions within age category

The natural progression of basal cell carcinomas (BCCs) awaiting surgical intervention.

Basal cell carcinomas (BCCs) are slow growing keratinocyte tumours with limited literature reporting the natural history of untreated BCCs. This study evaluated the natural progression and patient outcomes of BCCs whilst awaiting surgical intervention. Only patients with histologically proven BCCs were included in the data collection. Retrospective data analysis was performed on 55 patients (total of 70 lesions) and showed a statistically significant correlation between average growth of BCCs and time waiting for a procedure. Twenty percent of the cases had a larger procedure than originally planned at the time of booking. The top three symptoms reported include itching (39.4%), crusting (36.4%) and bleeding (30.3%). In conclusion, we reported a positive relationship between BCC growth and length of time from initial presentation to surgical treatment where patients often ended up with more symptoms, larger and complex surgical procedure than originally planned especially on the head and neck.

Natural course and outcomes of children with ubiquitin-specific protease 53 (USP53)-related genetic chronic cholestasis.

Ubiquitin-specific protease 53 (USP53) is essential for formation of cellular tight junctions and variations in this gene disrupt the tight junctions, resulting in cholestasis. We describe the clinical manifestations and outcomes of patients with USP53 mutations from the Indian progressive familial intrahepatic cholestasis registry. All 29 patients who harbored mutations in the USP53 gene either in the homozygous, compound heterozygous, or heterozygous state and presented with cholestasis were included. USP53 variants related to cholestasis had good outcomes, with native liver survival in 82.7%, whereas 17.3% required liver transplantation. Jaundice developed in 93% and within 3 months of age in 48.8%. Jaundice resolved in 21 (72.4%). Pruritus 76% at a median age of 7 months (severe in 10/22, 45% and refractory to medical therapy in 4, 18.1%). Majority of them (82.7%) had biallelic mutations. Protein-truncating mutations were present in 20 (69%) and missense mutations in 9 (31%). No correlation was found between the genotype and the outcome.

A 5-year natural history study in LAMA2-related muscular dystrophy and SELENON-related myopathy: the Extended LAST STRONG study

BackgroundSELENON-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive axial muscle weakness, rigidity of the spine, scoliosis, and respiratory insufficiency. Laminin-a2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, which ranges from severe, early-onset congenital muscular dystrophy type 1A (MDC1A) to milder forms presenting as childhood- or adult-onset limb-girdle type muscular dystrophy. The first 1.5-year natural history follow-up showed that 90% of the patients had low bone quality, respiratory impairments were found in all SELENON-RM and most of the LAMA2-MD patients, and many had cardiac risk factors. However, further extensive knowledge on long-term natural history data, and clinical and functional outcome measures is needed to reach trial readiness. Therefore, we extended the natural history study with 3- and 5-year follow-up visits (Extended LAST STRONG).MethodsThe Extended LAST STRONG is a long-term natural history study in Dutch-speaking patients of all ages diagnosed with genetically confirmed SELENON-RM or LAMA2-MD, starting in September 2023. Patients visit our hospital twice over a period of 2 years to complete a 5-year follow up from the initial LAST-STRONG study. At both visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, muscle ultrasound, respiratory assessments (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years), X-ray of the left hand (age ≤ 17 years), lower extremity MRI (age ≥ 10 years), accelerometry for 8 days (age ≥ 2 years), and questionnaires (patient report and/or parent proxy; age ≥ 2 years). All examinations are adapted to the patient’s age and functional abilities. Disease progression between all subsequent visits and relationships between outcome measures will be assessed.DiscussionThis study will provide valuable insights into the 5-year natural history of patients with SELENON-RM and LAMA2-MD and contribute to further selecting relevant and sensitive to change clinical and functional outcome measures. Furthermore, this data will help optimize natural history data collection in clinical care and help develop clinical care guidelines.Trial registrationThis study protocol including the patient information and consent forms has been approved by medical ethical reviewing committee (‘METC Oost-Nederland’; https://www.ccmo.nl/metcs/erkende-metcs/metc-oost-nederland, file number: 2023–16401). It is registered at ClinicalTrials.gov (NCT06132750; study registration date: 2023-10-05; study first passed date: 2023-11-15).

Cerebral venous sinus thrombosis - Current updates in the Asian context.

