Delay In Onset Research Articles

Whole exome sequencing-based testing of adult epilepsy in a Polish population.

Genetic panel testing in paediatric and mixed adult and children populations has demonstrated clinical utility and provided a diagnostic yield of 18-40%. The data on adult epilepsies is limited. We aimed to investigate the diagnostic yield and analyse genetic diagnoses in whole exome sequenced adult patients with epilepsies in Poland. We recruited 151 patients from 42 clinical centres across Poland. The patients had a diagnosis of epilepsy/ seizures, were 18 or older at the time of the genetic testing, and did not have a genetic diagnosis. All patients were tested with whole exome sequencing after an initial testing with a panel of 47 epilepsy-related genes. We reached a diagnostic yield when considering pathogenic/probably pathogenic variants according to ClinVar of 8.6% (n = 13) and 17% (n = 26) when applying the American College of Medical Genetics (ACMG) criteria. Most patients had a pathogenic/probably pathogenic variant in epilepsy-related genes (54%), followed by potential epilepsy-related genes (19%), and neurodevelopment-associated epilepsy genes (15%). Our study shows that whole exome sequencing-based testing reaches a slightly higher diagnostic yield that the traditional 300 gene panel. Genes related to childhood onset neurodevelopmental disorders and epilepsy should be considered as well. Clinical implications/future directions. Patients may have had a diagnosis related to a childhood syndrome, but due to limited diagnostic possibilities, it was not possible to diagnose them in childhood. We would consider testing adult patients with epilepsy with whole exome or genome sequencing (or if not possible with a panel) in cases of a diagnosis of epilepsy with no hints suggesting secondary epilepsy, and especially with clinical features indicating a genetic epilepsy diagnosis, such as neurodevelopmental delay and early onset of seizures.

Constrained Projections Indicate Less Delay in Onset of Summer Monsoon over the Bay of Bengal and South China Sea

AbstractThe summer monsoon onset over the Bay of Bengal and South China Sea signals the beginning of the Asian summer monsoon, critical for local fisheries, agriculture and livelihoods, so communities are concerned about its potential changes under global warming. Previous projections have suggested a delay, but the extent of this delay remains uncertain, undermining the reliability of the projections. Here, we show a significant correlation between the projected shift in Bay of Bengal/South China Sea monsoon onset and present‐day sea surface temperature (SST) simulation over the western Pacific (WP). This emergent relationship arises from the spread of the precipitation response over the western‐central Pacific to WP SST, as more precipitation induces stronger tropical upper‐tropospheric warming, increasing westerly vertical shear near South Asia, and facilitating the onset delay. The rectified projections indicate that the delayed shift is almost halved compared to raw projections, and the intermodel uncertainty is reduced by 30%.

Benefit of Avasopasem Manganese on Severe Oral Mucositis in Head and Neck Cancer in the ROMAN Trial: Unplanned Secondary Analysis

IntroductionOral mucositis is a debilitating side effect of cisplatin and intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer. The phase 3 ROMAN trial showed avasopasem manganese (AVA) significantly decreased individual endpoints of incidence and duration of severe oral mucositis (SOM, World Health Organization [WHO] grade 3-4), with nominal decrease in severity (WHO grade 4) and significant increase in the delay in onset of SOM. We sought to determine the Net Treatment Benefit (NTB) of AVA versus placebo (PBO) using the generalized pairwise comparisons (GPC) method. MethodsGPC is a statistical method that permits simultaneous analysis of several prioritized outcomes, comparing all possible pairs of a patient in the active (i.e., AVA) group and a patient from the control (i.e., PBO) group. NTB is the net benefit across all the outcomes for AVA compared to PBO. Key clinically relevant outcomes from ROMAN were prioritized: 1) WHO grade 4 OM incidence, 2) SOM incidence, 3) days of SOM, 4) days to SOM onset, with 7 days difference defined as the clinical relevance threshold for SOM days and SOM onset. ResultsGPC analysis of 407 patients (AVA = 241, Placebo = 166) stratified by cisplatin schedule and treatment setting resulted in 13,969 pairwise comparisons. AVA showed statistically significant net benefit on all four key outcomes with a 53.9% probability that AVA would benefit patients versus a 35.0% probability that PBO would; the difference between these probabilities was a NTB of 18.9% (p=0.0012), translating to an AVA number needed to treat of 5.3 patients. All outcomes contributed to NTB, reflecting improvements in SOM incidence, onset and duration, and in Grade 4 OM incidence seen in the original ROMAN analysis. ConclusionsThis GPC analysis shows compelling evidence from the ROMAN trial of AVA's clinical benefit across key parameters of SOM burden.