Background Cerebral venous sinus thrombosis (CVT) is a life-threatening cause of stroke in Asian countries. South Asia, comprising of India, Pakistan and Bangladesh and contributed to 40% of strokes in women. Major CVT registries are from the western nations, which differs from the Asian countries with respect to epidemiology, gender biases and risk factors. This review focusses on the various aspects of relevance in evaluation and management of patients with CVT in the Asian context. Summary The incidence of CVT is higher in Asia than in Western nations. Young age, female gender, especially in pregnancy and puerperal period, and dehydration appear to be the critical risk factors. Tropical infections like malaria, scrub typhus, and flaviviral encephalitis predispose to CVT. There is a higher prevalence of inherited thrombophilia in the Asian cohorts, contributing to prothrombotic states. Anticoagulation and supportive management offer excellent outcomes. Newer anticoagulants are safe and efficacious. In medically refractory cases, endovascular treatment offers modest benefits. Decompressive hemicraniectomy, when done early, offers mortality benefits in patients with large hemorrhagic venous infarctions. Key messages CVT is an important cause of stroke with high-burden in South Asian countries. Establishment of robust registries is the need of the hour; to study the natural history, course and outcomes and to develop management algorithms tailored to the available resources.

THE FIGHT INHERITED RETINAL BLINDNESS! PROJECT: A NEW TREATMENT OUTCOME AND NATURAL HISTORY REGISTRY FOR INHERITED RETINAL DISEASE.

To design and build a new disease registry to track the natural history and outcomes of approved gene therapy in patients with inherited retinal diseases (IRDs). A core committee of 6 members was convened to oversee the construction of the FIRB! module. A further 11 experts formed a steering committee, which discussed disease classification and variables to form minimum datasets via a consensus approach. The web-based FIRB! registry records baseline demographic, clinical and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the FIRB! architecture to standardise nomenclature. The registry software assigns individual diagnoses to one of 7 broad phenotypic groups, with minimum datasets dependent upon the broad phenotypic group. Additionally, minimum datasets were agreed upon for patients undergoing approved gene therapy with voretigene neparvovec (Luxturna). New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes. Fight Inherited Retinal Blindness! (FIRB!) is an organized, web-based system that uses observational study methods to collect uniform data from IRD patients to track natural history and (uniquely) treatment outcomes. It is free to Users, who have control over their data.

The distribution of beneficial mutational effects between two sister yeast species poorly explains natural outcomes of vineyard adaptation.

Domesticated strains of Saccharomyces cerevisiae have adapted to resist copper and sulfite, two chemical stressors commonly used in winemaking. S. paradoxus has not adapted to these chemicals despite being consistently present in sympatry with S. cerevisiae in vineyards. This contrast could be driven by a number of factors including niche differences or differential access to resistance mutations between species. In this study, we used a comparative mutagenesis approach to test whether S. paradoxus is mutationally constrained with respect to acquiring greater copper and sulfite resistance. For both species, we assayed the rate, effect size, and pleiotropic costs of resistance mutations and sequenced a subset of 150 mutants. We found that the distributions of mutational effects displayed by the two species were similar and poorly explained the natural pattern. We also found that chromosome VIII aneuploidy and loss of function mutations in PMA1 confer copper resistance in both species, whereas loss of function mutations in REG1 were only a viable route to copper resistance in S. cerevisiae. We also observed a de novo duplication of the CUP1 gene in S. paradoxus but not in S. cerevisiae. For sulfite, loss of function mutations in RTS1 and KSP1 confer resistance in both species, but mutations in RTS1 have larger effects in S. paradoxus. Our results show that even when available mutations are largely similar, species can differ in the adaptive paths available to them. They also demonstrate that assays of the distribution of mutational effects may lack predictive insight concerning adaptive outcomes.

Is pancreatic adenosquamous carcinoma (PASC) a surgical disease? A large healthcare system review

IntroductionPancreatic cancer represents an increasing cause of cancer-related deaths. Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreas cancer. Optimal treatment is not well-defined. This review aims to provide a detailed analysis of the natural history, management, and outcomes of the patients with PASC within a single large healthcare system. Materials and methodsA large healthcare database was used to retrospectively identify all patients with histological diagnosis of PASC from 2010 to 2020. The cohort was evaluated as a whole and according to the following management modalities: operative, non-metastatic non-operative, and patients with metastatic disease. Abstracted data included patient characteristics, oncologic characteristics at presentation, and details of surgical and non-surgical treatment. ResultsIn total, 60 patients with PASC were identified. All patients had confirmed histopathological diagnosis of PASC. Mean age at the time of diagnosis was 70.9 years, and 28 patients were male (46.7 %). Most patients presented with pancreas head tumors (60 %). Thirty-four patients presented with non-metastatic disease (56.6 %). The operative group consisted of 17 patients (28.3 %). Most patients received adjuvant systemic therapy (70.6 %). Majority of patients experienced recurrence (76.5 %), with median time to recurrence at 6.5 months. Median overall survival in the operative group was 19.1 months. Seventeen patients with non-metastatic disease (28.3 %) did not undergo resection. Median overall survival of this cohort was 3.3 months. Systemic chemotherapy was used in 8 patients. Approximately half of patients with non-metastatic disease (9/17) did not receive any treatment due to rapid physical deterioration or poor functional status at baseline. Median survival for the non-treatment group was 1.7 months. At presentation, 26 patients (43.3 %) had metastatic disease. Most common site of metastasis was the liver. Median survival for patients with metastatic disease was 3.1 months. DiscussionPASC is a distinct entity from glandular PDAC, and it appears to be a more aggressive disease process. Complete resection confers survival benefit but is not curative. Furthermore, few patients undergo surgery, even with seemingly resectable disease. Systemic therapy administration is limited in many patients due to physiologic decline. Dismal clinical course and poor survival is universal among all patients who do not undergo any treatment modality, regardless of metastatic status. Globally grim prognosis appears to be due early systemic effects, disease progression and lack of effective systemic therapy. ConclusionsPASC remains a poorly understood cancer and portends particularly poor prognosis. It is associated with a rapid clinical decline, poor response to systemic therapy, early recurrence, and poor overall survival. However, ability to treat with surgery and chemotherapy may best prolong survival. SynopsisPancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreatic cancer. In this study, we evaluated 60 patients with PASC. PASC is a systemic disease characterized by rapid clinical decline, poor response to systemic therapy, early recurrence, and poor survival. Despite resection or systemic therapy, patients succumb rapidly.

Population-based cohort across stroke life course in India-The NIMHANS-NH-SKAN stroke project: A study protocol.

Stroke is a leading cause of death and disability worldwide. In India, it is the fourth leading cause of death and fifth leading cause of disability, posing a major public health concern. National surveys reveal an increasing trend in stroke risk factors such as tobacco use, physical activity, alcohol use, hypertension, and dyslipidemia. However, knowledge regarding the combined effect of these risk factors and their various combinations is limited. Understanding the individual, combined, and synergistic effects of known risk factors, along with new risk factors, is essential to address gaps in stroke epidemiology. This study aims to examine the effect of various risk factors of acute stroke and their association with stroke occurrence and its outcomes (survival, disability and quality of life). This retrospective-prospective cohort will be conducted in one taluka of Kolara district and two urban wards of Bengaluru with a total population of ~400,000. All stroke-free individuals above 30 years of age ~200,000 individuals in the selected sites will be participants of stroke-free period and all first ever stroke patients in the community will be part of stroke and post-stroke period respectively. The study subjects will be recruited through a complete house-to-house survey at baseline and undergo annual follow-ups during the stroke-free period, with specific assessments at defined time points during the stroke and post-stroke period for a period of one year. Efforts are implemented to minimize loss to follow-up, including community engagement, a helpline number, and hospital-based surveillance. This large population-based cohort study addressing stroke epidemiology in the country, is one -of-its-kind, attempting to fill certain critical gaps in the natural history, management, and outcomes of stroke in India. This research has the potential to provide important insights into the effect of novel risk factors of stroke and various combinations of risk factors of stroke. Furthermore, the development of a stroke risk predictability calculator will add value to the existing Indian National Programme for Prevention & Control of Non-Communicable Diseases (NP-NCD) and offers a model for similar countries once developed.

Natural history and management outcomes of patients with ruptured Spetzler-Martin grade IV and V brain arteriovenous malformations.