Effects of ketamine on frontoparietal interactions in a rule-based antisaccade task in macaque monkeys.

Cognitive control is engaged by working memory processes and high-demand situations like antisaccade, where one must suppress a prepotent response. While it is known to be supported by the frontoparietal control network, how intra- and inter-areal dynamics contribute to cognitive control processes remain unclear. N-Methyl-D-aspartate glutamate receptors (NMDARs) play a key role in prefrontal dynamics that support cognitive control, and its antagonists, such as ketamine, are known to alter task-related prefrontal activities and impair cognitive performance. However, the role of NMDAR in cognitive control-related frontoparietal dynamics remain underexplored. Here, we simultaneously recorded local field potentials and single unit activities from lateral prefrontal (lPFC) and posterior parietal cortices (PPC) in two male macaque monkeys during a rule-based antisaccade task, with both Rule-Visible (RV) and Rule-Memorized (RM) conditions. In addition to altering the E/I balance in both areas, ketamine had a negative impact on rule-coding in true oscillatory activities. It also reduced frontoparietal coherence in a frequency- and rule-dependent manner. Granger prediction analysis revealed that ketamine induced an overall reduction in bidirectional connectivity. Among antisaccade trials, a greater reduction in lPFC-PPC connectivity during the delay period preceded a greater delay in saccadic onset under the RM condition, and a greater deficit in performance under the RV condition. Lastly, ketamine compromised rule coding in lPFC neurons in both RV and RM conditions, and in PPC neurons only in the RV condition. Our findings demonstrate the utility of acute NMDA receptor antagonist in understanding the mechanisms through which frontoparietal dynamics support cognitive control processes.Significance statement A low dose of ketamine is known to induce a transient cognitive control deficit in healthy humans and animals, but it remains unclear whether this deficit is related to a frontoparietal dysconnection. In macaque monkeys performing a rule-based pro- and anti-saccade task, we found that ketamine impaired information coding in frontoparietal neuron, local oscillations and inter-areal synchrony in a rule- and frequency-dependent manner. Notably, under the antisaccade rule, the amount of impairment in task performance could be predicted by the loss in fronto-parietal connectivity in the period just before the monkeys responded. The observations support the utility of NMDA receptor antagonists like ketamine as a tool to understand the role of frontoparietal dynamics in cognitive control.

Deep Fungal Infections of Skin and Role of Histopathology in Diagnosis

Abstract Introduction: Deep mycoses acquired by penetrating trauma to the skin can have varied and sometimes atypical morphological presentations resulting in diagnostic dilemmas and delay in treatment onset. Histopathology can be a useful tool in not only diagnosing but also differentiating various deep mycoses. Aims and Objectives: To observe various morphological presentations and histopathological features of deep fungal infections. Materials and Methods: A retrospective multi-centric study was conducted from 2010 to 2020 at 16 centres. The cases with diagnoses of various deep mycoses were included in the study. The patients presenting with cutaneous manifestations were included in the study. Their demographic details, history, presenting signs and symptoms, morphological presentations, histopathological features and treatment details were collected from the case sheets. Results: A total of 124 cases were found from the case records. The most common type was chromoblastomycosis (42) followed by mycetoma (28) and rhinosporidiosis (17). The mean age was 43.76 ± 5.44 years. The average duration of symptoms before presentation was between 2 months to 10 years (average 2.5 ± 1.33 years). Male to female ratio was 1:0.7. Prior history of trauma was recorded in 36% of cases. Chromoblastomycosis cases presented with verrucous to atrophic plaques with black dots on the surface and histopathology findings included pesudoepitheliomatous hyperplasia, epithelioid cell granulomas, copper penny bodies within granulomas and abscesses. Rhinosporidiosis cases had polypoid grape-like lesions in the nose and eyes most commonly with histopathology findings of abundant thick-walled sporangia in dermis packed with thousands of spores. Eumycetoma patients had pigmented, indurated swelling with multiple sinuses discharging black granules and histopathology showed dermal abscesses and foreign body granulomatous reaction with PAS-positive hyphae. Histoplasmosis patients presented with few to multiple nodulo-pustular lesions on skin and palatal ulcers while small basophilic bodies packed in the cytoplasm of histiocytes were noted in histopathology. Phaeohyphomycosis cases presented as deep-seated cystic lesions and biopsy revealed deepithelialized cysts in the dermis or hypodermis with lumen showing necro inflammatory debris and fungal hyphae. Sporotrichosis cases had erythematous, tender nodules and papules either as single lesions or as multiple lesions arranged in a linear fashion and histopathology showed pseudoepitheliomatous hyperplasia of epidermis, loose to well-defined epithelioid cell granulomas and microabscesses. Spores were found in two cases. Cryptococcosis patient had multiple umbilicated lesions resembling giant molluscum contagiosum loose epithelioid cell granulomas and medium-sized spores lying in both intra and extracellularly on histopathology. Penicilliosis patients had nodulo-pustular lesions and histopathology showed an admixture of histiocytes, epithelioid cells, plasma cells, lymphocytes and polymorphs in the dermis with the presence of yeast-like spores in the cytoplasm of histiocytes and epithelioid cells. Entomophthoromycosis cases presented with asymptomatic subcutaneous firm swelling with loss of skin pinchability. Conclusion: Though clinical findings of deep fungal infections are characteristic similar morphology and atypical presentations can be sometimes confusing. Histopathology is useful for confirming the diagnosis.

Prognostic impact of diagnostic and therapeutic time delays in breast cancer: an exploratory data analysis for patients at Parirenyatwa Hospital, Zimbabwe

Objective: This paper seeks to investigate factors related to time delays for diagnosis and treatment in breast cancer patients at Parirenyatwa Hospital in Zimbabwe and subsequently evaluate the effects of presentation and diagnosis delays on cancer stage. Methods: The study was done for 379 patients with histologically diagnosed invasive breast cancer, from 2015 through to 2029. The study sought to identify factors associated with the time delays ( months)using parametric and non-parametric methods, depending on whether underlying assumptions of such tests are met. A multiple logistic regression model was also used to analyse the association between factors, primary delay, secondary delay variables and cancer stage. Results: The median of the primary, secondary and treatment delay were found to be 7.6, 1 and 0.4 months respectively. Rural residence, Karnofsky Performance Score below 70%, hypertension comorbidity, tumor size (>5cm) and well differentiated tumors (grade 1) were significant factors for delayed presentation. Longer primary delay times and post-menopausal status were associated with secondary delay. Advanced cancer stage at diagnosis and those on medical aid were more likely to have a delay in treatment onset. Conclusion: Primary and secondary delay were predictive of advanced disease using logistic regression. Keywords: Breast cancer; primary delay; secondary delay; treatment delay; Zimbabwe.

Cas9 nickase-mediated contractions of CAG/CTG repeats are transcription-dependent and replication-independent

Abstract There is currently no disease-modifying treatment for expanded CAG/CTG repeat disorders. Given that longer repeat tracts lead to an earlier age of disease onset and faster progression, contracting them is expected to improve symptoms and/or delay onset. We have previously demonstrated that the Cas9 D10A nickase can effectively contract CAG/CTG repeats when targeted to the repeat tract itself. However, the mechanism remains unclear. Here, we tested whether nickase-mediated contractions depend on transcription or on replication using human cell models. We find that transcription promotes contractions and that they occur independently of the rate of cell division. These results support the therapeutic potential of this approach in non-dividing cells.

Patients carrying pathogenic SCN8A variants with loss‐ and gain‐of‐function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy

AbstractObjectivePhenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss‐ and gain‐ of‐ function vari‐ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.MethodsWe predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.ResultsTwo‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.SignificanceUnsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A‐related disorders.

Exposure to Per- and Polyfluoroalkyl Substances and Timing of Puberty in Norwegian Boys: Data from the Bergen Growth Study 2.

Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants with endocrine-disruptive properties. Their impact on puberty in boys is unclear. In this cross-sectional study, we investigated the association between PFAS exposure and pubertal timing in 300 Norwegian boys (9-16 years), enrolled in the Bergen Growth Study 2 during 2016. We measured 19 PFAS in serum samples and used objective pubertal markers, including ultrasound-measured testicular volume (USTV), Tanner staging of pubic hair development, and serum levels of testosterone, luteinizing hormone, and follicle-stimulating hormone. In addition to logistic regression of single pollutants and the sum of PFAS, Bayesian and elastic net regression were used to estimate the contribution of the individual PFAS. Higher levels of the sum of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS) were associated with later pubertal onset according to USTV (age-adjusted odds ratio (AOR): 2.20, 95% confidence interval (CI): 1.29, 3.93) and testosterone level (AOR: 2.35, 95% CI: 1.34, 4.36). Bayesian modeling showed that higher levels of PFNA and PFHxS were associated with later pubertal onset by USTV, while higher levels of PFNA and perfluoroundecanoic acid (PFUnDA) were associated with later pubertal onset by testosterone level. Our findings indicate that certain PFAS were associated with delay in male pubertal onset.

18F-FDG PET can effectively rule out conversion to dementia and the presence of CSF biomarker of neurodegeneration: a real-world data analysis

BackgroundPrecisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [18F] fluoro-2-deoxy-2-D-glucose (18F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain 18F-FDG PET scans. Here, we aimed to estimate the value of brain 18F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology.MethodsLongitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain 18F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer’s Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535–62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer’s Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777–88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain 18F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels.ResultsAmong the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a 18F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers.ConclusionA normal brain 18F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term.Trial registrationClinical Trials database (NCT04804722). March 18, 2021. Retrospectively registered.

AB078. Patterns of treatment delay in patients with symptomatic metastatic epidural spinal cord compression.

Delayed treatment in symptomatic metastatic epidural spinal cord compression (MESCC) is significantly associated with poorer functional outcomes. In this study, we aim to identify the patterns of treatment delay in patients and factors predictive of postoperative ambulatory function. Retrospective review of patients with symptomatic MESCC treated surgically between January 2015 and January 2022. MESCC symptoms were categorized into symptoms suggesting cord compression requiring immediate referral and symptoms suggestive of spinal metastases. Multivariate analysis was performed to identify factors predictive of postoperative ambulatory function. Delays in treatment were identified and categorized into patient delay (onset of symptoms till initial medical consultation), diagnostic delay (medical consultation till radiological diagnosis of MESCC), referral delay (from diagnosis till spine surgeon review) and surgical delay (from spine surgeon review till surgery) and compared between patients. One hundred and seventy-eight patients were identified. In this cohort 92 (52.0%) patients were able to ambulate independently, and 86 (48.3%) patients were non independent. One hundred and thirty-nine (78.1%) of patients had symptoms of cord compression and 93 (52.3%) had neurological deficits on presentation. On multivariate analysis, pre-operative neurological deficits (P=0.01) and symptoms of cord compression (P=0.01) were significantly associated with post-operative ambulatory function. Mean total delay was 66 days, patient delay was 41 days, diagnostic delay was 16 days, referral delay was 3 days and surgical delay was 6 days. In patients with neurological deficits, there was a significant decrease in all forms of treatment delay (P<0.05). There was no significant decrease in patient delay, diagnostic delay and referral delay in patients with symptoms of cord compression. Both patients and physicians understand the need for urgent surgical treatment of MESCC with neurological deficits, however there is still a need for increased education and recognition of the symptoms of MESCC.

Ability of Nicotinamide Riboside to Prevent Muscle Fatigue of Barrows Subjected to a Performance Test.