The natural history of ruptured high Spetzler-Martin grade IV and V brain arteriovenous malformations (bAVMs) is underreported given the scarcity of this pathology, and decision-making for patients with bAVMs remains unclarified. In this study, the authors sought to shed light on this topic. Patients harboring ruptured high-grade bAVMs were identified from an institutional database spanning from 1990 to 2020. The authors examined outcomes of annual hemorrhagic risk in natural history and after treatment, follow-up hemorrhage rate, bAVM obliteration, follow-up modified Rankin Scale (mRS) score > 2, worsened mRS score, and mortality. After reviewing the charts of 1066 patients without hereditary hemorrhagic telangiectasia, 84 patients with ruptured high-grade bAVMs were included in the study for analysis. For cortical bAVMs, the annual risk of hemorrhage during natural history was 2.68%. Surgery decreased the risk to 0.74%, while radiosurgery increased the risk to 5.35%, and embolization only increased the risk to 16.96%. For deep-seated high-grade bAVMs, the annual risk of hemorrhage during natural history was 8.37%. Radiosurgery decreased the risk to 3.11%, surgery decreased the risk to 5.25%, and embolization only increased the risk to 22.33%. Poisson regression analysis demonstrated that embolization only increased the risk of hemorrhage in cortical bAVMs (rate ratio 4.745, 95% CI 1.365-12.819; p = 0.005) and deep-seated bAVMs (rate ratio 6.290, 95% CI 0.997-21.932; p = 0.013). Logistic regression analysis showed that surgery (OR 52.000, 95% CI 8.083-1046.127; p = 0.004) and radiosurgery (OR 11.142, 95% CI 1.804-217.650; p = 0.029) were predictors of obliteration in cortical and deep-seated bAVMs, respectively. The proportions of patients experiencing a worsened mRS score, a follow-up mRS score > 2, and mortality were similar between conservative and treatment groups. The natural history of cortical ruptured high-grade bAVMs bears a risk similar to that of incidental bAVMs, whereas deep-seated ruptured high-grade bAVMs have an increased risk of hemorrhage. With extremely prudent patient selection, surgery might be a viable option for cortical bAVMs to obliterate the bAVM and reduce hemorrhagic risk, while preserving functional status. Radiosurgery might be beneficial to lower hemorrhagic risk in deep-seated bAVMs. Embolization as a single modality should be avoided as it provides no benefit to reduce hemorrhagic risk.

DESI dark energy time evolution is recovered by cosmologically coupled black holes

Recent baryon acoustic oscillation (BAO) measurements by the Dark Energy Spectroscopic Instrument (DESI) provide evidence that dark energy (DE) evolves with time, as parameterized by a w 0 w a equation of state. Cosmologically coupled black holes (BHs) provide a DE source that naturally evolves with time, because BH production tracks cosmic star-formation. Using DESI BAO measurements and priors informed by Big Bang Nucleosynthesis, we measure the fraction of baryonic density converted into BHs, assuming that all DE is sourced by BH production. We find that the best-fit DE density tracks each DESI best-fit w 0 w a model within 1σ, except at redshifts z ≲ 0.2, highlighting limitations of the w 0 w a parameterization. Cosmologically coupled BHs produce H 0 = (69.94 ± 0.81) km s-1 Mpc-1, with the same χ 2 as ΛCDM, and with two fewer parameters than w 0 w a . This value reduces tension with SH0ES to 2.7σ and is in excellent agreement with recent measurements from the Chicago-Carnegie Hubble Program. Because cosmologically coupled BH production depletes the baryon density established by primordial nucleosynthesis, these BHs provide a physical explanation for the “missing baryon problem” and the anomalously low sum of neutrino masses preferred by DESI.The global evolution of DE is an orthogonal probe of cosmological coupling, complementing constraints on BH mass-growth from elliptical galaxies, stellar binaries, globular clusters, the LIGO-Virgo-KAGRA merging population, and X-ray binaries.A DE density that correlates with cosmic star-formation: 1) is a natural outcome of cosmological coupling in BH populations; 2) eases tension between early and late-time cosmological probes; and 3) produces time-evolution toward a late-time ΛCDM cosmology different from Cosmic Microwave Background projections.

Long-term evolutionary links between the isolated neutron star populations

ABSTRACT We have investigated the evolutionary connections of the isolated neutron star (NS) populations including radio pulsars (RPs), anomalous X-ray pulsars (AXPs), soft gamma repeaters (SGRs), dim isolated NSs (XDINs), ‘high-magnetic field’ RPs (‘HBRPs’), central compact objects (CCOs), rotating radio transients (RRATs), and long-period pulsars (LPPs) in the fallback disc model. The model can reproduce these NS families as a natural outcome of different initial conditions (initial period, disc mass, and dipole moment, μ) with a continuous μ distribution in the $\sim 10^{27} - 5 \times 10^{30}$ G cm$^3$ range. Results of our simulations can be summarized as follows: (1) A fraction of ‘HBRPs’ with relatively high μ evolve into the persistent AXP/SGR properties, and subsequently become LPPs. (2) Persistent AXP/SGRs do not have evolutionary links with CCOs, XDINs, and RRATs. (3) For a wide range of μ, most RRATs evolve passing through RP or ‘HBRP’ properties during their early evolutionary phases. (4) A fraction of RRATs which have the highest estimated birth rate seem to be the progenitors of XDINs. (5) LPPs, whose existence was predicted by the fallback disc model, are the sources evolving in the late stage of evolution before the discs become inactive. These results provide concrete support to the ideas proposing evolutionary connections between the NS families to account for the ‘birth rate problem’, the discrepancy between the cumulative birth rate estimated for these systems and the core-collapse supernova rate.

Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort.

Hepatitis Delta Virus (HDV) infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a United States-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with hepatitis B virus (HBV). infection. In a national cohort of 4,817 HBV infected veterans tested for HDV (99.6% US-born, 3.3% HDV positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of hepatocellular carcinoma (HCC), decompensation, and liver-related mortality (LRM), as well as all-cause mortality of patients with HDV compared to HBV mono-infection. HDV coinfection (vs. HBV monoinfection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p<0.001), and 10 years (19.14 vs. 10.18, p<0.001) respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by non-hepatic malignancies, (15.6 vs. 14.8%),cardiac (11.7 vs. 15.2%), and lung disease (5.2 vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (aHR 2.57, 95% CI 1.87-3.52, p<0.001), and all-cause mortality (aHR 1.52, 95% CI 1.20-1.93, p<0.001). In a predominantly U.S born cohort of Veterans, HDV co-infection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.

Multi-path long-term vessel trajectories forecasting with probabilistic feature fusion for problem shifting

This paper presents a deep auto-encoder model and a phased framework approach to predict the next 12 h of vessel trajectories using 1 to 3 h of Automatic Identification System data as input. The strategy involves fusing spatiotemporal features from AIS messages with probabilistic features engineered from historical AIS data to reduce forecasting uncertainty. The probabilistic features have an F1-Score of approximately 85% and 75% for the vessel route and destination prediction, respectively. Under such circumstances, we achieved an R2 Score of over 98% with different layer structures and varying feature combinations; the high R2 Score is a natural outcome of the well-defined shipping lanes in the study region. However, our proposal stands out among competing approaches as it demonstrates the capability of complex decision-making during turnings and route selection. Furthermore, we have shown that our model achieves more accurate forecasting with average and median errors of 11km and 6km, respectively, a 25% improvement from the current state-of-the-art approaches. The resulting model from this proposal is deployed as part of a broader Decision Support System to safeguard whales by preventing the risk of vessel-whale collisions under the smartWhales initiative and acting on the Gulf of St. Lawrence in Atlantic Canada.

Analisis Literatur Tentang Model Pembelajaran Problem Based Learning Dalam Meningkatkan Hasil Belajar Ilmu Pengetahuan Alam

The problem based learning model is an approach proposed to improve students' natural science learning outcomes. This study aims to investigate the influence of PBL on science learning outcomes in elementary schools through systematic literature analysis. The literature study method was used to analyze ten scientific articles related to PBL and science learning outcomes in elementary schools. The results of the analysis show that PBL is effective in stimulating interest in learning, strengthening critical thinking skills, and improving problem-solving abilities in a scientific context. The implication of this research is the need for support in training and professional development for educators, as well as further research to identify key factors that influence the success of PBL implementation. The integration of PBL into the science education curriculum needs to be strengthened through collaboration between education stakeholders. Thus, the use of PBL is expected to improve students' science learning outcomes in a holistic and sustainable manner.

Traditional Prostate Cancer Risk Assessment Scales Do Not Predict Outcomes from Brain Metastases: A Population-Based Predictive Nomogram.

Brain metastases are an uncommon yet life-limiting manifestation of prostate cancer. However, there is limited insight into the natural progression, therapeutics, and patient outcomes for prostate cancer once metastasized to the brain. This is a retrospective study of 461 patients with metastatic prostate cancer to the brain with a primary outcome of median overall survival (OS). The Surveillance, Epidemiology, and End Results (SEER) database was examined using Cox regression univariate and multivariable analyses, and a corresponding nomogram was developed. The median overall survival was 15 months. In the multivariable analysis, Hispanic patients had significantly increased OS (median OS 17 months, p = 0.005). Patients with tumor sizes greater than three centimeters exhibited significantly reduced OS (median OS 19 months, p = 0.014). Patients with additional metastases to the liver exhibited significantly reduced OS (median OS 3.5 months, p < 0.001). Increased survival was demonstrated in patients treated with chemotherapy or systemic treatment (median OS 19 months, p = 0.039), in addition to radiation and chemotherapy (median OS 25 months, p = 0.002). The nomogram had a C-index of 0.641. For patients with prostate metastases to the brain, median OS is influenced by race, tumor size, presence of additional metastases, and treatment. The lack of an association between traditional prostate cancer prognosis metrics, including Gleason and ISUP grading, and mortality highlights the need for individualized, metastasis-specific prognosis metrics. This prognostic nomogram for prostate metastases to the brain can be used to guide the management of affected patients.