The objective of this study was to determine the daily dietary nicotinamide riboside (NR) dose required to maximize the delay of subjective muscle fatigue onset. Barrows (N = 100) were assigned to one of five treatments: a conventional swine finishing diet containing 0 (CON), 15 (15NR), 30 (30NR), 45 (45NR) mg·kg body weight-1·d-1 NR, or CON supplemented with 45 mg·kg body weight-1·d-1 NR by drench or cookie dough (DRE). All treatments were administered for the final 11 days of feeding. On supplementation d 10, barrows individually experienced a performance test at 1.09 m/s until they were subjectively exhausted. Wireless electromyography (EMG) sensors were affixed to the biceps femoris (BF), tensor fascia latae (TFL), and semitendinosus (ST) to measure real-time muscle activity. There were no treatment effects for barrow speed (p = 0.57), a tendency for a treatment effect (p = 0.07) for distance, and a treatment effect (p = 0.04) on time to exhaustion. Barrows of the 15NR and DRE treatments had greater (p = 0.05) distances to exhaustion than CON barrows but did not differ from other NR barrows (p > 0.11). Barrows in the 45NR treatment did not differ (p = 0.11) in distance from 30NR barrows but tended to have a greater (p = 0.07) distance compared to CON barrows. All other treatment comparisons did not differ (p > 0.27). Barrows in the DRE treatment moved for longer (p < 0.01) than CON barrows, but all other treatments did not differ from each other (p > 0.15). There was no treatment × period interaction for all muscles' root mean square (RMS) values (p > 0.16), but there were Period effects for all muscles (p < 0.01) and a Treatment effect (p = 0.04) in the TFL. For all muscles, period 4 had greater RMS values than all other periods (p < 0.01), who did not differ from each other (p > 0.29). In the TFL, CON barrows had greater RMS values during the performance test compared to all NR treatments (p < 0.02), who did not differ from each other (p > 0.18). Overall, NR demonstrates potential in being a useful tool in fatigue prevention, but efficient administration of the compound needs further investigation.

Peptide Coated Polycaprolactone-Benzalkonium Chloride Nanocapsules for Targeted Drug Delivery to the Pancreatic β-Cell.

Targeting of current therapies to treat or prevent loss of pancreatic islet β-cells in Type 1 Diabetes (T1D) may provide improved efficacy and reduce off target effects. Current efforts to target the β-cell are limited by a lack of β-cell specific targets and the inability to test multiple targeting moieties with the same delivery vehicle. Here we fabricate a novel tailorable polycaprolactone nanocapsule (NC) where multiple different targeting peptides can be interchangeably attached for β-cell specific delivery. Incorporation of a cationic surfactant in the NC shell allows for the attachment of Exendin-4 and an antibody for ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) for β-cell specific targeting. The average NC size ranges from 250-300nm with a polydispersity index under 0.2. The NCs are non-toxic, stable in media culture, and can be lyophilized and reconstituted. NCs coated with targeting peptide were taken up by human cadaveric islet β-cells and human stem cell-derived β-like cells (sBC) in vitro with a high level of specificity. Furthermore, NCs successfully delivered both hydrophobic and hydrophilic cargo to human β-cells. Finally, Exendin-4 coated NCs were stable and targeted the mouse pancreatic islet β-cell in vivo . Our unique NC design allows for the interchangeable coating of targeting peptides for future screening of targets with improved cell specificity. The ability to target and deliver thera-peutics to human pancreatic β-cells opens avenues for improved therapies and treatments to help the delay onset, prevent, or reverse T1D.

Prevalence and prognostic implications of the no-reflux phenomenon in patients undergoing primary percutaneous coronary intervention at a university center in a middle-income country.

To analyze the prevalence of no-reflow and the 30-day mortality in a university center in a middle-income country. We analyzed 2463 patients who underwent primary PCI from January 2006 to December 2021. The outcome measure was 30-day mortality. Of a total of 2463 patients, no-reflow phenomenon was found in 413 (16.8%) patients, 30-day mortality was 16.7 vs. 4.29% (p < 0.001). Patients with no-reflow were older 60 (53-69.5) vs. 59 (51-66) (p = 0.001), with a higher delay in onset of symptom to emergency department arrival 270 vs. 247 min (p = 0.001). No-reflow patients also had had fewer previous myocardial infarction, 11.6 vs. 18.4 (p = 0.001) and a Killip class > 1, 37 vs. 26% (p < 0.001). No-reflow patients were more likely to have an anterior myocardial infarction (55.4 vs. 47.8%; p = 0.005) and initial TIMI flow 0 (76 vs. 68%; p < 0.001). No-reflow occurred in 16.8% of STEMI patients undergoing primary PCI and was more likely with older age, delayed presentation, anterior myocardial infarction and Killip class > 1. No-reflow was associated with a higher mortality at 30-day follow-up.

Real-world evaluation of access-driven Canadian treatment sequences in progressive prostate cancer (REACTIVATE).

The results of the phase 3 ALSYMPCA trial showed that Radium-223 (Ra-223) improves overall survival (OS) and delays onset of first symptomatic skeletal event vs. placebo in patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of the REACTIVATE study was to inform the optimal placement of Ra-233 in the treatment sequence by evaluating clinical outcomes and healthcare resource utilization using real-world data from multiple Canadian provinces. This retrospective cohort study analyzed patient outcomes according to Ra-223 placement using administrative databases of four Canadian provinces, encompassing 4301 patients with mCRPC who received at least two lines of life-prolonging therapy (LPT) for mCRPC. Outcomes included OS, event-free survival (EFS), and healthcare resource utilization. Each province was analyzed separately. OS, measured from the start of second-line LPT, differed between provinces: those in Ontario receiving second-line Ra-223 had a longer OS vs. those receiving it in third-line or later (hazard ratio [HR ] 0.79, 95% confidence interval [CI] 0.66-0.95). There was no difference between lines of therapy in patients in British Columbia (HR 1.165, 95% CI, 0.894-1.518, p=0.2576), and OS was numerically worse but not statistically significant in patients receiving Ra-223 in second-line in Quebec (HR 1.44, 95% CI, 0.93-2.24). Other outcomes also varied across provinces, with second-line use of Ra-223 being associated with longer EFS and reduced healthcare utilization vs. third-line use in Ontario but not in Quebec. Significant heterogeneity exists in the management and outcomes of mCRPC between provinces, particularly regarding the placement of Ra-223 in the treatment sequence.

Longitudinal Assessment of Seasonal Impacts and Depression Associations on Circadian Rhythm Using Multimodal Wearable Sensing: Retrospective Analysis.

Previous mobile health (mHealth) studies have revealed significant links between depression and circadian rhythm features measured via wearables. However, the comprehensive impact of seasonal variations was not fully considered in these studies, potentially biasing interpretations in real-world settings. This study aims to explore the associations between depression severity and wearable-measured circadian rhythms while accounting for seasonal impacts. Data were sourced from a large longitudinal mHealth study, wherein participants' depression severity was assessed biweekly using the 8-item Patient Health Questionnaire (PHQ-8), and participants' behaviors, including sleep, step count, and heart rate (HR), were tracked via Fitbit devices for up to 2 years. We extracted 12 circadian rhythm features from the 14-day Fitbit data preceding each PHQ-8 assessment, including cosinor variables, such as HR peak timing (HR acrophase), and nonparametric features, such as the onset of the most active continuous 10-hour period (M10 onset). To investigate the association between depression severity and circadian rhythms while also assessing the seasonal impacts, we used three nested linear mixed-effects models for each circadian rhythm feature: (1) incorporating the PHQ-8 score as an independent variable, (2) adding seasonality, and (3) adding an interaction term between season and the PHQ-8 score. Analyzing 10,018 PHQ-8 records alongside Fitbit data from 543 participants (n=414, 76.2% female; median age 48, IQR 32-58 years), we found that after adjusting for seasonal effects, higher PHQ-8 scores were associated with reduced daily steps (β=-93.61, P<.001), increased sleep variability (β=0.96, P<.001), and delayed circadian rhythms (ie, sleep onset: β=0.55, P=.001; sleep offset: β=1.12, P<.001; M10 onset: β=0.73, P=.003; HR acrophase: β=0.71, P=.001). Notably, the negative association with daily steps was more pronounced in spring (β of PHQ-8 × spring = -31.51, P=.002) and summer (β of PHQ-8 × summer = -42.61, P<.001) compared with winter. Additionally, the significant correlation with delayed M10 onset was observed solely in summer (β of PHQ-8 × summer = 1.06, P=.008). Moreover, compared with winter, participants experienced a shorter sleep duration by 16.6 minutes, an increase in daily steps by 394.5, a delay in M10 onset by 20.5 minutes, and a delay in HR peak time by 67.9 minutes during summer. Our findings highlight significant seasonal influences on human circadian rhythms and their associations with depression, underscoring the importance of considering seasonal variations in mHealth research for real-world applications. This study also indicates the potential of wearable-measured circadian rhythms as digital biomarkers for depression.