Natural History, Phenotype Spectrum and Clinical Outcomes of Desmin (DES)-Associated Cardiomyopathy.

Pathogenic/likely pathogenic (P/LP) desmin (DES) variants cause heterogeneous cardiomyopathy and/or skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACE), including cardiac conduction disease (CCD), sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, LVAD/cardiac transplant, HF-related death), in patients with P/LP DES variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization. We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with P/LP DES variants through a systematic review and individual patient data meta-analysis using published reports. We searched Medline (PubMed) and Embase for studies that evaluated cardiac phenotypes in patients with P/LP DES variants. Cardiomyopathy diagnosis or occurrence of MACE were considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from CCD, sustained VA, HF events, and composite MACE was assessed. Out of 4,212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% male, 52.2% probands, median age: 31 years [22.0; 42.8] at first evaluation, median follow-up: 3 years [0; 11.0]). Overall, 124 (53.9%) patients were diagnosed with cardiomyopathy, predominantly dilated cardiomyopathy (14.8%), followed by restrictive cardiomyopathy (13.5%), whereas other forms were less common: arrhythmogenic cardiomyopathy (7.0%), hypertrophic cardiomyopathy (6.1%), arrhythmogenic right ventricular cardiomyopathy (5.2%), and other forms (7.4%). Overall, 132 (57.4%) patients developed MACE, with 96 [41.7%] having CCD, 36 [15.7%] sustained VA, and 43 [18.7%] HF events. Familial penetrance of cardiac disease was 63.6% among relatives with P/LP DES variants. Male sex was associated with increased risk of sustained VA (HR 2.28, p=0.02) and HF events (HR 2.45, p=0.008). DES cardiomyopathy exhibits heterogeneous phenotypes and distinct natural history, characterized by high familial penetrance and substantial MACE burden. Male patients face higher risk of sustained VA events.

Natural history and outcome of nonketotic hyperglycinemia in China.

Nonketotic hyperglycinemia (NKH) is a rare, life-threatening genetic disorder. The patients usually show heterogeneous and nonspecific symptoms, resulting in diagnosis challenges using conventional approaches. Here, the clinical presentation and genetic features of 20 Chinese patients were examined and reported in order to clarify the natural history and prognosis of NKH in China. The Human Gene Mutation Database and literature regarding NKH in China were reviewed. Age of onset, clinical characteristics, genetic analysis, cranial magnetic resonance imaging (MRI) and electroencephalography (EEG) examinations, and outcome of the patients were analyzed. Natural history experiences and follow-up assays for five patients who were followed in our center were described. Among all 20 NKH patients, 17 (85%) had the neonatal type and 3 (15%) had the infantile type, no late-onset cases were detected. Patients showed up for admission with a history of seizures (15/20), lethargy (14/20), hypotonia (11/20), apnea (9/20), and feeble sobbing (4/20). Brain MRI findings included abnormal signals in the internal capsule, cerebellum, or brainstem (6/14), dysplasia of the corpus callosum (5/14), and white matter abnormalities (3/14). EEG evaluations showed anomalies such as burst suppression (4/8) and hypsarrhythmia and/or epileptic activity (6/8). Median values of cerebrospinal fluid (CSF) glycine levels, plasma glycine levels and CSF/plasma glycine ratios were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range, 0.03-0.60) respectively. Genetic analyses revealed four new variations and GLDC, AMT gene abnormalities in 13 (65%), 7 (35%) case, respectively. Prognosis information was available for 18 cases: nine patients died, eight in the neonatal period. Among the nine survivors, varying developmental disorders were observed. Different disease processes and outcomes were found in Chinese NKH patients, according to this study. The initial clinical presentations, CSF glycine levels and CSF to plasma glycine ratios do not reliably predict prognosis, while MRI and EEG abnormalities may indicate a poor outlook. NKH diagnosis should be considered for neonates presenting specific symptoms. The present survey provides clinical data that support the development of a standardized protocol for diagnosing and treating NKH in China.