Survival analysis and life expectancy of pediatric patients with spinal muscular atrophy in Thailand

BackgroundSurvival data for Thai patients with 5q spinal muscular atrophy (SMA), the leading cause of infant mortality worldwide, are lacking. ObjectiveThis study aimed to determine the survival rates and life expectancies of pediatric patients with SMA types 1, 2, and 3. MethodsWe conducted a retrospective cohort analysis of genetically confirmed 5q SMA patients aged 0–18 years who were treated between 1999 and 2021 at the pediatric neuromuscular clinic of Siriraj Hospital, Bangkok, Thailand. Mortality data were sourced from the Civil Registration Office. ResultsThe study included 113 patients: 37 with SMA type 1, 53 with type 2, and 23 with type 3. Life expectancy varied significantly by SMA type: 2.2 years for type 1, 11 years for type 2, and 16.5 years for type 3. The median survival times for SMA type 1 and 2 were 1.9 and 19 years, respectively. In SMA type 2, early onset (<1 year) correlated with a shorter median survival than later onset (≥1 year) (log-rank test P = 0.009). Early onset SMA type 2 had a median survival time of 15.9 years, while 75 % of those with later onset SMA type 2 survived until the age of 19 years. Cox proportional hazards analysis revealed that each month's delay in disease onset reduced the annual mortality risk by 17 % for type 1 patients and by 20 % for type 2 patients. Compared with female patients, male patients with type 2 disease had a 12-fold increased mortality risk. ConclusionsAge at onset is a significant predictor of survival and life expectancy in patients with SMA types 1 and 2. These insights are crucial for genetic counseling and prognostic discussions in clinical settings.

A mini-review on influence of physical exercise in remodeling the immune mechanism

Exercising on a regular basis has been associated with delay in onset of many lifestyle disorders and chronic conditions. Different types of exercise have varied effects on our innate immune cells, both positively and negatively. Low-intensity exercises like yoga or brisk walking, medium-intensity exercises like swimming or cycling, and long-term high-intensity exercises like playing sports like volleyball or working out in the gym are some examples. The immune system's function is impacted differently by exercise training depending on the type, duration, intensity, and other factors. Exercise training is a double-edged sword that helps the body's immune system by changing the immune cells' post-exercise reaction mechanisms. Regular physical exercise is one of the lifestyle adjustments aimed at minimizing morbidity and mortality associated with contemporary illnesses such as obesity, diabetes, cardiovascular disease, and cancer. Regular leisure exercise training is regarded to be beneficial, but extreme exercise, such as that performed by professional athletes, is thought to have possibly detrimental consequences. This review summarizes current information in the field of exercise-associated alterations of infection susceptibility and indicates knowledge gaps for further investigation. It highlights that long term effects of physical activity shows a positive association with longevity and exercise.

Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders.

We aimed to develop consensus for diagnosis/management of SCN8A-related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A-related disorders. A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty-eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%-79% fully/partially agree, <10% disagree. Early diagnosis is important for long-term clinical outcomes in SCN8A-related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self-limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first-line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first-line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First-line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. This is the first-ever global consensus for the diagnosis and treatment of SCN8A-related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence-based care and empowers SCN8A families to advocate for their children.

Proactive care for frailty.

Many providers aspire to scale up proactive care that prevents escalation of health and care needs, delays onset of disability, and reduces demand for emergency department attendance or admission to hospital or care home. NHS England offers guidance on personalised and coordinated multi-professional support and interventions for people with moderate or severe frailty. This article reflects on the growing international evidence for an integrated proactive approach for older people with frailty and why investing in high-quality, joined-up care for older people across the whole system improves outcomes for people, reduces demand for services, increases system resilience, and delivers economic and societal benefits. Facing up to frailty requires creative whole system workforce planning and development that will be challenging to deliver in the current financial and recruitment context yet all the more worthwhile as scaling up proactive care has the potential to be a game changer.